PubAnnotation

Id	Subject	Object	Predicate	Lexical cue
T19	0-10	Sentence	denotes	Background
T20	11-168	Sentence	denotes	On December 2019 a new coronavirus (SARS-CoV-2) emerged in Wuhan, China, triggering a pandemic of severe acute respiratory syndrome in humans (COVID-19) [1].
T21	169-307	Sentence	denotes	Today, the scientific community is investing all the resources available to find any therapy and prevention strategies to defeat COVID-19.
T22	308-439	Sentence	denotes	At the beginning of this pandemic, it was difficult to identify COVID-19 risk factors, that can be targeted for disease prevention.
T23	440-517	Sentence	denotes	Working on risk factors can, in fact, prevent infection and improve outcomes.
T24	518-640	Sentence	denotes	Now it is well known that obesity represents a significant risk factor both for COVID-19 susceptibility and prognosis [2].
T25	641-790	Sentence	denotes	Applying immunonutrition to obese patients can also prevent hospitalization, representing an additional risk factor for worsening COVID-19 prognosis.
T26	791-972	Sentence	denotes	Moreover, immunonutrition in obese patients may be a relevant strategy to lower the burden of COVID-19 disease [3], given that obesity affects almost 13% of people in the world [4].
T27	973-1246	Sentence	denotes	The present umbrella review seeks to answer the question of whether a nutritional approach could be used to enhance the immune system’s response to obesity in patients affected by COVID-19, focusing on the interplay between immunonutrition, inflammation and gut microbiota.
T28	1248-1288	Sentence	denotes	Immune system, inflammation and COVID-19
T29	1289-1413	Sentence	denotes	The immune system protects the human body from infections by a series of pathogen (bacteria, viruses, fungi, parasites) [5].
T30	1414-1495	Sentence	denotes	A self-tolerance system prevents the immune response from damaging human tissues.
T31	1496-1558	Sentence	denotes	The immune system is always active, carrying out surveillance.
T32	1559-1809	Sentence	denotes	The defense to first exposure to the pathogen is represented by two complementary and cooperating functional divisions, the innate immune and, on the other hand, the adaptive immune response, that represents a response based on previous exposure [6].
T33	1810-2035	Sentence	denotes	The innate immune system is represented by dendritic cells, macrophages and neutrophils, with phagocytic activity, and by eosinophils, mast cells and natural killer cells, which release specific soluble antimicrobial factors.
T34	2036-2310	Sentence	denotes	The innate immune system includes physical barriers, represented by interconnected epithelial cells (e.g. tight junctions and cellular interactions mediated by cadherin), epithelial cilia and the mucus layer of the respiratory, gastrointestinal and genitourinary epithelium.
T35	2311-2585	Sentence	denotes	Moreover, soluble proteins and small bioactive molecules such as complement proteins, defensins and ficolins 1-3, pro-inflammatory cytokines, chemokines, lipid mediators of inflammation, membrane-bound receptors and cytoplasmic proteins are part of the innate immune system.
T36	2586-2646	Sentence	denotes	Both innate and adaptive immunity is mediated by leukocytes.
T37	2647-2868	Sentence	denotes	Lymphocytes circulate between the blood system and the lymphatic system, passing through the peripheral lymphoid organs, which includes the spleen, tonsils, appendix, lymph nodes and gut-associated lymphoid tissue (GALT).
T38	2869-3103	Sentence	denotes	From a common lymphoid progenitor, four major populations of mature lymphocytes are derived, that belong to the adaptive immune system: of B lymphocytes (B cells) and T lymphocytes (T cells), natural killer (NK) cells, and NK-T cells.
T39	3104-3215	Sentence	denotes	T-cells can be further categorized to cytotoxic T-cells (TC cells), helper T-cells (Th) and suppressor T-cells.
T40	3216-3400	Sentence	denotes	The specific antigenic receptors of the adaptive response are represented by genes that code for an intact T cell receptor (TCR) and immunoglobulin genes (B cell antigen receptor; Ig).
T41	3401-3483	Sentence	denotes	TCR is capable of binding the antigen processed by antigen-presenting cells (APC).
T42	3484-3706	Sentence	denotes	Dendritic cells represent the most powerful class of APC, and express molecules of the major histocompatibility complex (MHC) of class I and II, necessary for the recognition of the antigen processed by TCR on T cells [7].
T43	3707-3851	Sentence	denotes	Following the presentation of viral antigens via MHC II, the T helper CD4+ lymphocytes are activated and switch to the T helper 1 phenotype [8].
T44	3852-4010	Sentence	denotes	The activated T helper lymphocytes proliferate and release cytokines: after stimulation by antigen and APC, the Th0 cells begin to produce interleukin (IL)-2.
T45	4011-4413	Sentence	denotes	Meanwhile, Th cells differentiate into Th1, Th2 and Th17 according to the nature of the cytokines present in the activation site: IL-12 produced by macrophages and type I Interferon (IFN) or NK cells induce differentiation towards Th1, IL-4 produced by NK1.1 + T cells, basophils or mast cells induce differentiation towards Th2, and IL-1b, IL-23, TGFβ and IL-6 induce differentiation towards Th17 [9].
T46	4414-4483	Sentence	denotes	Th17 cells produce IL-17 and IL-22, and antigen-induced Treg (iTreg).
T47	4484-4720	Sentence	denotes	The binding of the cytokine to its transmembrane cell surface receptor activates an intracellular signal transduction pathway, generally a Janus kinase (Jak), which, via a kinase cascade, phosphorylates its transcription protein (STAT).
T48	4721-4810	Sentence	denotes	Phosphorylated STAT dimers and moves to the nucleus, initiating a new gene transcription.
T49	4811-5306	Sentence	denotes	Mutation of STAT1 increases susceptibility to virus infections because it is involved in various signalling pathways, including IFN-α/β, IFN- γ, IFN-l, IL-2, IL-3, IL-6, IL-9, IL-10, IL-11, IL-12, IL-15, IL-21, IL-22, IL-26 and IL-27 [10], and chemokines of several types such as C-X-C motif chemokine ligand 10 (CXCL-10), Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted (RANTES)/Chemokine (C–C motif) ligand 5 (CCL-5), Monocyte Chemoattractant Protein-1 (MCP-1) [11].
T50	5307-5400	Sentence	denotes	IFN-γ promotes antigen-specific antibody production, increasing the activity of phagocytosis.
T51	5401-5572	Sentence	denotes	In the meantime, PRRs trigger inflammatory signalling, with activation of transcription factors like nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB).
T52	5573-5940	Sentence	denotes	NFκB is the key transcriptional regulator of many pro-inflammatory cytokines, adhesion molecules, chemokines, growth factors and other mediators of inflammation, as tumour necrosis factor (TNF), interleukins 1 (IL-1β), 6 (IL-6), and 12 (IL-12), promotes cellular proliferation and protects against apoptosis providing a mechanism that determines chronic inflammation.
T53	5941-6048	Sentence	denotes	The recognition of pathogens is achieved through the presence of pattern recognition receptors (PRRs) [12].
T54	6049-6151	Sentence	denotes	PRRs identify the microbe-associated molecular patterns (MAMPs), and defensive responses is activated.
T55	6152-6287	Sentence	denotes	PRRs include Toll-like receptors (TLRs), that are able to recognize viral DNA, viral double-stranded RNA and viral single-stranded RNA.
T56	6288-6401	Sentence	denotes	TLRs are expressed on macrophages, dendritic cells, neutrophils, eosinophils, epithelial cells and keratinocytes.
T57	6402-6525	Sentence	denotes	In particular, intracellular TLR-7 and TLR-8 allow the innate recognition of the single-stranded RNA of coronaviruses [13].
T58	6526-6684	Sentence	denotes	Intracellular and extracellular PRRs recognized spike glycoprotein, of the coronavirus coat, starting the inflammatory process, through the NFκB pathway [14].
T59	6685-6902	Sentence	denotes	Moreover, Nucleotide-Binding Domain, Leucine-Rich Repeat (NLR) proteins have also been identified, and NALP3 (NACHT, LRR and PYD domains-containing protein 3) has a special function in the innate immune response [15].
T60	6903-6967	Sentence	denotes	The processes involved in antiviral immunity is shown in Fig. 1.
T61	6968-7041	Sentence	denotes	Fig. 1 Graphical representation of antiviral SARS-Coronavirus 2 immunity.
T62	7042-7044	Sentence	denotes	B:
T63	7045-7306	Sentence	denotes	B lymphocyte; CTL: cytotoxic; T lymphocyte; IFN: interferon; Ig: immunoglobulin; IL: interleukin; MHC: major histocompatibility class; NFκB: nuclear factor kappa-light- chain- enhancer of activated B cells; NK: natural killer cell; Th: helper T lymphocyte; TLR:
T64	7307-7354	Sentence	denotes	Toll-like receptor; TNF: tumour necrosis factor
T65	7355-7583	Sentence	denotes	Normal inflammation is self-limiting because the production of pro-inflammatory cytokines (Th1 cytokines) is followed almost immediately by the production of anti-inflammatory cytokines (Th2 cytokines; IL-1, IL-10, IL-13, etc.).
T66	7584-7717	Sentence	denotes	Chronic inflammation seems to result when the initiating factors persist, or there is some sort of failure of the resolution process.
T67	7718-8007	Sentence	denotes	Dysfunction of the immune system and the loss of homeostatic equilibrium between TREG cells (IL- 10) and Th17 cells (IL-17) was observed in different pathological situations [16], and it is believed to increase the risk of viral infections, including SARS- coronavirus 2 (SARS-CoV-2) [14].
T68	8008-8263	Sentence	denotes	SARS-CoV-2 is an enveloped positive-strand RNA virus in the family Coronaviridae, group 2b, which encodes the viral replicase and four structural proteins: spike (S), envelope (E) and membrane (M), present in the viral envelope, and nucleocapsid (N) [17].
T69	8264-8419	Sentence	denotes	The access route of SARS-CoV-2 is represented by a hydrophobic pocket of the extracellular catalytic domain of Angiotensin-converting enzyme 2 (ACE2) [18].
T70	8420-8583	Sentence	denotes	SARS-CoV peak S protein trimers bind ACE2, expressed in endothelial cells of the vasculature and in the epithelia of the lungs, intestine, heart, brain and kidney.
T71	8584-8647	Sentence	denotes	SARS-CoV-2 enters the cell for endocytosis and membrane fusion.
T72	8648-8851	Sentence	denotes	Once the virus has infected the cell, it follows a downregulation of ACE2 with a consequent local increase in the levels of Ang II, and the development of acute respiratory distress syndrome (ARDS) [19].
T73	8852-9005	Sentence	denotes	The role of ACE2 in the gut, for expression of neutral amino acid transporters, could explain diarrhoea and intestinal inflammation observed in COVID-19.
T74	9006-9187	Sentence	denotes	Moreover, SARS-CoV2 protein E activates the NFκB inflammatory pathway with the consequent activation of MAPK p38, resulting in exacerbation of inflammation and immunopathology [20].
T75	9188-9457	Sentence	denotes	Following the SARS-CoV-2 infection, in the incubation stage and in the non-serious form of COVID-19, the immune system activates the specific adaptive immune response to eliminate the virus, which should be sufficient to block viral propagation and disease progression.
T76	9458-9568	Sentence	denotes	The antiviral system functions well in the presence of general good health and an adequate genetic background.
T77	9569-9888	Sentence	denotes	However, the presence of concomitant pathologies (obesity, cardiovascular diseases, diabetes, neurodegenerative diseases and cancer), malnutrition, and impaired immune response determine the spread of the virus and a massive destruction of the affected tissues, especially in organs that have high ACE2 expression [21].
T78	9889-10245	Sentence	denotes	As noted earlier, SARS-CoV-2 enters the cell via ACE2; that inactivates des-Arg bradykinin, which is a potent ligand of the bradykinin receptor type 1 (BDKRB1).This receptor, localized on endothelial cells, is up-regulated by inflammatory cytokines, which is unlike the B2 receptor, that is constituently expressed and is the receptor for bradykinin (BDK).
T79	10246-10529	Sentence	denotes	BDK is produced from an inactive pre-protein kininogen through activation by the serine protease kallikrein; in addition, it is considered a potent regulator of blood pressure [22], because it induces vasodilation, natriuresis, and hypotension upon activation of the BDKRB2 receptor.
T80	10530-10644	Sentence	denotes	BDK is strongly integrated with the RAS, and the BDK receptor signaling is increased by angiotensin’s action [23].
T81	10645-10816	Sentence	denotes	Interestingly, ACE has a higher affinity for BDK [24] and therefore in conditions where ACE is low, the vasopressor system is moved toward a BDK-directed hypotensive axis.
T82	10817-11022	Sentence	denotes	BDK takes part in the inflammatory response after injury and acts to induce pain via stimulation of the BDKRB1 receptor, which also causes neutrophil recruitment and a major vascular permeability [25, 26].
T83	11023-11213	Sentence	denotes	During the infection, as long as the virus persists, there is dysfunction of ACE2 function, leading to the dysregulation of the kinin-kallikrein pathway and thus causing the angioedema [27].
T84	11214-11410	Sentence	denotes	Some evidence that the edema is bradykinin-generated includes resistance to corticosteroids, epinephrine, and antihistamines in the management of reducing the pulmonary edema in COVID-19 patients.
T85	11411-11516	Sentence	denotes	In fact, the so called Bradykinin Storm is likely responsible for most of the observed COVID-19 symptoms.
T86	11517-11759	Sentence	denotes	Inflammation plays a fundamental role in the pathogenesis and progression of COVID-19, ranging from common colds to fatal cases of pneumonia due to the cytokine release syndrome (CRS) that affected patients, determining the severe conditions.
T87	11760-12058	Sentence	denotes	In COVID-19 the homeostatic equilibrium between TREG cells (IL-10) and Th17 cells (IL-17) is broken: inflammatory cytokine levels (IL-1, TNF) are elevated in the lungs of COVID-19 patients, resulting in an increase in HA-synthase-2 (HAS2) in alveolar epithelial cells CD31+, EpCAM+ and fibroblasts.
T88	12059-12198	Sentence	denotes	The imbalance between pro-inflammatory and anti-inflammatory cytokines, leads to the CRS, an excessive and damaging host inflammation [28].
T89	12199-12339	Sentence	denotes	As a consequence of CRS [29], due to a severe infection of SARS-CoV-2 of the respiratory epithelium, the ARDS was observed in COVID-19 [30].
T90	12340-12431	Sentence	denotes	Edema and an IL-1β mediated proinflammatory response were increased in the lung parenchyma.
T91	12432-12724	Sentence	denotes	Macrophages and dendritic cells produce IL-1β through macro-molecular complexes called inflammasomes, including the major element present in the pulmonary tissue and the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome [20].
T92	12725-12990	Sentence	denotes	Following a precise stimulus, the activation and recruitment domain of caspase (ASC) and the catalytically inactive procaspase-1 assemble, the procaspase-1 turns into active caspase-1, the inactive pro-IL-1β matures in IL-1β and the NLRP3 inflammasome is activated.
T93	12991-13134	Sentence	denotes	The NLRP3 inflammasomes and IL-1β driven proinflammatory cascades correlate with worsening of several respiratory diseases, including COVID-19.
T94	13135-13363	Sentence	denotes	Patients affected by obesity showed a severe consequence of COVID-19 [31], due to the high concentrations of TNF-α, MCP-1 and IL-6 produced in the meantime by visceral and subcutaneous adipose tissue and by innate immunity [32].
T95	13364-13497	Sentence	denotes	Moreover, leptin, released by adipose tissue, helps to increase inflammatory milieu with a dysregulation of the immune response [33].
T96	13498-13684	Sentence	denotes	This umbrella review seeks to answer the question of whether a nutritional approach can be used to enhance the immune system’s response to obesity in obese patients affected by COVID-19.
T97	13685-13822	Sentence	denotes	Immunonutrition has been based on the concept that malnutrition impairs immune function, used to modify inflammatory or immune responses.
T98	13823-13964	Sentence	denotes	This concept may be applied to any situation in which a supply of specific nutrients is necessary to modify inflammatory or immune responses.
T99	13965-14078	Sentence	denotes	Immunonutrients can promote patient recovery by inhibiting inflammatory responses and regulating immune function.
T100	14079-14402	Sentence	denotes	Therefore, immunonutrition involves feeding enriched with various pharmaconutrients (arginine, glutamine, omega-3-fatty acids, ribonucleotides and certain trace elements and antioxidants compound, vitamins and minerals) to modulate inflammatory responses, the acquired immune response, and to improve patient outcomes [34].
T101	14403-14574	Sentence	denotes	Personalized immunonutrition for patients with obesity should be the first therapeutic choice to reduce the risk of infections and the disease course in COVID-19 patients.
T102	14575-14667	Sentence	denotes	That therapeutic strategy could be effective in case of other potential epidemic infections.
T103	14668-14775	Sentence	denotes	It would also allow a reduction of the enormous medical care cost supported by the National Health Service.
T104	14777-14804	Sentence	denotes	Immunonutrition and obesity
T105	14805-15084	Sentence	denotes	According to the World Health Organization (WHO), obesity is defined as a condition in which percentage of body fat (PBF) is increased to an extent in which health and well-being are impaired, and, due to the alarming prevalence increase, declared it as a “global epidemic” [35].
T106	15085-15230	Sentence	denotes	It is characterized by a state of low-grade, chronic inflammation, in addition to altered levels of circulating nutrients and metabolic hormones.
T107	15231-15420	Sentence	denotes	The condition of obesity is a multifactorial pathology that can be related to an altered nutritional behaviour or secondary to genetic, hypothalamic, iatrogenic or endocrine disorders [36].
T108	15421-15522	Sentence	denotes	Underlining the importance of nutritional behaviour, it depends directly on food nutritional quality.
T109	15523-15608	Sentence	denotes	Obesity is considered as a malnutritional status due to the poor quality of the diet.
T110	15609-15690	Sentence	denotes	The chance to get healthy foods is largely determined by one’s own profitability.
T111	15691-15832	Sentence	denotes	Nowadays, the most vulnerable communities fight disadvantage conditions because of socioeconomic, educational, and environmental disparities.
T112	15833-15938	Sentence	denotes	People, who follow a poor quality of diet combined with economic disparity, are at major risk of obesity.
T113	15939-16060	Sentence	denotes	The expansion of fat mass, in turn, is linked to various chronic diseases, including cardiovascular disease and diabetes.
T114	16061-16239	Sentence	denotes	In the context of Covid-19 pandemic, these conditions affect severe outcomes from SARS-CoV-2 infection, as well as contribute to increasing the risk of mortality in general [37].
T115	16240-16317	Sentence	denotes	Adiposopathy, also known as “sick fat”, is at the basis of obesity condition.
T116	16318-16416	Sentence	denotes	It is defined as pathological dysfunction of both anatomical and functional within adipose tissue.
T117	16417-16555	Sentence	denotes	It is promoted by an excess of caloric energy intake and a sedentary lifestyle in genetically and environmentally susceptible individuals.
T118	16556-16647	Sentence	denotes	This latter may cause or worsen metabolic disease in adverse endocrine and immune response.
T119	16648-16817	Sentence	denotes	Modifiable lifestyle choices play a role in fat function and dysfunction, but the strong genetic component has a real chance on predisposition to dysfunctional fat [38].
T120	16818-17134	Sentence	denotes	The disruption of adipose tissue processes, as occurs in adipocyte hypertrophy and visceral fat accumulation, results in the production of pro-inflammatory components (like the plethora of cytokines) and adipocyte factors dysregulation, which may be both genesis and/or main contributors to metabolic disorders [39].
T121	17135-17230	Sentence	denotes	Adipose tissue is not only part of the endocrine system, but it is an active immune organ [40].
T122	17231-17507	Sentence	denotes	As an organ suitable to manage the adaptive and innate immune responses, in healthy lean individuals, its immune cells have the main role in the formation of extracellular matrix modelling, insulin sensitivity, adipogenesis, angiogenesis and clearance of apoptotic adipocytes.
T123	17508-17675	Sentence	denotes	On the contrary, during the expansion of adipose tissue like in obesity, inflammation results in adipocyte hypertrophy, cell death, fibrosis and metabolic dysfunction.
T124	17676-17803	Sentence	denotes	The inflammatory process, involving both innate and adaptive immune cells, plays an important role in adipose immunometabolism.
T125	17804-17936	Sentence	denotes	Among those, macrophages are fundamental for adipose tissue homeostasis and are most thoroughly studied in response to obesity [41].
T126	17937-18058	Sentence	denotes	As a result of the augmentation of the PBF in obesity, there is the proportional increment of adipose tissue macrophages.
T127	18059-18344	Sentence	denotes	Consequently, the system undergoes to a massive pro-inflammatory response resulting by adipose tissue secretion of pro-inflammatory factors, the adipocytes stimulation of inflammation-inducing factors in other tissues and the reduction of anti-inflammatory and protective factors [42].
T128	18345-18739	Sentence	denotes	Understanding the relationship between the adipose tissue, classified as an endocrine organ, and its immune function, the development of new therapeutic and immunonutritional strategies for obesity in COVID-19, may have important implications especially because it may act as a reservoir for more severe viral spread, with increased shedding, immune activation, and cytokine amplification [43].
T129	18740-18853	Sentence	denotes	In the cytokine storm milieu in obesity and COVID-19, over 50 adipokines with diverse roles have been identified.
T130	18854-18999	Sentence	denotes	Leptin, adiponectin, IL-6 and TNF-α mainly act in adipocyte metabolism, insulin sensitivity and metabolic disorders associated with obesity [44].
T131	19000-19175	Sentence	denotes	Leptin is an adipocyte-derived hormone with an important role in the central control of energy metabolism and with many pleiotropic effects in different physiological systems.
T132	19176-19315	Sentence	denotes	One of these is the regulatory role between energy metabolism and the immune system, being a pillar in the new concept of immunometabolism.
T133	19316-19426	Sentence	denotes	Leptin receptor, expressed overall in the immune system, acts in both innate and adaptive immune system cells.
T134	19427-19516	Sentence	denotes	As an adipokine, leptin is responsible for the inflammatory state found in overnutrition.
T135	19517-19613	Sentence	denotes	Moreover, in undernutrition status, it plays as crucial mediator of the immunosuppressive state.
T136	19614-19811	Sentence	denotes	New research frontiers for immunometabolic pathophysiology are considering leptin and leptin receptor as markers of inflammation and immune activation in the context of innate-adaptive system [45].
T137	19812-19919	Sentence	denotes	In the light of above mentioned, leptin represents a connection between metabolism and the immune response.
T138	19920-20031	Sentence	denotes	Its dysregulatory activity would have serious consequences during an eventual infection, such as COVID-19 [46].
T139	20032-20202	Sentence	denotes	By altering the metabolic setting, hyperleptinemia and insulin resistance in obesity disrupt T-cell function, resulting in a suppressed T-cell response to infection [47].
T140	20203-20392	Sentence	denotes	This metabolic condition compromises the immune response and leads patients to morbidity and mortality from SARS-CoV-2 infection, coupled with the lack of containing viral replication [46].
T141	20393-20521	Sentence	denotes	The pivotal role of IL-6 in mediating the acute phase response seems to interest the strategical treatment in COVID-19 patients.
T142	20522-20772	Sentence	denotes	Researches are still in progress and it would be intriguing to investigate whether people with obesity and higher circulating IL-6 levels, compared with lean controls, respond more favourably to IL-6 inhibition strategies in SARS-CoV-2 pandemic [43].
T143	20773-20877	Sentence	denotes	TNF-α is a pyrogen cytokine released in the acute phase of inflammation by macrophages and immune cells.
T144	20878-20999	Sentence	denotes	It is well known that during influenzae and viral infections, the expression of TNF-α in lung epithelial cells is higher.
T145	21000-21115	Sentence	denotes	In patients with COVID-19 and obesity, the IL-6 and TNF-α high serum levels are negatively associated with T-cells.
T146	21116-21210	Sentence	denotes	On the contrary, T cell levels are restored by reducing concentrations of both IL-6 and TNF-α.
T147	21211-21323	Sentence	denotes	These findings suggested that these cytokines could represent important targets of anti-COVID-19 therapies [48].
T148	21324-21420	Sentence	denotes	Infectious diseases, like COVID-19, are characterized by an increased production of adiponectin.
T149	21421-21722	Sentence	denotes	In fact, it seems that adiponectin can reduce innate and adaptive immune cell proliferation and polarization on two fronts: acting on the production blockage of pro-inflammatory cytokines such as TNF-α, IL-2, and IL-6, and enhancing the secretion of anti-inflammatory cytokines such as IL-10 [49, 50].
T150	21723-21823	Sentence	denotes	It seems interesting the possibility to improve the action of adiponectin through diet intervention.
T151	21824-21962	Sentence	denotes	A healthy lifestyle and a Mediterranean diet seem to ameliorate adiponectin levels in human, working on omega-3 biochemical pathways [51].
T152	21963-22091	Sentence	denotes	Finally, in light of the above, a possible COVID-19 therapy would combine drug therapy with a personalized immunonutrition [48].
T153	22092-22273	Sentence	denotes	Whereas healthy adipose tissue is essential to achieve a metabolic health status, sick inflamed fat leads to metabolic pathways dysregulation and different chronic pathologies [52].
T154	22274-22630	Sentence	denotes	According to what mentioned above and considering the endocrine and inflammatory role of the adipose tissue, it is necessary to classify obesity on the basis of body fat composition and distribution [53], rather than simply anthropometric measurements, e.g. Body Mass Index (BMI) classification, that could lead to a large error and misclassification [54].
T155	22631-22912	Sentence	denotes	As different phenotypes of obesity can be diagnosed according to percentage of total bodyfat mass (PBF), associated with an early inflammatory status, and high oxidative stress level [55], to identify obese subjects at risk of COVID-19 it is necessary to evaluate body composition.
T156	22913-23059	Sentence	denotes	Moreover, obesity and adiposopathy contribute to the pathways related to appetite regulation, fat storage and alteration of intestinal microbiota.
T157	23060-23166	Sentence	denotes	Dysbiosis of gut microbiota can influence the onset and progression of chronic degenerative diseases [56].
T158	23167-23268	Sentence	denotes	The impact of these metabolic abnormalities has undergone intense investigation over the past decade.
T159	23269-23427	Sentence	denotes	Although that, it is still not clear how the immune system and host defense are influenced by the pro-inflammatory and excess energy milieu of the obese [57].
T160	23428-23602	Sentence	denotes	There is strong evidence in literature indicating that abundant adiposity negatively impacts on immune system functionality and host defense in individuals with obesity [57].
T161	23603-23737	Sentence	denotes	In people with obesity, the caloric balance surplus is not directly proportional to the high nutritional food components quality [53].
T162	23738-23914	Sentence	denotes	Hence, the overfed malnourished patient may be compared to the underfed malnourishment, because malnutrition is considered the primary cause of immunodeficiency worldwide [58].
T163	23915-24012	Sentence	denotes	Chronic diseases, such as obesity, have been recognized as virulence factors for severe COVID-19.
T164	24013-24138	Sentence	denotes	These morbidities are usually coupled to protein-energy malnutrition, which is demonstrated to impair immune cell activation.
T165	24139-24239	Sentence	denotes	This process allows longer viral persistence and increased dealing of pro-inflammatory factors [59].
T166	24240-24350	Sentence	denotes	This will allow you to make a personalized emergency intervention, in all the subjects suffering from obesity.
T167	24351-24483	Sentence	denotes	In the onset of COVID-19 era, the nutritional approach might be managed in two different strategies, considering the disease status.
T168	24484-24715	Sentence	denotes	In a severe phase of COVID-19 in a patient with obesity, immunonutrition would be fundamental to support the immune response and protein synthesis, and, at the same time, to reduce inflammation caused by the pathological condition.
T169	24716-24871	Sentence	denotes	The organism fights both the acute inflammatory state triggered by COVID-19 and, in addition, the latent chronic inflammation due to the obesity condition.
T170	24872-25076	Sentence	denotes	This latter is employed in the case of malnourished surgical patients, where immunonutrition significantly reduced the risk of acquired infections, wound complications, and length of stay at the hospital.
T171	25077-25220	Sentence	denotes	In this context, immunomodulating diets (IMDs) have been demonstrated to improve immune system response and modulate inflammation cascade [60].
T172	25221-25449	Sentence	denotes	Furthermore, the nutritional approach should be firstly preventive to reduce the large number of complications linked to obesity condition; and, secondly, could be predictive to act on the etiopathogenesis of SARS-CoV-2 disease.
T173	25450-25563	Sentence	denotes	In the current pandemic panorama, the connection between nutrition science and virology takes a predictable turn.
T174	25564-25663	Sentence	denotes	It is worth that nutritional innovation must correlate all the previously treated clinical aspects.
T175	25664-25955	Sentence	denotes	By referring to WHO guidelines, it is fundamental to follow healthy eating habits and lifestyle to achieve an optimal health status supporting immune cells system, and to switch from an unhealthy condition of dysbiosis to a healthy condition of eubiosis and modulating systemic inflammation.
T176	25956-26075	Sentence	denotes	This is essentially possible pursuing a balanced diet based on the Mediterranean concept and staying physically active.
T177	26077-26139	Sentence	denotes	Immunonutrition: the role of specific nutrients and microbiota
T178	26140-26285	Sentence	denotes	An optimal nutritional status guarantees the main modulating processes of inflammatory and oxidative stress, both connected to the immune system.
T179	26286-26391	Sentence	denotes	The metabolic system applied for biosynthesis and energy request needs many different dietary components.
T180	26392-26600	Sentence	denotes	In fact, some nutrients and their metabolites are direct regulators of gene expression of the immune compartment and play a key role in the maturation, differentiation and responsiveness of immune cells [61].
T181	26601-26733	Sentence	denotes	It is easy to understand that an adequate and balanced supply of these nutrients is essential to set an appropriate immune response.
T182	26734-26868	Sentence	denotes	Basically, good nutrition creates a setting in which the immune system can respond appropriately to challenge, whatever this might be.
T183	26869-26980	Sentence	denotes	On the contrary, poor nutrition produces an environment in which the immune system cannot respond well [62–64].
T184	26981-27127	Sentence	denotes	Furthermore, nutritional status, the role of diet and lifestyle may play an important part in different severe infections, especially in COVID-19.
T185	27128-27306	Sentence	denotes	The importance of nutrition as a mitigation strategy to support immune function, is reachable identifying food groups and key nutrients as defense against respiratory infections.
T186	27307-27528	Sentence	denotes	A balanced diet, rich in some foods, is associated with anti-inflammatory and immunomodulatory compounds, including vitamins (C, D, and E) and minerals (zinc and selenium), and may influence human nutritional status [16].
T187	27529-27615	Sentence	denotes	During this COVID-19 pandemic many myths surfaced on how strengthen the immune system.
T188	27616-27749	Sentence	denotes	Several research publications have focused on the role of diet and specific nutrients, some focusing on respiratory viral infections.
T189	27750-27877	Sentence	denotes	The most of micronutrients have been identified as the main responsible for maintenance the complex needs of the immune system.
T190	27878-27971	Sentence	denotes	Below we will focus on the main nutrients with specific reference to respiratory health [65].
T191	27973-27992	Sentence	denotes	Omega 3 fatty acids
T192	27993-28141	Sentence	denotes	Reactive oxygen species create a pro-oxidant environment against which the body needs protection through vitamins, enzymes and antioxidant feedings.
T193	28142-28354	Sentence	denotes	Particularly, omega-3 fatty acids are known to exert anti-inflammatory and antioxidant properties [66, 67], and to support the immune system, specifically by helping to resolve the inflammatory response [63, 68].
T194	28355-28540	Sentence	denotes	The intake of omega-3 fatty acids from fish and seafood has been shown to trigger anti-inflammatory reactions via oxygenated metabolites (oxylipins), including resolvins and protectins.
T195	28541-28780	Sentence	denotes	Omega-3 fatty acids include linolenic acid (ALA) consumed from various plant sources and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) consumed especially from fish and seafood sources, such as salmon, mackerel, and tuna [69].
T196	28781-28992	Sentence	denotes	Notably, the omega-3 fatty acids EPA and DHA involved in the inflammation process, are enzymatically converted to specialized pro-resolving mediators (SPMs) known as resolvins, protectins, and maresins [66, 67].
T197	28993-29156	Sentence	denotes	These molecules, alongside with others, function together to orchestrate the resolution of inflammation and to support healing, including in the respiratory tract.
T198	29157-29279	Sentence	denotes	Deficiencies of omega-3 fatty acids EPA and DHA are accountable for delayed or suboptimal resolution of inflammation [70].
T199	29280-29442	Sentence	denotes	This could be very important in the context of severe COVID-19, which manifests as uncontrolled inflammation, the so-called cytokine storm, linked with ARDS [71].
T200	29444-29462	Sentence	denotes	Oleoylethanolamide
T201	29463-29626	Sentence	denotes	Oleoylethanolamide (OEA), synthesized in the gastrointestinal tract, is a bioactive lipid mediator derived from the omega-9 monounsaturated fatty acid, oleic acid.
T202	29627-29818	Sentence	denotes	Based on previous evidences, OEA showed anti-inflammatory activities, a role in modulation of immune response, anti-oxidant effects and stimulation of lipolysis and fatty acid oxidation [72].
T203	29819-30026	Sentence	denotes	In this context OEA is considered an endocannabinoid-like lipid, which interacts with the peroxisome proliferator-activated receptor-alpha (PPAR-α) and intervenes during the anti-inflammatory processes [73].
T204	30027-30245	Sentence	denotes	Scientific researchers recently showed that endocannabinoid system is involved in the management of infectious agents such as viruses, bacteria, and some protozoa, also reducing inflammation and pain in the lungs [74].
T205	30246-30557	Sentence	denotes	In view of the fact that SARS-CoV-2 infection leads to increase the pro-inflammatory cytokines, including IL-6 and IL-1β in COVID-19 patients via binding to the TLRs, an important components of the innate immune system, it is assumed that OEA inhibits this pathway through its anti-inflammatory properties [75].
T206	30558-30775	Sentence	denotes	OEA binds with high affinity to PPAR-α receptors and increases the expression level of anti-inflammatory cytokine such as IL-10, then initiates a cascade of events, which can attenuate the inflammatory responses [73].
T207	30776-30933	Sentence	denotes	Furthermore, OEA attenuates the inflammatory responses modulating the expression of TLR-4, and interfering with the ERK1/2/AP-1/STAT3 signaling cascade [73].
T208	30934-31081	Sentence	denotes	OEA may modulate cross-talk between PPAR-α and TLRs and regulates the inflammatory responses with beneficial synergistic effect against SARS-CoV-2.
T209	31082-31417	Sentence	denotes	Nowadays, discovering therapeutic options from currently available agents appears to be essential for the treatment and prophylaxis of this pandemic, especially in obese patients with comorbidities [76] and this bioactive lipid mediator can be considered as a novel potential pharmacological alternative for the management of COVID-19.
T210	31419-31428	Sentence	denotes	Vitamin A
T211	31429-31561	Sentence	denotes	The role of vitamin A and its metabolites in the immune system and host susceptibility is discussed in a series of reviews [77, 78].
T212	31562-31881	Sentence	denotes	This nutrient is involved in normal differentiation of epithelial tissue, furthermore retinoic acid is essential for imprinting T and B cells with gut-homing specificity and T array cells and IgA cells in intestinal tissues [79], thus enhancing the intestinal immune response and supporting the intestinal barrier [80].
T213	31882-32107	Sentence	denotes	Carotenoids (both provitamin A and non-provitamin A carotenoids) have immunoregulatory actions including the reduction of the toxic effects of ROS and the regulation of membrane fluidity and gap-junctional communication [81].
T214	32108-32236	Sentence	denotes	Vitamin A deficiency impairs barrier function, impairs immune responses and increases susceptibility to a variety of infections.
T215	32237-32342	Sentence	denotes	Furthermore, many aspects of innate immunity, in addition to barrier function, are affected by vitamin A.
T216	32343-32567	Sentence	denotes	For example, vitamin A regulates the number and function of NK cells [82], contributes to the phagocytic and oxidative activity of the macrophage burst [79] and controls the maturation of neutrophils and its deficiency [83].
T217	32568-32650	Sentence	denotes	The activity of natural killer cells is therefore reduced by vitamin A deficiency.
T218	32651-32803	Sentence	denotes	The impact of vitamin A on acquired immunity is however clear since it is involved in the development and differentiation of Th1 and Th2 cells [62, 79].
T219	32804-32991	Sentence	denotes	Moreover there is evidence that vitamin A deficiency alters the balance of Th1 and Th2 cells, decreasing the Th2 response, without affecting or, in some cases, enhancing the Th1 response.
T220	32992-33069	Sentence	denotes	This suggests that vitamin A increases the Th1 cell average in immunity [84].
T221	33070-33403	Sentence	denotes	However, studies in several experimental models have shown how the retinoic acid metabolite of vitamin A reduces the responses of Th1-type cells (cytokines, cytokine receptors and the transcription factor T-bet, which promotes Th1), improving responses to Th2-type cells (cytokines and Th2-favoring transcription factor GATA-3) [62].
T222	33404-33546	Sentence	denotes	Indeed, it maintains the normal Th2 response mediated by antibodies by suppressing the production of IL-12, TNF-α and IFN-γ by Th1 cells [85].
T223	33547-33742	Sentence	denotes	Vitamin A appears to be important in the differentiation of regulatory T lymphocytes by suppressing Th17 differentiation, which have implications for the control of adverse immune reactions [86].
T224	33743-33922	Sentence	denotes	It helps regulate the production of IL-2 and the pro-inflammatory TNF-γ, which activates the phagocytic and oxidative action of the macrophages activated during inflammation [79].
T225	33923-34046	Sentence	denotes	It ensures the normal functioning of B lymphocytes, necessary for the generation of antibody responses to the antigen [85].
T226	34047-34233	Sentence	denotes	Retinoic acid appears to promote the movement of T cells to gut-associated lymphoid tissue and, interestingly, some gut-associated immune cells are able to synthesize retinoic acid [87].
T227	34234-34410	Sentence	denotes	Vitamin A deficiency is associated with increased morbidity and mortality in children and appears to predispose to respiratory infections, diarrhea and severe measles [88, 89].
T228	34411-34541	Sentence	denotes	Moreover, supplementing vitamin A in deficient children improves recovery from infectious diseases and reduces mortality [78, 90].
T229	34542-34635	Sentence	denotes	The Recommended Dietary Allowance (RDA) for vitamin A reports a range of 900–700 µg/day [91].
T230	34637-34646	Sentence	denotes	Vitamin C
T231	34647-34757	Sentence	denotes	The role of vitamin C in immunity and in host susceptibility to infection has been scientifically proven [92].
T232	34758-34918	Sentence	denotes	Vitamin C, in fact, is necessary for the biosynthesis of collagen and is essential for maintaining epithelial integrity and protecting against oxidative stress.
T233	34919-35166	Sentence	denotes	It protects cell membranes from damage caused by free radicals, so as to support the integrity of the epithelial barriers [79], also improves keratinocytic differentiation and lipid synthesis as well as fibroblast proliferation and migration [92].
T234	35167-35582	Sentence	denotes	It plays a role in various aspects of immunity, in fact it is involved in the proliferation, function and movement of neutrophils, monocytes and phagocytes [82] and the migration of leukocytes to sites of infection, phagocytosis and bacterial killing, in the activity of natural killer cells and in the function of T lymphocytes (especially CD8 cytotoxic T lymphocytes) and in the production of antibodies [79, 82].
T235	35583-35806	Sentence	denotes	Vitamin C is also involved in apoptosis and elimination of depleted neutrophils from macrophage infection sites [92] and attenuates the formation of extracellular trap (NET), thus reducing the associated tissue damage [92].
T236	35807-35940	Sentence	denotes	Infections have a significant impact on vitamin C levels, due to the increased energy needs required by the body during inflammation.
T237	35941-36080	Sentence	denotes	This nutrient, in fact, promotes the proliferation of lymphocytes, with a consequent increase in the generation of antibodies [79, 85, 92].
T238	36081-36351	Sentence	denotes	It is well known that infections increase oxidative stress and usually activate phagocytes that release ROS, so vitamin C is a well-known antioxidant that can counteract these effects by increasing phagocytosis and ROS generation and improving microbial killing [92–94].
T239	36352-36477	Sentence	denotes	Furthermore, supplementation with vitamin C appears to be able to prevent and treat respiratory and systemic infections [92].
T240	36478-36655	Sentence	denotes	High levels of this nutrient can enhance antimicrobial effects and increase serum levels of complement proteins, also playing an important role in IFN-γ production [85, 92, 95].
T241	36656-36779	Sentence	denotes	Low levels of vitamin C are responsible for an increased susceptibility to severe respiratory infections such as pneumonia.
T242	36780-36970	Sentence	denotes	Indeed, a meta-analysis reported a significant reduction in the risk of pneumonia with vitamin C supplementation, particularly in individuals with a low dietary intake of this nutrient [96].
T243	36971-37182	Sentence	denotes	Vitamin C supplementation has also been demonstrated to reduce the duration and severity of upper respiratory tract infections, such as the common cold, especially in people under increased physical stress [96].
T244	37183-37287	Sentence	denotes	Currently, there are limited recommendations for taking vitamin C supplementation against COVID-19 [97].
T245	37288-37457	Sentence	denotes	Nevertheless, there is sufficient evidence to conduct several clinical trials to assess vitamin C efficacy in COVID-19 prevention and treatment (www.clinicaltrials.gov).
T246	37458-37547	Sentence	denotes	Previously, doses of 1–2 g/day were effective in preventing upper respiratory infections.
T247	37548-37692	Sentence	denotes	As those levels are not attainable through dietary sources, supplementation may be advised for those at a higher risk of respiratory infections.
T248	37693-37767	Sentence	denotes	Doses above 200 mg/day may not be beneficial for healthy individuals [98].
T249	37769-37778	Sentence	denotes	Vitamin D
T250	37779-37901	Sentence	denotes	Many reviews discuss the role of vitamin D and its metabolites in host immunity and susceptibility to infections [99–101].
T251	37902-38128	Sentence	denotes	Vitamin D receptors have been identified in most immune cells, of which some can also synthesize the active form of vitamin D from its precursor, therefore suggesting that might have important immunoregulatory properties [99].
T252	38129-38295	Sentence	denotes	Vitamin D is synthesized at skin level in the presence of UV-light from cholesterol and it is also taken up from the diet (fish, eggs, fortified milk, and mushrooms).
T253	38296-38603	Sentence	denotes	The active form of vitamin D, calcitriol (1,25-dihydroxy vitamin D3), formed following kidney and liver hydroxylation, is most renowned for its regulating role in calcium homeostasis and bone health status, but it has also been shown to regulate the immune system, mainly in the functioning of T-cell [102].
T254	38604-38878	Sentence	denotes	Among the main functions of vitamin D, its ability to improve the integrity of the epithelium has mainly been observed as well as the ability to induce the synthesis of an antimicrobial peptide in epithelial cells and macrophages, thus directly improving host defense [103].
T255	38879-39088	Sentence	denotes	Vitamin D also promotes the differentiation of monocytes from macrophages [95], promotes the movement and phagocyability of macrophages [79], superoxide production and bacterial killing by innate immune cells.
T256	39089-39172	Sentence	denotes	Hence, it promotes the processing of antigen presentation by dendritic cells [104].
T257	39173-39320	Sentence	denotes	Calcitriol regulates the expression of antimicrobial proteins (cathelicidin and defensin), which directly kill pathogens, especially bacteria [99].
T258	39321-39500	Sentence	denotes	It inhibits the production of IFN-γ [71] and reduces the expression of pro-inflammatory cytokines by increasing the expression of anti-inflammatory cytokines by macrophages [105].
T259	39501-39708	Sentence	denotes	Calcitriol modulates antimicrobial proteins (cathelicidin and β-defensin), responsible for modifying the intestinal microbiota, favoring a healthy composition and supporting the intestinal barrier [80, 106].
T260	39709-39961	Sentence	denotes	It also helps protect the lungs against infection, increases the expression of the tight junction protein, E-cadherin and connexion 43 in the intestine, maintains renal-epithelial barrier function and improves corneal epithelial barrier function [104].
T261	39962-40145	Sentence	denotes	The 1,25-dihydroxyvitamin D3 can bind to a specific nuclear receptor (vitamin D receptor, VDR) and its role for both the innate and adaptive immune systems has been highlighted [107].
T262	40146-40250	Sentence	denotes	Moreover, vitamin D has been controversially discussed for its role in influenza prevention and therapy.
T263	40251-40393	Sentence	denotes	As shown in literature, 1,25-dihydroxyvitamin D3 undoubtedly plays a strong role as an immunomodulating agent in adaptive and innate immunity.
T264	40394-40541	Sentence	denotes	Different reviews have also reported that individuals with low vitamin D status have a higher risk of viral respiratory tract infections [99, 108].
T265	40542-40872	Sentence	denotes	Several systematic reviews show that levels of this vitamin are inversely related to respiratory tract infection [109, 110] and underlines that individuals with low vitamin D levels show an increased risk of viral tract infections, concluding that its supplementation can reduce the risk of respiratory tract infections [82, 111].
T266	40873-41063	Sentence	denotes	Some studies on the influenza prevention provide a negative correlation between the enhanced post-immunization vaccine and obese patients, because obesity involves a deficiency of vitamin D.
T267	41064-41251	Sentence	denotes	According to most authors, more randomized controlled trials with large populations are needed to explore the preventive effect of vitamin D supplementation on viral flu infections [107].
T268	41253-41262	Sentence	denotes	Vitamin E
T269	41263-41436	Sentence	denotes	Vitamin E exists mainly in the form of tocopherols present in high amounts in nuts and vegetable oils, whereas tocotrienols are found predominantly in some seeds and grains.
T270	41437-41517	Sentence	denotes	This vitamin is involved in immunity and host susceptibility to infection [112].
T271	41518-41754	Sentence	denotes	A positive association was demonstrated between plasma vitamin E and cell-mediated immune responses, while a negative association was observed among plasma vitamin E and the risk of infections in healthy adults over 60 years of age [8].
T272	41755-41873	Sentence	denotes	It protects cell membranes from damage caused by free radicals and supports the integrity of epithelial barriers [79].
T273	41874-42034	Sentence	denotes	Vitamin E has also been shown to regulate the maturation and functions of dendritic cells, which are important for the innate and adaptive immune systems [112].
T274	42035-42532	Sentence	denotes	The immune response mechanisms in which vitamin E is involved are as follows: (i) maintains or improves the cytotoxic activity of NK cells [82] and reduces prostaglandin E2 (PGE2) production by the inhibition of cyclooxygenase-2 (COX-2) activity, mediated through decreasing of nitric oxide production [64, 112, 113]; (ii) the improvement of immune synapse formation in naive T cells, increasing the percentage of memory experienced with the antigen [112]; (iii) the modulation of Th1/Th2 balance.
T275	42533-42679	Sentence	denotes	Indeed it improves lymphocyte proliferation and T cell mediated functions, optimizes and improves the Th1 response and suppress Th2 response [95].
T276	42680-42830	Sentence	denotes	The role of this vitamin in the prevention of infections such as influenza has been discussed, but more controlled studies in humans are needed [114].
T277	42831-43021	Sentence	denotes	Notably, it is accepted that vitamin E may exert its immune-enhancing effects by scavenging oxygen species to reduce oxidative stress [112] and it may induce anti-inflammatory effects [113].
T278	43022-43206	Sentence	denotes	In particular, it appears to be an important fat-soluble antioxidant that hinders the chain reaction induced by free radicals (chain breaking effect) and protects cells from them [95].
T279	43208-43212	Sentence	denotes	Zinc
T280	43213-43470	Sentence	denotes	Zinc is considered a “guardian” for the body, as it plays an essential role in the functioning of the immune system [115], plays a central role in cell growth and differentiation of the immune system cells that have rapid differentiation and turnover [116].
T281	43471-43759	Sentence	denotes	Most of the studies have recently reported a very interesting evaluation of the function of zinc in antiviral immunity, suggesting how it can play a role in host defense against RNA viruses, inhibiting the RNA polymerase required by RNA viruses (such as coronaviruses) to replicate [117].
T282	43760-43846	Sentence	denotes	The zinc-binding metallothionein seems to play an important role in antiviral defense.
T283	43847-44062	Sentence	denotes	Zinc deficiency has a marked impact on bone marrow, decreasing the number of immune precursor cells, with reduced output of naive B lymphocytes, and causes thymic atrophy, reducing the output of naive T lymphocytes.
T284	44063-44224	Sentence	denotes	Therefore, zinc is essential for cell growth and differentiation of immune cells, helping to modulate the cytokine release and trigger CD8+ T cell proliferation.
T285	44225-44505	Sentence	denotes	Among the main activities of zinc in immune function there are: maintaining skin and mucosal integrity (e.g., cofactor for metalloenzymes required for cell membrane repair) [118]; improving the cytotoxic activity of NK cells [79, 82] and the phagocytic capacity of monocytes [64].
T286	44506-44762	Sentence	denotes	It is involved in the complement activity and in the production of IFN-γ [92, 95]; it is an important anti-inflammatory agent [119] and helps modulate the release of cytokines [95] by attenuating the development of pro-inflammatory Th17 and Th9 cells [64].
T287	44763-44935	Sentence	denotes	Furthermore, by influencing the generation of cytokines such as IL-2, IL-6 and TNF, it has antioxidant effects that protect against ROS and reactive nitrogen species [120].
T288	44936-45089	Sentence	denotes	Zinc also induces the proliferation of cytotoxic T cells [62] and is involved in the production of Th1 cytokines and thus supports the Th1 response [95].
T289	45090-45363	Sentence	denotes	It is essential for the intracellular binding of tyrosine kinase to T cell receptors, which is required for T cell development, differentiation and activation [118] and induces the development of Treg cells and is therefore important for maintaining immune tolerance [120].
T290	45364-45528	Sentence	denotes	Finally, zinc is involved in the production of antibodies [79, 121] and it is important to maintain immune tolerance in recognizing the “self” from “non-self” [64].
T291	45529-45650	Sentence	denotes	Low zinc status impairs many aspects of innate immunity, including phagocytosis, respiratory burst and NK cells activity.
T292	45651-45745	Sentence	denotes	Zinc also supports the release of neutrophil extracellular traps, that capture microbes [122].
T293	45746-45876	Sentence	denotes	Zinc malabsorption also displays severe immune impairments and increased susceptibility to bacterial, viral and fungal infections.
T294	45877-46045	Sentence	denotes	It has widely been suggested that increasing zinc intakes may be useful against COVID-19 infections, by reducing viral replication and lower respiratory symptoms [123].
T295	46046-46257	Sentence	denotes	Recent systematic reviews report a shorter duration of the common cold in adults with a good level of zinc and a reduced incidence of mortality when it is supplemented to adults with severe pneumonia [124, 125].
T296	46258-46338	Sentence	denotes	Further research will be necessary to support a zinc supplementation in advices.
T297	46339-46603	Sentence	denotes	The RDA of zinc, according to the Dietary Recommendation Intake (DRI), is 8–11 mg/day for adults (tolerable upper intake level 40 mg/day), suggesting that a zinc intake of 30–50 mg/day might aid in the RNA viruses control, such as influenza and coronaviruses [98].
T298	46605-46613	Sentence	denotes	Selenium
T299	46614-46742	Sentence	denotes	Selenium is an essential micronutrient that plays a significant role in many physiological processes including immune responses.
T300	46743-46895	Sentence	denotes	The immune system needs an adequate intake of this nutrient mostly through its incorporation into selenoproteins to exerts its biological effects [126].
T301	46896-47069	Sentence	denotes	In fact, it has an important antioxidant role to quench ROS, influencing leukocyte and NK cell function and consequently modulating the host antioxidant defense system [85].
T302	47070-47217	Sentence	denotes	In fact, selenoproteins act as redox regulators and cellular antioxidants, potentially counteracting the ROS produced during oxidative stress [82].
T303	47218-47344	Sentence	denotes	Selenium is involved in T-lymphocyte proliferation and the humoral system [85], especially in immunoglobulin production [127].
T304	47345-47459	Sentence	denotes	It helps improve Th cell counts and maintain antibody levels [85] and also increases the production of IFN-γ [95].
T305	47460-47660	Sentence	denotes	Selenium deficiencies have been associated with viral infections such as influenza, determining adaptive and innate immunity responses and leading to a high level of virus-related pathogenicity [128].
T306	47661-47797	Sentence	denotes	Low concentrations of selenium in humans have been linked to the reduced activity of NK cells and the increase in mycobacterial disease.
T307	47798-47947	Sentence	denotes	Moreover, selenium deficiency has been shown to allow mutations of coxsackievirus, poliovirus and murine influenza virus, increasing their virulence.
T308	47948-48070	Sentence	denotes	Dietary selenium supplementations were suggested as adjuvant therapies of influenza, supporting the immune response [129].
T309	48071-48284	Sentence	denotes	The beneficial effects of a higher selenium status have been supported for some viral infections, although there are some studies that do not conclusively demonstrate effective improvements in anti-viral immunity.
T310	48285-48424	Sentence	denotes	On the contrary, the antioxidant properties of some selenoproteins have been suggested to contribute to boosting anti-viral immunity [129].
T311	48425-48670	Sentence	denotes	Currently, the recommended amounts of adequate selenium intake for adults range between 25 and 100 μg/die [130], with an average of 60 μg/die for men and 53 μg/die for women [131]; the tolerable upper intake level is set at 300–450 μg/die [132].
T312	48671-48775	Sentence	denotes	More research is needed to improve knowledge of selenium metabolism and requirements for optimal health.
T313	48776-48929	Sentence	denotes	The relationships between selenium dietary intake and health status, or risk of disease, are complex and require elucidation to inform clinical practice.
T314	48931-48935	Sentence	denotes	Iron
T315	48936-49034	Sentence	denotes	The role of iron in immunonutrition has been widely discussed and confirmed by many studies [133].
T316	49035-49235	Sentence	denotes	Iron is required for a number of different cellular functions and there is a constant balance between iron uptake, transport, storage, and utilization required to maintain iron homeostasis [134, 135].
T317	49236-49368	Sentence	denotes	As the body lacks a defined mechanism for the active excretion of iron, iron balance is mainly regulated at the point of absorption.
T318	49369-49481	Sentence	denotes	Iron deficiency induces thymus atrophy and has multiple effects on immune function in human subjects [133, 136].
T319	49482-49715	Sentence	denotes	The effects of this micronutrient in modulating the immune system include the regulation of T cell differentiation and proliferation [85], also helping to regulate the interplay between helper T cells and cytotoxic T cells [95, 137].
T320	49716-49888	Sentence	denotes	It also play a role in IFN-γ production and participates in the production of cytokines, in fact it is involved in the regulation of the production and action of cytokines.
T321	49889-50122	Sentence	denotes	It forms highly toxic hydroxyl radicals, involved in the killing of bacteria by neutrophils and it is a component of enzymes critical for the functioning of immune cells (e.g. ribonucleotide reductase involved in DNA synthesis) [95].
T322	50123-50249	Sentence	denotes	The iron-rich state promotes the M2-like macrophage phenotype and negatively regulates the M1 pro-inflammatory response [138].
T323	50250-50373	Sentence	denotes	This nutrient is necessary for the generation of ROS, that kill pathogens (by neutrophils) during the oxidative burst [85].
T324	50374-50471	Sentence	denotes	Finally, it appears to be essential for the differentiation and growth of epithelial tissue [95].
T325	50472-50611	Sentence	denotes	Iron at doses above the upper threshold has been associated with increased risk of malaria and other infections, including pneumonia [139].
T326	50612-50742	Sentence	denotes	Obviously it should be noted that treatment for anemia in a malarious area must be preceded by an effective anti-malarial therapy.
T327	50743-50866	Sentence	denotes	Notably, iron rich status promotes M2-like macrophage phenotype and negatively regulates M1 pro-inflammatory response [65].
T328	50867-50943	Sentence	denotes	On the other hand, iron overload causes impairment of immune function [140].
T329	50944-51096	Sentence	denotes	Iron excess increases the harmfulness of inflammation and the microorganisms themselves require iron as it can contribute to the growth of the pathogen.
T330	51097-51147	Sentence	denotes	RDA for iron reports a range of 8–18 mg/day [138].
T331	51149-51158	Sentence	denotes	Glutamine
T332	51159-51305	Sentence	denotes	The consumption of high biological value proteins is an essential component for a healthy diet and for the optimal production of antibodies [141].
T333	51306-51429	Sentence	denotes	Proteins, or amino acids, deficiency is known to impair immune function and increase susceptibility to infectious diseases.
T334	51430-51508	Sentence	denotes	In fact, some amino acids modulate both metabolism and immune functions [142].
T335	51509-51748	Sentence	denotes	Most reviews indicate an important role for amino acids in the immunity by regulating the activation of T lymphocytes, B lymphocytes, natural killer cells and macrophages; cellular redox state, gene expression and lymphocyte proliferation.
T336	51749-51941	Sentence	denotes	Evidence shows that the dietary integration of specific amino acids in humans with malnutrition and infectious diseases improves the immune status, thus reducing morbidity and mortality [141].
T337	51942-52135	Sentence	denotes	Glutamine is the most abundant and versatile amino acid present in the body and its level in the immune cells is similar to, or even greater than, glucose in both health and disease conditions.
T338	52136-52323	Sentence	denotes	The biological activities of this nutrient are also associated with the reduced cellular potential of oxygen, which mainly depends on the ratio between reduced/oxidized glutathione [143].
T339	52324-52511	Sentence	denotes	In addition, glutamine is an essential nutrient for lymphocyte proliferation and cytokine production, macrophage phagocytes plus secretory activities and bacterial killing of neutrophils.
T340	52512-52738	Sentence	denotes	In immune cells, glucose is mainly converted into lactate (glycolysis), while glutamine is converted into glutamate, aspartate and alanine undergoing a partial oxidation in carbon dioxide, in a process of glutaminolysis [142].
T341	52739-52824	Sentence	denotes	This unique conversion plays a crucial role in the effective functioning of immunity.
T342	52825-53163	Sentence	denotes	Glutamine is necessary for the expression of a variety of immune system genes [144], in particular through the activation of proteins, such as the ERK and JNK kinases which are involved in the activation of transcription factors, including JNK and AP-1, finally promoting the transcription of genes that participate in cell proliferation.
T343	53164-53353	Sentence	denotes	Besides, a sufficient level of glutamine is important to express the key markers of the cell surface of the lymphocytes and also various cytokines, for example, IL-6, IFN and TNF [143–145].
T344	53354-53680	Sentence	denotes	In healthy subjects with a balanced diet, glutamine supplementation does not increase the effectiveness of immune surveillance or prevent disease episodes, as reported by some reviews, but in some catabolic situations or in a low glutamine intake obtained from the diet, the amino acid supplementation could be required [142].
T345	53682-53690	Sentence	denotes	Arginine
T346	53691-53850	Sentence	denotes	The modulation of metabolism and immune functions, essential in the interaction and susceptibility to infectious diseases, is also regulated by arginine [146].
T347	53851-53980	Sentence	denotes	Arginine is a precursor for the synthesis of proteins, nitric oxide, urea, polyamines, proline, glutamate, creatine and agmatine.
T348	53981-54344	Sentence	denotes	The role and relationships between the pathways of arginine synthesis and catabolism are complex, due to the compartmentalized expression of various enzymes in different organs (e.g. liver, small intestine and kidney) and subcellular compartments (cytosol and mitochondria), as well as changes in gene expression in response to diet, hormones and cytokines [147].
T349	54345-54617	Sentence	denotes	As reported by several studies, arginine is the precursor of macrophages and it is now clear that arginine metabolism of immune cells is particularly involved in cancer, inflammation, infections, fibrotic diseases, pregnancy and the regulation of immune system [148, 149].
T350	54618-54734	Sentence	denotes	Macrophage arginine metabolism influences the outcome of immune responses in which innate immune cells are involved.
T351	54735-54895	Sentence	denotes	Arginine supplementation is reported to increase T lymphocyte response and Th cell numbers, suggesting a possible role in prolonged or repeated infection [150].
T352	54896-55155	Sentence	denotes	The importance of arginine metabolism as a new field of investigation includes that its depletion delays the growth of some types of tumours, while others report that its integration improves anticancer effects, probably by ameliorating immune function [150].
T353	55156-55300	Sentence	denotes	As discussed, vitamins E, C, D, zinc and selenium are important examples of nutrients that play a key role in supporting the immune system [65].
T354	55301-55342	Sentence	denotes	They can work individually or in synergy.
T355	55343-55464	Sentence	denotes	Furthermore, other dietary components are likely to play a role in modulating immunity, but have not yet been identified.
T356	55465-55541	Sentence	denotes	It is clear how nutritional deficiencies can compromise the immune response.
T357	55542-55718	Sentence	denotes	In addition, inflammation related to unhealthy eating habits has reached alarming proportions, particularly concerning chronic non-communicable diseases [100] (Tables 1 and 2).
T358	55719-55781	Sentence	denotes	Table 1 Dietary sources and immune function roles of nutrients
T359	55782-55833	Sentence	denotes	Nutrient Good dietary sources Immune function roles
T360	55834-56258	Sentence	denotes	Vitamin A Milk and cheese, eggs, liver, oily fish, fortified cereals, dark orange or green vegetables (e.g., carrots, sweet potatoes, pumpkin, squash, kale, spinach, broccoli), orange fruits (e.g., apricots, peaches, papaya, mango, cantaloupe melon), tomato juice Normal differentiation of epithelial tissue; retinoic acid ↑ T and B cells with gut-homing specificity and array T cells and IgA + cells into intestinal tissues
T361	56259-56424	Sentence	denotes	Supporting the gut barrier; carotenoids; ↑immunoregulatory actions including ↓ toxic effects of ROS and regulating membrane fluidity and gap-junctional communication
T362	56425-56526	Sentence	denotes	Regulates number and function of NK cells,↑ to phagocytic and oxidative burst activity of macrophages
T363	56527-56555	Sentence	denotes	Downregulates IFN production
T364	56556-56760	Sentence	denotes	Helps to regulate the production of IL-2 and the pro-inflammatory TNF-γ, ↑ microbial action of macrophages; involved in phagocytic and oxidative burst activity of macrophages activated during inflammation
T365	56761-56960	Sentence	denotes	Development and differentiation of Th1 and Th2 cells; ↑ TGF- β-dependent conversion of naïve T cells into regulatory T cells; plays a role in acquisition of mucosal-homing properties by T and B cells
T366	56961-57126	Sentence	denotes	Development and differentiation of Th 1 and Th2 cells; maintains normal antibody-mediated Th2 response by suppressing IL-12, TNF-α, and IFN-γ production of Th1 cells
T367	57127-57329	Sentence	denotes	Normal functioning of B cells, necessary for generation of antibody responses to antigen; required for B cell-mediated IgA antibody responses to bacterial polysaccharide antigens [62, 79–82, 85, 92, 95]
T368	57330-57638	Sentence	denotes	Vitamin C Oranges and orange juice, red and green peppers, strawberries, blackcurrants, kiwi, broccoli, brussels sprouts, potatoes ↑ collagen synthesis and protects cell membranes from damage caused by free radicals; ↑ keratinocyte differentiation; ↑ lipid synthesis; ↑ fibroblast proliferation and migration
T369	57639-57754	Sentence	denotes	Proliferation, function, and movement of neutrophils, monocytes and phagocytes; ↑ NK cell activities and chemotaxis
T370	57755-57809	Sentence	denotes	↑ Phagocytosis and ROS generation; ↑ microbial killing
T371	57810-57895	Sentence	denotes	↑ Apoptosis and clearance of spent neutrophils from sites of infection by macrophages
T372	57896-57949	Sentence	denotes	↓ Extracellular trap (NET) formation, ↓ tissue damage
T373	57950-58012	Sentence	denotes	↑ Antimicrobial effects; ↑ serum levels of complement proteins
T374	58013-58263	Sentence	denotes	Maintains redox homeostasis within cells and protects against ROS and RNS during oxidative burst; regenerates other important antioxidants, such as glutathione and vitamin E, to their active state; modulates cytokine production and ↓ histamine levels
T375	58264-58444	Sentence	denotes	Roles in production, differentiation, and proliferation of T cells, particularly cytotoxic T cells; ↑ proliferation of lymphocytes, ↑ generation of antibodies [79, 85, 92, 95, 120]
T376	58445-58889	Sentence	denotes	Vitamin D Oily fish, liver, eggs, fortified foods (spreads and some breakfast cereals) Regulates antimicrobial proteins (cathelicidin and β-defensin), modifying intestinal microbiota to a healthier composition and supporting the gut, as well as protecting the lungs against infection; ↑ tight junction protein expression, E-cadherin and connexion 43 in the gut; maintains renal epithelial barrier function; ↑ corneal epithelial barrier function
T377	58890-59064	Sentence	denotes	Vitamin D receptor found in, e.g., monocytes, macrophages, and DCs; ↑ differentiation of monocytes to macrophages; calcitriol ↑ movement and phagocytic ability of macrophages
T378	59065-59207	Sentence	denotes	Regulates antimicrobial protein expression (cathelicidin and defensin), which directly kill pathogens, especially bacteria; ↓ IFN-γ production
T379	59208-59415	Sentence	denotes	↑ The oxidative burst potential of macrophages; increases superoxide synthesis; reduces the expression of pro-inflammatory cytokines and increases the expression of anti-inflammatory cytokines by macrophages
T380	59416-59800	Sentence	denotes	Homing of T cells to the skin; ↓ T-cell proliferation; inhibitory effects mainly in adaptive immunity (e.g., Th1-cell activity); stimulatory effects in innate immunity; ↓ the effector functions of T helper cells and cytotoxic T cells; ↑ the production of Tregs; inhibitory effect on the differentiation and maturation of the antigen-presenting DCs, and helps program DCs for tolerance
T381	59801-59833	Sentence	denotes	↓ Antibody production by B cells
T382	59834-59940	Sentence	denotes	↑ Antigen processing; role in the down-regulation of MHC-II) [64, 71, 79–81, 85, 95, 99, 104–106, 151–153]
T383	59941-60120	Sentence	denotes	Vitamin E Many vegetable oils, nuts and seeds, wheat germ (e.g., in cereals) Protects cell membranes from damage caused by free radicals and ↑ the integrity of epithelial barriers
T384	60121-60228	Sentence	denotes	↑ NK cell cytotoxic activity; ↓ PGE2 production by macrophages (thus indirectly protecting T-cell function)
T385	60229-60456	Sentence	denotes	Important fat-soluble antioxidant that hinders the chain reaction induced by free radicals (chain-breaking effect) and protects cells against them; ↑ IL-2 production; ↓ production of PGE2 (indirectly protecting T-cell function)
T386	60457-60674	Sentence	denotes	↑ Lymphocyte proliferation and T-cell-mediated functions; ↑ Th1 response; ↓ Th2 response; helps to form effective immune synapses between Th cells; ↑ proportion of antigen-experienced memory [64, 79, 82, 95, 112, 113]
T387	60675-60888	Sentence	denotes	Zinc Shellfish, meat, cheese, some grains and seeds, cereals, seeded or whole grain breads Helps maintain integrity of skin and mucosal membrane (e.g., cofactor for metalloenzymesrequired for cell membrane repair)
T388	60889-61069	Sentence	denotes	↑ NK cell cytotoxic activity; central role in cellular growth and differentiation of immune cells that have a rapid differentiation and turnover; ↑ phagocytic capacity of monocytes
T389	61070-61127	Sentence	denotes	Involved in complement activity; role in IFN-γ production
T390	61128-61452	Sentence	denotes	Anti-inflammatory agent; helps to modulate cytokine release by dampening the development of pro-inflammatory Th17 and Th9 cells and influencing the generation of cytokines such as IL-2, IL-6, and TNF; has antioxidant effects that protect against ROS and reactive nitrogen species; influences activity of antioxidant proteins
T391	61453-61782	Sentence	denotes	↑ Proliferation of cytotoxic T cells; involved in Th1 cytokine production and thus supports Th1 response; essential for intracellular binding of tyrosine kinase to T cell receptors, required for T cell development, differentiation, and activation; ↑ development of Treg cells and is thus important in maintaining immune tolerance
T392	61783-61989	Sentence	denotes	Involved in antibody production, particularly IgG; involved in antibody response; important in maintaining immune tolerance (i.e., the ability to recognize “self” from “non-self”) [64, 82, 95, 116, 118–121]
T393	61990-62078	Sentence	denotes	Selenium Fish, shellfish, meat, eggs, some nuts especially brazil nuts ↑ IFN-γproduction
T394	62079-62181	Sentence	denotes	Selenoproteins important for antioxidant host defense system, affecting leukocyte and NK cell function
T395	62182-62341	Sentence	denotes	Essential for function of selenoproteins that act as redox regulators and cellular antioxidants, potentially counteracting ROS produced during oxidative stress
T396	62342-62395	Sentence	denotes	Roles in differentiation and proliferation of T cells
T397	62396-62461	Sentence	denotes	↑ Th cell counts and to maintain antibody levels [82, 85, 92, 95]
T398	62462-62684	Sentence	denotes	Iron Meat, liver, beans, nuts, dried fruit (e.g., apricots), wholegrains (e.g., brown rice), fortified cereals, most dark green leafy vegetables (spinach, kale) Essential for differentiation and growth of epithelial tissue
T399	62685-63040	Sentence	denotes	Forms highly-toxic hydroxyl radicals, thus involved in killing of bacteria by neutrophils; component of enzymes critical for functioning of immune cells (e.g., ribonucleotide reductase involved in DNA synthesis); involved in regulation of cytokine production and action; ↑ M2-like macrophage phenotype and negatively regulates M1 pro-inflammatory response
T400	63041-63065	Sentence	denotes	Role in IFN-γ production
T401	63066-63209	Sentence	denotes	Involved in regulation of cytokine production and action; required for generation of pathogen-killing ROS by neutrophils during oxidative burst
T402	63210-63351	Sentence	denotes	Important in differentiation and proliferation of T cells; helps to regulate ratio between T helper cells and cytotoxic T cells [85, 95, 138]
T403	63352-63570	Sentence	denotes	Long chain omega-3 fatty acids (EPA and DHA) Oilyfish Anti-inflammatory and antioxidant properties when enzymatically converted to specialized pro-resolving mediators (SPMs) known as resolvins, protectins, and maresins
T404	63571-63648	Sentence	denotes	↑ Immune system, by helping to resolve the inflammatory response [63, 66, 67]
T405	63649-63730	Sentence	denotes	Table 2 Nutrient’s supplementation suggested in support of respiratory infections
T406	63731-63814	Sentence	denotes	Nutrient Recommended supplementation suggested in support of respiratory infections
T407	63815-63849	Sentence	denotes	Omega 3 fatty acids 2–4 g/day [68]
T408	63850-63882	Sentence	denotes	Vitamin D 20,000–50,000 IU [154]
T409	63883-63909	Sentence	denotes	Vitamin E 135 mg/day [114]
T410	63910-63932	Sentence	denotes	Zinc 30–50 mg/day [98]
T411	63933-63961	Sentence	denotes	Selenium 25–100 μg/day [130]
T412	63962-64007	Sentence	denotes	Arginine and glutamine 25–35 g/day [142, 146]
T413	64008-64032	Sentence	denotes	Vitamin C 1–2 g/day [98]
T414	64033-64062	Sentence	denotes	Vitamin A 900–700 µg/day [91]
T415	64063-64085	Sentence	denotes	Iron 8–18 mg/day [138]
T416	64087-64141	Sentence	denotes	The role of gut microbiota in COVID-19 immunonutrition
T417	64142-64224	Sentence	denotes	The human intestine hosts a complex bacterial community called the gut microbiota.
T418	64225-64344	Sentence	denotes	The microbiota is specific to each individual despite the existence of several bacterial species shared by most adults.
T419	64345-64414	Sentence	denotes	Scientific studies reveal its influence on human health and diseases.
T420	64415-64619	Sentence	denotes	In particular they have shown that the intestinal microbiota can play a causal role in the development of obesity and associated metabolic disorders, leading to the identification of different mechanisms.
T421	64620-64852	Sentence	denotes	In humans, differences are observed in the composition of the microbiota, in the functional genes and in the metabolic activities between obese and lean individuals, that suggest a contribution of the microbiota to these phenotypes.
T422	64853-65067	Sentence	denotes	Finally, the evidence linking intestinal bacteria to host metabolism could allow the development of new therapeutic strategies based on the modulation of the intestinal microbiota to treat or prevent obesity [155].
T423	65068-65193	Sentence	denotes	Microbiota plays a crucial role in the maturation, development and functions of both innate and adaptive immune system [156].
T424	65194-65337	Sentence	denotes	The gut microbiota has been shown to affect lung health through a vital crosstalk between gut microbiota and lungs, called the “gut-lung axis”.
T425	65338-65566	Sentence	denotes	This axis communicates through a bi-directional pathway in which endotoxins, or microbial metabolites, may affect the lung through the blood and when inflammation occurs in the lung, this, in turn, can affect the gut microbiota.
T426	65567-65689	Sentence	denotes	The immunological health of the gut, primarily mediated by the microbiota, influences lung health via the “gut-lung axis”.
T427	65690-65863	Sentence	denotes	In addition, microbial communities inhabiting the mucosal surfaces of the respiratory tract also contribute towards host defense against viral respiratory infections (VRIs).
T428	65864-65994	Sentence	denotes	Acute VRIs are associated with microbial dysbiosis in these communities, thus acting the optimal functioning of the immune system.
T429	65995-66235	Sentence	denotes	Alterations in the microbiota during influenza virus infection contributes to the pathogenesis of secondary bacterial infections, thus increasing the severity of the clinical course in the absence of appropriate immune responses [157, 158].
T430	66236-66450	Sentence	denotes	It is also known that alterations of the immune functions associated with chronic inflammation and related metabolic dysfunctions lead to a compromise of innate and acquired immune functions in the host [159, 160].
T431	66451-66633	Sentence	denotes	Moreover, chronic inflammation and the use of antibiotics are known to accompany disorders in the gut microbiota, resulting in dysbiosis and aggravation of immune dysfunctions [161].
T432	66634-66916	Sentence	denotes	In addition, the prevalence of comorbid conditions (including chronic lung disease, diabetes, hypertension and cardiovascular diseases) and old age predispose to infection, the development of ARDS and pneumonia, factors already observed for other infections such as influenza [162].
T433	66917-67032	Sentence	denotes	This point raises an interesting possibility that the new SARS-Cov-2 may also have an impact on the gut microbiota.
T434	67033-67166	Sentence	denotes	Indeed, several studies have shown that respiratory infections are associated with a change in the composition of the gut microbiota.
T435	67167-67316	Sentence	denotes	Numerous experimental and clinical observations have suggested that the gut microbiota plays a key role in the pathogenesis of sepsis and ARDS [163].
T436	67317-67540	Sentence	denotes	Moreover, it is known that the signals derived from the intestinal microbiota tune the cells of the immune system for pro and anti-inflammatory responses which thus influence the susceptibility to various diseases (Fig. 2).
T437	67541-67646	Sentence	denotes	Fig. 2 Graphical representation of immune homeostasis disequilibrium during SARS-Coronavirus 2 infection.
T438	67647-67773	Sentence	denotes	ARDS: acute respiratory distress syndrome; T lymphocyte; IL: interleukin; Th: helper T lymphocyte; TNF: tumour necrosis factor
T439	67774-67867	Sentence	denotes	It is also known that respiratory virus infection causes perturbations in the gut microbiota.
T440	67868-67993	Sentence	denotes	Diet, environmental factors and genetics play an important role in shaping gut microbiota which can influence immunity [164].
T441	67994-68099	Sentence	denotes	There is growing evidence that supports the roles of the gut microbiota and diet to shape immunity [165].
T442	68100-68270	Sentence	denotes	Modulating the composition and metabolic capacity of the microbiome for specific dietary components is a promising strategy for influencing immune responses against VRIs.
T443	68271-68491	Sentence	denotes	Functional food components including probiotics, prebiotics and other bioactive ingredients of plant origin have been associated with immune benefits, mainly via microbiota modulation and impact on oxidative stress [65].
T444	68492-68718	Sentence	denotes	Several papers, regarding body composition, evaluated the correlation between fat mass and disease risk and then identified a new frontier of gut microbiota composition in the bodyweight decrease and anti-inflammatory effects.
T445	68719-69070	Sentence	denotes	As shown, the prevention of cardiometabolic diseases, considering the relationship with obesity, may be possible reducing the inflammatory state, acting on the gut-microbiota and on the intestinal permeability improving the health of the intestinal flora, with 4P medicine and treatment with probiotics, prebiotics, postbiotics, and polyphenols [166].
T446	69071-69255	Sentence	denotes	Prebiotic from fruits and vegetables is well-established to modulate the gut microbiota and numerous benefits have been reported in chronic inflammatory and metabolic conditions [167].
T447	69256-69434	Sentence	denotes	In fact, dietary fibers are a good source of accessible carbohydrates for microbiota then prebiotics have been studied in the context of modification of the human gut microbiota.
T448	69435-69606	Sentence	denotes	The compounds such as inulin, polydextrose, maize fiber have been shown to improve the immunity, gut diversity, digestion in humans and especially in elderly people [164].
T449	69607-69755	Sentence	denotes	Moreover, increased dietary fiber consumption is linked to reduced mortality rates in respiratory-related diseases and improved lung function [162].
T450	69756-69890	Sentence	denotes	Thus, plant-based diets, functional foods, and supplements present a promising strategy for protecting against respiratory infections.
T451	69891-70048	Sentence	denotes	Prebiotics lead the influence of microbiota composition and undergo microbial fermentation to produce SCFAs, such as butyrate, acetate, and propionate [168].
T452	70049-70308	Sentence	denotes	Overall, it is apparent that diet and personalized nutritional interventions acting in modulation of gut microbiota especially to control dysbiosis state and to some extent even lung microbiota can influence health status such as immunity conditions (Fig. 3).
T453	70309-70397	Sentence	denotes	Fig. 3 Graphical representation of personalized nutritional intervention during COVID-19
T454	70398-70624	Sentence	denotes	In addition, probiotics which are generally defined as “live microorganisms, which, when administered in adequate amounts, confer a health benefit on the host” have been shown to have profound effect on the health of the host.
T455	70625-70929	Sentence	denotes	In the intestine, the probiotics mainly refer to the genera Lactobacillus and Bifidobacterium and include many different strains such as L. johnsonii, L. fermentum, L. reuteri, L. paracasei, L. rhamnosus, L. acidophilus, L. plantarum, B. longum, B. breve, B. bifidum, and B. animalis subsp. lactis [169].
T456	70930-71016	Sentence	denotes	Fermented foods such as cultured milk products and yoghurt are enriched in probiotics.
T457	71017-71196	Sentence	denotes	They have shown good results in modulating inflammatory conditions as well as regulating innate immunity using toll-like receptors and the corresponding signalling pathways [170].
T458	71197-71393	Sentence	denotes	The capacity of probiotics to induce immunomodulation could be mediated either directly through interaction with immune cells or indirectly by supporting the challenged commensal microbiota [171].
T459	71394-71746	Sentence	denotes	Ingested probiotics with diet or through supplementation stimulate the immune system and initiate a complex of signals mediated by the whole bacteria, they then interact with intestinal epithelial cells also with immune cells associated with the lamina propria or other microbial PRRs and trigger the production of an array of cytokines and chemokines.
T460	71747-71881	Sentence	denotes	These molecules then interact with other immune cells through other pathways, leading to the activation of the mucosal immune systems.
T461	71882-72003	Sentence	denotes	As reported by many reviews specific probiotics have been demonstrated to enhance Th1 and regulatory Treg function [162].
T462	72004-72180	Sentence	denotes	It is clear that probiotics have an important role in the maintenance of immunologic equilibrium in the gastrointestinal tract through the direct interaction with immune cells.
T463	72181-72320	Sentence	denotes	Probiotic effectiveness can be species-, dose-, and disease-specific, and the duration of therapy depends on the clinical indication [170].
T464	72321-72566	Sentence	denotes	Additionally, phytochemicals including vitamins, micronutrients, and polyphenols present in fruits and vegetables have been shown a considerable importance in nutritional strategies for addressing the severity of viral respiratory diseases [65].
T465	72567-72686	Sentence	denotes	Some polyphenols influence microbiota composition and also have antioxidant, anti-inflammatory, and anti-viral effects.
T466	72687-72895	Sentence	denotes	The antiviral effect of polyphenols have been demonstrated to be mediated either by direct inhibitory effects on virus replication or through the induction of immunomodulatory and antioxidant responses [172].
T467	72896-73037	Sentence	denotes	In fact, oxidative stress has been implicated in lung tissue injury and epithelial barrier dysfunction in acute respiratory viral infections.
T468	73038-73168	Sentence	denotes	Dietary polyphenols are present in foods such as vegetables, fruits, cereals, tea, coffee, dark chocolate, cocoa powder, and wine.
T469	73169-73294	Sentence	denotes	The main groups of dietary polyphenols consist in phenolic acids, flavonoids, tannins, stilbenes and diferuloylmethane [173].
T470	73295-73469	Sentence	denotes	Many evidences revealed the excellent immunomodulatory effects of epigallocatechin-3-gallate (EGCG), abundant in green tea on both innate and adaptive immune responses [174].
T471	73470-73622	Sentence	denotes	Finally, in this context there is an important role explained by postbiotics (also known as metabiotic, biogenic, or metabolite cell-free supernatants).
T472	73623-73790	Sentence	denotes	Postbiotics are products or metabolic byproducts secreted by live bacteria or released after bacterial lysis and they provide physiological benefits to the host [175].
T473	73791-73977	Sentence	denotes	There are multiple types of postbiotics with varied structures, such as Short Chain Fatty Acids (SCFAs), peptides, enzymes, teichoic acids, exo- and endo-polysaccharides, vitamins [176].
T474	73978-74156	Sentence	denotes	A protective role of postbiotics like SCFAs has been found in the immune system modulation; particularly in regulation of neutrophil migration in acute inflammation in the colon.
T475	74157-74404	Sentence	denotes	The benefits of microbially-fermented SCFAs are suggested to be mediated through the direct actions of G-protein-coupled receptors (GPRs) expressed on the gut epithelium, adipose tissues and immune cells, including monocytes and neutrophils [177].
T476	74405-74534	Sentence	denotes	Gut-derived SCFAs have been shown to influence the functions of innate immune cells as well as impact acquired immune components.
T477	74535-74816	Sentence	denotes	Studying microbiota and therefore the human immune system and its dysregulation, or controlling the effects of postbiotics in the symbiotic status represents an important opportunity to develop new drugs, and combining probiotic supplements, with vaccines and immunotherapies [16].
T478	74818-74829	Sentence	denotes	Conclusions
T479	74830-74918	Sentence	denotes	Immunonutrition has been based on the concept that malnutrition impairs immune function.
T480	74919-75194	Sentence	denotes	Therefore, immunonutrition involves feeding enriched with various pharmaconutrients (Omega 3 Fatty Acids, Vitamin C, Arginine, Glutamine, Selenium, Zinc, Vitamin, E and Vitamin D) to modulate inflammatory responses, acquired immune response and to improve patients’ outcomes.
T481	75195-75388	Sentence	denotes	Finally, we can conclude that personalized immunonutrition for obese patients should be the first therapeutic choice to reduce the risk of infections and the disease course in COVID-19 patient.
T482	75389-75527	Sentence	denotes	In particular, the nutritional approach might be managed in two different strategies, considering the disease status of the obese patient.
T483	75528-75631	Sentence	denotes	First, immunonutrition can decrease the risk of infections, reducing characteristic inflammation state.
T484	75632-75763	Sentence	denotes	In addition, immunonutrition would be fundamental to support the immune response and protein synthesis in severe phase of COVID-19.

T19

0-10

Sentence

denotes

Background

T20

11-168

Sentence

denotes

On December 2019 a new coronavirus (SARS-CoV-2) emerged in Wuhan, China, triggering a pandemic of severe acute respiratory syndrome in humans (COVID-19) [1].

T21

169-307

Sentence

denotes

Today, the scientific community is investing all the resources available to find any therapy and prevention strategies to defeat COVID-19.

T22

308-439

Sentence

denotes

At the beginning of this pandemic, it was difficult to identify COVID-19 risk factors, that can be targeted for disease prevention.

T23

440-517

Sentence

denotes

Working on risk factors can, in fact, prevent infection and improve outcomes.

T24

518-640

Sentence

denotes

Now it is well known that obesity represents a significant risk factor both for COVID-19 susceptibility and prognosis [2].

T25

641-790

Sentence

denotes

Applying immunonutrition to obese patients can also prevent hospitalization, representing an additional risk factor for worsening COVID-19 prognosis.

T26

791-972

Sentence

denotes

Moreover, immunonutrition in obese patients may be a relevant strategy to lower the burden of COVID-19 disease [3], given that obesity affects almost 13% of people in the world [4].

T27

973-1246

Sentence

denotes

The present umbrella review seeks to answer the question of whether a nutritional approach could be used to enhance the immune system’s response to obesity in patients affected by COVID-19, focusing on the interplay between immunonutrition, inflammation and gut microbiota.

T28

1248-1288

Sentence

denotes

Immune system, inflammation and COVID-19

T29

1289-1413

Sentence

denotes

The immune system protects the human body from infections by a series of pathogen (bacteria, viruses, fungi, parasites) [5].

T30

1414-1495

Sentence

denotes

A self-tolerance system prevents the immune response from damaging human tissues.

T31

1496-1558

Sentence

denotes

The immune system is always active, carrying out surveillance.

T32

1559-1809

Sentence

denotes

The defense to first exposure to the pathogen is represented by two complementary and cooperating functional divisions, the innate immune and, on the other hand, the adaptive immune response, that represents a response based on previous exposure [6].

T33

1810-2035

Sentence

denotes

The innate immune system is represented by dendritic cells, macrophages and neutrophils, with phagocytic activity, and by eosinophils, mast cells and natural killer cells, which release specific soluble antimicrobial factors.

T34

2036-2310

Sentence

denotes

The innate immune system includes physical barriers, represented by interconnected epithelial cells (e.g. tight junctions and cellular interactions mediated by cadherin), epithelial cilia and the mucus layer of the respiratory, gastrointestinal and genitourinary epithelium.

T35

2311-2585

Sentence

denotes

Moreover, soluble proteins and small bioactive molecules such as complement proteins, defensins and ficolins 1-3, pro-inflammatory cytokines, chemokines, lipid mediators of inflammation, membrane-bound receptors and cytoplasmic proteins are part of the innate immune system.

T36

2586-2646

Sentence

denotes

Both innate and adaptive immunity is mediated by leukocytes.

T37

2647-2868

Sentence

denotes

Lymphocytes circulate between the blood system and the lymphatic system, passing through the peripheral lymphoid organs, which includes the spleen, tonsils, appendix, lymph nodes and gut-associated lymphoid tissue (GALT).

T38

2869-3103

Sentence

denotes

From a common lymphoid progenitor, four major populations of mature lymphocytes are derived, that belong to the adaptive immune system: of B lymphocytes (B cells) and T lymphocytes (T cells), natural killer (NK) cells, and NK-T cells.

T39

3104-3215

Sentence

denotes

T-cells can be further categorized to cytotoxic T-cells (TC cells), helper T-cells (Th) and suppressor T-cells.

T40

3216-3400

Sentence

denotes

The specific antigenic receptors of the adaptive response are represented by genes that code for an intact T cell receptor (TCR) and immunoglobulin genes (B cell antigen receptor; Ig).

T41

3401-3483

Sentence

denotes

TCR is capable of binding the antigen processed by antigen-presenting cells (APC).

T42

3484-3706

Sentence

denotes

Dendritic cells represent the most powerful class of APC, and express molecules of the major histocompatibility complex (MHC) of class I and II, necessary for the recognition of the antigen processed by TCR on T cells [7].

T43

3707-3851

Sentence

denotes

Following the presentation of viral antigens via MHC II, the T helper CD4+ lymphocytes are activated and switch to the T helper 1 phenotype [8].

T44

3852-4010

Sentence

denotes

The activated T helper lymphocytes proliferate and release cytokines: after stimulation by antigen and APC, the Th0 cells begin to produce interleukin (IL)-2.

T45

4011-4413

Sentence

denotes

Meanwhile, Th cells differentiate into Th1, Th2 and Th17 according to the nature of the cytokines present in the activation site: IL-12 produced by macrophages and type I Interferon (IFN) or NK cells induce differentiation towards Th1, IL-4 produced by NK1.1 + T cells, basophils or mast cells induce differentiation towards Th2, and IL-1b, IL-23, TGFβ and IL-6 induce differentiation towards Th17 [9].

T46

4414-4483

Sentence

denotes

Th17 cells produce IL-17 and IL-22, and antigen-induced Treg (iTreg).

T47

4484-4720

Sentence

denotes

The binding of the cytokine to its transmembrane cell surface receptor activates an intracellular signal transduction pathway, generally a Janus kinase (Jak), which, via a kinase cascade, phosphorylates its transcription protein (STAT).

T48

4721-4810

Sentence

denotes

Phosphorylated STAT dimers and moves to the nucleus, initiating a new gene transcription.

T49

4811-5306

Sentence

denotes

Mutation of STAT1 increases susceptibility to virus infections because it is involved in various signalling pathways, including IFN-α/β, IFN- γ, IFN-l, IL-2, IL-3, IL-6, IL-9, IL-10, IL-11, IL-12, IL-15, IL-21, IL-22, IL-26 and IL-27 [10], and chemokines of several types such as C-X-C motif chemokine ligand 10 (CXCL-10), Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted (RANTES)/Chemokine (C–C motif) ligand 5 (CCL-5), Monocyte Chemoattractant Protein-1 (MCP-1) [11].

T50

5307-5400

Sentence

denotes

IFN-γ promotes antigen-specific antibody production, increasing the activity of phagocytosis.

T51

5401-5572

Sentence

denotes

In the meantime, PRRs trigger inflammatory signalling, with activation of transcription factors like nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB).

T52

5573-5940

Sentence

denotes

NFκB is the key transcriptional regulator of many pro-inflammatory cytokines, adhesion molecules, chemokines, growth factors and other mediators of inflammation, as tumour necrosis factor (TNF), interleukins 1 (IL-1β), 6 (IL-6), and 12 (IL-12), promotes cellular proliferation and protects against apoptosis providing a mechanism that determines chronic inflammation.

T53

5941-6048

Sentence

denotes

The recognition of pathogens is achieved through the presence of pattern recognition receptors (PRRs) [12].

T54

6049-6151

Sentence

denotes

PRRs identify the microbe-associated molecular patterns (MAMPs), and defensive responses is activated.

T55

6152-6287

Sentence

denotes

PRRs include Toll-like receptors (TLRs), that are able to recognize viral DNA, viral double-stranded RNA and viral single-stranded RNA.

T56

6288-6401

Sentence

denotes

TLRs are expressed on macrophages, dendritic cells, neutrophils, eosinophils, epithelial cells and keratinocytes.

T57

6402-6525

Sentence

denotes

In particular, intracellular TLR-7 and TLR-8 allow the innate recognition of the single-stranded RNA of coronaviruses [13].

T58

6526-6684

Sentence

denotes

Intracellular and extracellular PRRs recognized spike glycoprotein, of the coronavirus coat, starting the inflammatory process, through the NFκB pathway [14].

T59

6685-6902

Sentence

denotes

Moreover, Nucleotide-Binding Domain, Leucine-Rich Repeat (NLR) proteins have also been identified, and NALP3 (NACHT, LRR and PYD domains-containing protein 3) has a special function in the innate immune response [15].

T60

6903-6967

Sentence

denotes

The processes involved in antiviral immunity is shown in Fig. 1.

T61

6968-7041

Sentence

denotes

Fig. 1 Graphical representation of antiviral SARS-Coronavirus 2 immunity.

T62

7042-7044

Sentence

denotes

B:

T63

7045-7306

Sentence

denotes

B lymphocyte; CTL: cytotoxic; T lymphocyte; IFN: interferon; Ig: immunoglobulin; IL: interleukin; MHC: major histocompatibility class; NFκB: nuclear factor kappa-light- chain- enhancer of activated B cells; NK: natural killer cell; Th: helper T lymphocyte; TLR:

T64

7307-7354

Sentence

denotes

Toll-like receptor; TNF: tumour necrosis factor

T65

7355-7583

Sentence

denotes

Normal inflammation is self-limiting because the production of pro-inflammatory cytokines (Th1 cytokines) is followed almost immediately by the production of anti-inflammatory cytokines (Th2 cytokines; IL-1, IL-10, IL-13, etc.).

T66

7584-7717

Sentence

denotes

Chronic inflammation seems to result when the initiating factors persist, or there is some sort of failure of the resolution process.

T67

7718-8007

Sentence

denotes

Dysfunction of the immune system and the loss of homeostatic equilibrium between TREG cells (IL- 10) and Th17 cells (IL-17) was observed in different pathological situations [16], and it is believed to increase the risk of viral infections, including SARS- coronavirus 2 (SARS-CoV-2) [14].

T68

8008-8263

Sentence

denotes

SARS-CoV-2 is an enveloped positive-strand RNA virus in the family Coronaviridae, group 2b, which encodes the viral replicase and four structural proteins: spike (S), envelope (E) and membrane (M), present in the viral envelope, and nucleocapsid (N) [17].

T69

8264-8419

Sentence

denotes

The access route of SARS-CoV-2 is represented by a hydrophobic pocket of the extracellular catalytic domain of Angiotensin-converting enzyme 2 (ACE2) [18].

T70

8420-8583

Sentence

denotes

SARS-CoV peak S protein trimers bind ACE2, expressed in endothelial cells of the vasculature and in the epithelia of the lungs, intestine, heart, brain and kidney.

T71

8584-8647

Sentence

denotes

SARS-CoV-2 enters the cell for endocytosis and membrane fusion.

T72

8648-8851

Sentence

denotes

Once the virus has infected the cell, it follows a downregulation of ACE2 with a consequent local increase in the levels of Ang II, and the development of acute respiratory distress syndrome (ARDS) [19].

T73

8852-9005

Sentence

denotes

The role of ACE2 in the gut, for expression of neutral amino acid transporters, could explain diarrhoea and intestinal inflammation observed in COVID-19.

T74

9006-9187

Sentence

denotes

Moreover, SARS-CoV2 protein E activates the NFκB inflammatory pathway with the consequent activation of MAPK p38, resulting in exacerbation of inflammation and immunopathology [20].

T75

9188-9457

Sentence

denotes

Following the SARS-CoV-2 infection, in the incubation stage and in the non-serious form of COVID-19, the immune system activates the specific adaptive immune response to eliminate the virus, which should be sufficient to block viral propagation and disease progression.

T76

9458-9568

Sentence

denotes

The antiviral system functions well in the presence of general good health and an adequate genetic background.

T77

9569-9888

Sentence

denotes

However, the presence of concomitant pathologies (obesity, cardiovascular diseases, diabetes, neurodegenerative diseases and cancer), malnutrition, and impaired immune response determine the spread of the virus and a massive destruction of the affected tissues, especially in organs that have high ACE2 expression [21].

T78

9889-10245

Sentence

denotes

As noted earlier, SARS-CoV-2 enters the cell via ACE2; that inactivates des-Arg bradykinin, which is a potent ligand of the bradykinin receptor type 1 (BDKRB1).This receptor, localized on endothelial cells, is up-regulated by inflammatory cytokines, which is unlike the B2 receptor, that is constituently expressed and is the receptor for bradykinin (BDK).

T79

10246-10529

Sentence

denotes

BDK is produced from an inactive pre-protein kininogen through activation by the serine protease kallikrein; in addition, it is considered a potent regulator of blood pressure [22], because it induces vasodilation, natriuresis, and hypotension upon activation of the BDKRB2 receptor.

T80

10530-10644

Sentence

denotes

BDK is strongly integrated with the RAS, and the BDK receptor signaling is increased by angiotensin’s action [23].

T81

10645-10816

Sentence

denotes

Interestingly, ACE has a higher affinity for BDK [24] and therefore in conditions where ACE is low, the vasopressor system is moved toward a BDK-directed hypotensive axis.

T82

10817-11022

Sentence

denotes

BDK takes part in the inflammatory response after injury and acts to induce pain via stimulation of the BDKRB1 receptor, which also causes neutrophil recruitment and a major vascular permeability [25, 26].

T83

11023-11213

Sentence

denotes

During the infection, as long as the virus persists, there is dysfunction of ACE2 function, leading to the dysregulation of the kinin-kallikrein pathway and thus causing the angioedema [27].

T84

11214-11410

Sentence

denotes

Some evidence that the edema is bradykinin-generated includes resistance to corticosteroids, epinephrine, and antihistamines in the management of reducing the pulmonary edema in COVID-19 patients.

T85

11411-11516

Sentence

denotes

In fact, the so called Bradykinin Storm is likely responsible for most of the observed COVID-19 symptoms.

T86

11517-11759

Sentence

denotes

Inflammation plays a fundamental role in the pathogenesis and progression of COVID-19, ranging from common colds to fatal cases of pneumonia due to the cytokine release syndrome (CRS) that affected patients, determining the severe conditions.

T87

11760-12058

Sentence

denotes

In COVID-19 the homeostatic equilibrium between TREG cells (IL-10) and Th17 cells (IL-17) is broken: inflammatory cytokine levels (IL-1, TNF) are elevated in the lungs of COVID-19 patients, resulting in an increase in HA-synthase-2 (HAS2) in alveolar epithelial cells CD31+, EpCAM+ and fibroblasts.

T88

12059-12198

Sentence

denotes

The imbalance between pro-inflammatory and anti-inflammatory cytokines, leads to the CRS, an excessive and damaging host inflammation [28].

T89

12199-12339

Sentence

denotes

As a consequence of CRS [29], due to a severe infection of SARS-CoV-2 of the respiratory epithelium, the ARDS was observed in COVID-19 [30].

T90

12340-12431

Sentence

denotes

Edema and an IL-1β mediated proinflammatory response were increased in the lung parenchyma.

T91

12432-12724

Sentence

denotes

Macrophages and dendritic cells produce IL-1β through macro-molecular complexes called inflammasomes, including the major element present in the pulmonary tissue and the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome [20].

T92

12725-12990

Sentence

denotes

Following a precise stimulus, the activation and recruitment domain of caspase (ASC) and the catalytically inactive procaspase-1 assemble, the procaspase-1 turns into active caspase-1, the inactive pro-IL-1β matures in IL-1β and the NLRP3 inflammasome is activated.

T93

12991-13134

Sentence

denotes

The NLRP3 inflammasomes and IL-1β driven proinflammatory cascades correlate with worsening of several respiratory diseases, including COVID-19.

T94

13135-13363

Sentence

denotes

Patients affected by obesity showed a severe consequence of COVID-19 [31], due to the high concentrations of TNF-α, MCP-1 and IL-6 produced in the meantime by visceral and subcutaneous adipose tissue and by innate immunity [32].

T95

13364-13497

Sentence

denotes

Moreover, leptin, released by adipose tissue, helps to increase inflammatory milieu with a dysregulation of the immune response [33].

T96

13498-13684

Sentence

denotes

This umbrella review seeks to answer the question of whether a nutritional approach can be used to enhance the immune system’s response to obesity in obese patients affected by COVID-19.

T97

13685-13822

Sentence

denotes

Immunonutrition has been based on the concept that malnutrition impairs immune function, used to modify inflammatory or immune responses.

T98

13823-13964

Sentence

denotes

This concept may be applied to any situation in which a supply of specific nutrients is necessary to modify inflammatory or immune responses.

T99

13965-14078

Sentence

denotes

Immunonutrients can promote patient recovery by inhibiting inflammatory responses and regulating immune function.

T100

14079-14402

Sentence

denotes

Therefore, immunonutrition involves feeding enriched with various pharmaconutrients (arginine, glutamine, omega-3-fatty acids, ribonucleotides and certain trace elements and antioxidants compound, vitamins and minerals) to modulate inflammatory responses, the acquired immune response, and to improve patient outcomes [34].

T101

14403-14574

Sentence

denotes

Personalized immunonutrition for patients with obesity should be the first therapeutic choice to reduce the risk of infections and the disease course in COVID-19 patients.

T102

14575-14667

Sentence

denotes

That therapeutic strategy could be effective in case of other potential epidemic infections.

T103

14668-14775

Sentence

denotes

It would also allow a reduction of the enormous medical care cost supported by the National Health Service.

T104

14777-14804

Sentence

denotes

Immunonutrition and obesity

T105

14805-15084

Sentence

denotes

According to the World Health Organization (WHO), obesity is defined as a condition in which percentage of body fat (PBF) is increased to an extent in which health and well-being are impaired, and, due to the alarming prevalence increase, declared it as a “global epidemic” [35].

T106

15085-15230

Sentence

denotes

It is characterized by a state of low-grade, chronic inflammation, in addition to altered levels of circulating nutrients and metabolic hormones.

T107

15231-15420

Sentence

denotes

The condition of obesity is a multifactorial pathology that can be related to an altered nutritional behaviour or secondary to genetic, hypothalamic, iatrogenic or endocrine disorders [36].

T108

15421-15522

Sentence

denotes

Underlining the importance of nutritional behaviour, it depends directly on food nutritional quality.

T109

15523-15608

Sentence

denotes

Obesity is considered as a malnutritional status due to the poor quality of the diet.

T110

15609-15690

Sentence

denotes

The chance to get healthy foods is largely determined by one’s own profitability.

T111

15691-15832

Sentence

denotes

Nowadays, the most vulnerable communities fight disadvantage conditions because of socioeconomic, educational, and environmental disparities.

T112

15833-15938

Sentence

denotes

People, who follow a poor quality of diet combined with economic disparity, are at major risk of obesity.

T113

15939-16060

Sentence

denotes

The expansion of fat mass, in turn, is linked to various chronic diseases, including cardiovascular disease and diabetes.

T114

16061-16239

Sentence

denotes

In the context of Covid-19 pandemic, these conditions affect severe outcomes from SARS-CoV-2 infection, as well as contribute to increasing the risk of mortality in general [37].

T115

16240-16317

Sentence

denotes

Adiposopathy, also known as “sick fat”, is at the basis of obesity condition.

T116

16318-16416

Sentence

denotes

It is defined as pathological dysfunction of both anatomical and functional within adipose tissue.

T117

16417-16555

Sentence

denotes

It is promoted by an excess of caloric energy intake and a sedentary lifestyle in genetically and environmentally susceptible individuals.

T118

16556-16647

Sentence

denotes

This latter may cause or worsen metabolic disease in adverse endocrine and immune response.

T119

16648-16817

Sentence

denotes

Modifiable lifestyle choices play a role in fat function and dysfunction, but the strong genetic component has a real chance on predisposition to dysfunctional fat [38].

T120

16818-17134

Sentence

denotes

The disruption of adipose tissue processes, as occurs in adipocyte hypertrophy and visceral fat accumulation, results in the production of pro-inflammatory components (like the plethora of cytokines) and adipocyte factors dysregulation, which may be both genesis and/or main contributors to metabolic disorders [39].

T121

17135-17230

Sentence

denotes

Adipose tissue is not only part of the endocrine system, but it is an active immune organ [40].

T122

17231-17507

Sentence

denotes

As an organ suitable to manage the adaptive and innate immune responses, in healthy lean individuals, its immune cells have the main role in the formation of extracellular matrix modelling, insulin sensitivity, adipogenesis, angiogenesis and clearance of apoptotic adipocytes.

T123

17508-17675

Sentence

denotes

On the contrary, during the expansion of adipose tissue like in obesity, inflammation results in adipocyte hypertrophy, cell death, fibrosis and metabolic dysfunction.

T124

17676-17803

Sentence

denotes

The inflammatory process, involving both innate and adaptive immune cells, plays an important role in adipose immunometabolism.

T125

17804-17936

Sentence

denotes

Among those, macrophages are fundamental for adipose tissue homeostasis and are most thoroughly studied in response to obesity [41].

T126

17937-18058

Sentence

denotes

As a result of the augmentation of the PBF in obesity, there is the proportional increment of adipose tissue macrophages.

T127

18059-18344

Sentence

denotes

Consequently, the system undergoes to a massive pro-inflammatory response resulting by adipose tissue secretion of pro-inflammatory factors, the adipocytes stimulation of inflammation-inducing factors in other tissues and the reduction of anti-inflammatory and protective factors [42].

T128

18345-18739

Sentence

denotes

Understanding the relationship between the adipose tissue, classified as an endocrine organ, and its immune function, the development of new therapeutic and immunonutritional strategies for obesity in COVID-19, may have important implications especially because it may act as a reservoir for more severe viral spread, with increased shedding, immune activation, and cytokine amplification [43].

T129

18740-18853

Sentence

denotes

In the cytokine storm milieu in obesity and COVID-19, over 50 adipokines with diverse roles have been identified.

T130

18854-18999

Sentence

denotes

Leptin, adiponectin, IL-6 and TNF-α mainly act in adipocyte metabolism, insulin sensitivity and metabolic disorders associated with obesity [44].

T131

19000-19175

Sentence

denotes

Leptin is an adipocyte-derived hormone with an important role in the central control of energy metabolism and with many pleiotropic effects in different physiological systems.

T132

19176-19315

Sentence

denotes

One of these is the regulatory role between energy metabolism and the immune system, being a pillar in the new concept of immunometabolism.

T133

19316-19426

Sentence

denotes

Leptin receptor, expressed overall in the immune system, acts in both innate and adaptive immune system cells.

T134

19427-19516

Sentence

denotes

As an adipokine, leptin is responsible for the inflammatory state found in overnutrition.

T135

19517-19613

Sentence

denotes

Moreover, in undernutrition status, it plays as crucial mediator of the immunosuppressive state.

T136

19614-19811

Sentence

denotes

New research frontiers for immunometabolic pathophysiology are considering leptin and leptin receptor as markers of inflammation and immune activation in the context of innate-adaptive system [45].

T137

19812-19919

Sentence

denotes

In the light of above mentioned, leptin represents a connection between metabolism and the immune response.

T138

19920-20031

Sentence

denotes

Its dysregulatory activity would have serious consequences during an eventual infection, such as COVID-19 [46].

T139

20032-20202

Sentence

denotes

By altering the metabolic setting, hyperleptinemia and insulin resistance in obesity disrupt T-cell function, resulting in a suppressed T-cell response to infection [47].

T140

20203-20392

Sentence

denotes

This metabolic condition compromises the immune response and leads patients to morbidity and mortality from SARS-CoV-2 infection, coupled with the lack of containing viral replication [46].

T141

20393-20521

Sentence

denotes

The pivotal role of IL-6 in mediating the acute phase response seems to interest the strategical treatment in COVID-19 patients.

T142

20522-20772

Sentence

denotes

Researches are still in progress and it would be intriguing to investigate whether people with obesity and higher circulating IL-6 levels, compared with lean controls, respond more favourably to IL-6 inhibition strategies in SARS-CoV-2 pandemic [43].

T143

20773-20877

Sentence

denotes

TNF-α is a pyrogen cytokine released in the acute phase of inflammation by macrophages and immune cells.

T144

20878-20999

Sentence

denotes

It is well known that during influenzae and viral infections, the expression of TNF-α in lung epithelial cells is higher.

T145

21000-21115

Sentence

denotes

In patients with COVID-19 and obesity, the IL-6 and TNF-α high serum levels are negatively associated with T-cells.

T146

21116-21210

Sentence

denotes

On the contrary, T cell levels are restored by reducing concentrations of both IL-6 and TNF-α.

T147

21211-21323

Sentence

denotes

These findings suggested that these cytokines could represent important targets of anti-COVID-19 therapies [48].

T148

21324-21420

Sentence

denotes

Infectious diseases, like COVID-19, are characterized by an increased production of adiponectin.

T149

21421-21722

Sentence

denotes

In fact, it seems that adiponectin can reduce innate and adaptive immune cell proliferation and polarization on two fronts: acting on the production blockage of pro-inflammatory cytokines such as TNF-α, IL-2, and IL-6, and enhancing the secretion of anti-inflammatory cytokines such as IL-10 [49, 50].

T150

21723-21823

Sentence

denotes

It seems interesting the possibility to improve the action of adiponectin through diet intervention.

T151

21824-21962

Sentence

denotes

A healthy lifestyle and a Mediterranean diet seem to ameliorate adiponectin levels in human, working on omega-3 biochemical pathways [51].

T152

21963-22091

Sentence

denotes

Finally, in light of the above, a possible COVID-19 therapy would combine drug therapy with a personalized immunonutrition [48].

T153

22092-22273

Sentence

denotes

Whereas healthy adipose tissue is essential to achieve a metabolic health status, sick inflamed fat leads to metabolic pathways dysregulation and different chronic pathologies [52].

T154

22274-22630

Sentence

denotes

According to what mentioned above and considering the endocrine and inflammatory role of the adipose tissue, it is necessary to classify obesity on the basis of body fat composition and distribution [53], rather than simply anthropometric measurements, e.g. Body Mass Index (BMI) classification, that could lead to a large error and misclassification [54].

T155

22631-22912

Sentence

denotes

As different phenotypes of obesity can be diagnosed according to percentage of total bodyfat mass (PBF), associated with an early inflammatory status, and high oxidative stress level [55], to identify obese subjects at risk of COVID-19 it is necessary to evaluate body composition.

T156

22913-23059

Sentence

denotes

Moreover, obesity and adiposopathy contribute to the pathways related to appetite regulation, fat storage and alteration of intestinal microbiota.

T157

23060-23166

Sentence

denotes

Dysbiosis of gut microbiota can influence the onset and progression of chronic degenerative diseases [56].

T158

23167-23268

Sentence

denotes

The impact of these metabolic abnormalities has undergone intense investigation over the past decade.

T159

23269-23427

Sentence

denotes

Although that, it is still not clear how the immune system and host defense are influenced by the pro-inflammatory and excess energy milieu of the obese [57].

T160

23428-23602

Sentence

denotes

There is strong evidence in literature indicating that abundant adiposity negatively impacts on immune system functionality and host defense in individuals with obesity [57].

T161

23603-23737

Sentence

denotes

In people with obesity, the caloric balance surplus is not directly proportional to the high nutritional food components quality [53].

T162

23738-23914

Sentence

denotes

Hence, the overfed malnourished patient may be compared to the underfed malnourishment, because malnutrition is considered the primary cause of immunodeficiency worldwide [58].

T163

23915-24012

Sentence

denotes

Chronic diseases, such as obesity, have been recognized as virulence factors for severe COVID-19.

T164

24013-24138

Sentence

denotes

These morbidities are usually coupled to protein-energy malnutrition, which is demonstrated to impair immune cell activation.

T165

24139-24239

Sentence

denotes

This process allows longer viral persistence and increased dealing of pro-inflammatory factors [59].

T166

24240-24350

Sentence

denotes

This will allow you to make a personalized emergency intervention, in all the subjects suffering from obesity.

T167

24351-24483

Sentence

denotes

In the onset of COVID-19 era, the nutritional approach might be managed in two different strategies, considering the disease status.

T168

24484-24715

Sentence

denotes

In a severe phase of COVID-19 in a patient with obesity, immunonutrition would be fundamental to support the immune response and protein synthesis, and, at the same time, to reduce inflammation caused by the pathological condition.

T169

24716-24871

Sentence

denotes

The organism fights both the acute inflammatory state triggered by COVID-19 and, in addition, the latent chronic inflammation due to the obesity condition.

T170

24872-25076

Sentence

denotes

This latter is employed in the case of malnourished surgical patients, where immunonutrition significantly reduced the risk of acquired infections, wound complications, and length of stay at the hospital.

T171

25077-25220

Sentence

denotes

In this context, immunomodulating diets (IMDs) have been demonstrated to improve immune system response and modulate inflammation cascade [60].

T172

25221-25449

Sentence

denotes

Furthermore, the nutritional approach should be firstly preventive to reduce the large number of complications linked to obesity condition; and, secondly, could be predictive to act on the etiopathogenesis of SARS-CoV-2 disease.

T173

25450-25563

Sentence

denotes

In the current pandemic panorama, the connection between nutrition science and virology takes a predictable turn.

T174

25564-25663

Sentence

denotes

It is worth that nutritional innovation must correlate all the previously treated clinical aspects.

T175

25664-25955

Sentence

denotes

By referring to WHO guidelines, it is fundamental to follow healthy eating habits and lifestyle to achieve an optimal health status supporting immune cells system, and to switch from an unhealthy condition of dysbiosis to a healthy condition of eubiosis and modulating systemic inflammation.

T176

25956-26075

Sentence

denotes

This is essentially possible pursuing a balanced diet based on the Mediterranean concept and staying physically active.

T177

26077-26139

Sentence

denotes

Immunonutrition: the role of specific nutrients and microbiota

T178

26140-26285

Sentence

denotes

An optimal nutritional status guarantees the main modulating processes of inflammatory and oxidative stress, both connected to the immune system.

T179

26286-26391

Sentence

denotes

The metabolic system applied for biosynthesis and energy request needs many different dietary components.

T180

26392-26600

Sentence

denotes

In fact, some nutrients and their metabolites are direct regulators of gene expression of the immune compartment and play a key role in the maturation, differentiation and responsiveness of immune cells [61].

T181

26601-26733

Sentence

denotes

It is easy to understand that an adequate and balanced supply of these nutrients is essential to set an appropriate immune response.

T182

26734-26868

Sentence

denotes

Basically, good nutrition creates a setting in which the immune system can respond appropriately to challenge, whatever this might be.

T183

26869-26980

Sentence

denotes

On the contrary, poor nutrition produces an environment in which the immune system cannot respond well [62–64].

T184

26981-27127

Sentence

denotes

Furthermore, nutritional status, the role of diet and lifestyle may play an important part in different severe infections, especially in COVID-19.

T185

27128-27306

Sentence

denotes

The importance of nutrition as a mitigation strategy to support immune function, is reachable identifying food groups and key nutrients as defense against respiratory infections.

T186

27307-27528

Sentence

denotes

A balanced diet, rich in some foods, is associated with anti-inflammatory and immunomodulatory compounds, including vitamins (C, D, and E) and minerals (zinc and selenium), and may influence human nutritional status [16].

T187

27529-27615

Sentence

denotes

During this COVID-19 pandemic many myths surfaced on how strengthen the immune system.

T188

27616-27749

Sentence

denotes

Several research publications have focused on the role of diet and specific nutrients, some focusing on respiratory viral infections.

T189

27750-27877

Sentence

denotes

The most of micronutrients have been identified as the main responsible for maintenance the complex needs of the immune system.

T190

27878-27971

Sentence

denotes

Below we will focus on the main nutrients with specific reference to respiratory health [65].

T191

27973-27992

Sentence

denotes

Omega 3 fatty acids

T192

27993-28141

Sentence

denotes

Reactive oxygen species create a pro-oxidant environment against which the body needs protection through vitamins, enzymes and antioxidant feedings.

T193

28142-28354

Sentence

denotes

Particularly, omega-3 fatty acids are known to exert anti-inflammatory and antioxidant properties [66, 67], and to support the immune system, specifically by helping to resolve the inflammatory response [63, 68].

T194

28355-28540

Sentence

denotes

The intake of omega-3 fatty acids from fish and seafood has been shown to trigger anti-inflammatory reactions via oxygenated metabolites (oxylipins), including resolvins and protectins.

T195

28541-28780

Sentence

denotes

Omega-3 fatty acids include linolenic acid (ALA) consumed from various plant sources and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) consumed especially from fish and seafood sources, such as salmon, mackerel, and tuna [69].

T196

28781-28992

Sentence

denotes

Notably, the omega-3 fatty acids EPA and DHA involved in the inflammation process, are enzymatically converted to specialized pro-resolving mediators (SPMs) known as resolvins, protectins, and maresins [66, 67].

T197

28993-29156

Sentence

denotes

These molecules, alongside with others, function together to orchestrate the resolution of inflammation and to support healing, including in the respiratory tract.

T198

29157-29279

Sentence

denotes

Deficiencies of omega-3 fatty acids EPA and DHA are accountable for delayed or suboptimal resolution of inflammation [70].

T199

29280-29442

Sentence

denotes

This could be very important in the context of severe COVID-19, which manifests as uncontrolled inflammation, the so-called cytokine storm, linked with ARDS [71].

T200

29444-29462

Sentence

denotes

Oleoylethanolamide

T201

29463-29626

Sentence

denotes

Oleoylethanolamide (OEA), synthesized in the gastrointestinal tract, is a bioactive lipid mediator derived from the omega-9 monounsaturated fatty acid, oleic acid.

T202

29627-29818

Sentence

denotes

Based on previous evidences, OEA showed anti-inflammatory activities, a role in modulation of immune response, anti-oxidant effects and stimulation of lipolysis and fatty acid oxidation [72].

T203

29819-30026

Sentence

denotes

In this context OEA is considered an endocannabinoid-like lipid, which interacts with the peroxisome proliferator-activated receptor-alpha (PPAR-α) and intervenes during the anti-inflammatory processes [73].

T204

30027-30245

Sentence

denotes

Scientific researchers recently showed that endocannabinoid system is involved in the management of infectious agents such as viruses, bacteria, and some protozoa, also reducing inflammation and pain in the lungs [74].

T205

30246-30557

Sentence

denotes

In view of the fact that SARS-CoV-2 infection leads to increase the pro-inflammatory cytokines, including IL-6 and IL-1β in COVID-19 patients via binding to the TLRs, an important components of the innate immune system, it is assumed that OEA inhibits this pathway through its anti-inflammatory properties [75].

T206

30558-30775

Sentence

denotes

OEA binds with high affinity to PPAR-α receptors and increases the expression level of anti-inflammatory cytokine such as IL-10, then initiates a cascade of events, which can attenuate the inflammatory responses [73].

T207

30776-30933

Sentence

denotes

Furthermore, OEA attenuates the inflammatory responses modulating the expression of TLR-4, and interfering with the ERK1/2/AP-1/STAT3 signaling cascade [73].

T208

30934-31081

Sentence

denotes

OEA may modulate cross-talk between PPAR-α and TLRs and regulates the inflammatory responses with beneficial synergistic effect against SARS-CoV-2.

T209

31082-31417

Sentence

denotes

Nowadays, discovering therapeutic options from currently available agents appears to be essential for the treatment and prophylaxis of this pandemic, especially in obese patients with comorbidities [76] and this bioactive lipid mediator can be considered as a novel potential pharmacological alternative for the management of COVID-19.

T210

31419-31428

Sentence

denotes

Vitamin A

T211

31429-31561

Sentence

denotes

The role of vitamin A and its metabolites in the immune system and host susceptibility is discussed in a series of reviews [77, 78].

T212

31562-31881

Sentence

denotes

This nutrient is involved in normal differentiation of epithelial tissue, furthermore retinoic acid is essential for imprinting T and B cells with gut-homing specificity and T array cells and IgA cells in intestinal tissues [79], thus enhancing the intestinal immune response and supporting the intestinal barrier [80].

T213

31882-32107

Sentence

denotes

Carotenoids (both provitamin A and non-provitamin A carotenoids) have immunoregulatory actions including the reduction of the toxic effects of ROS and the regulation of membrane fluidity and gap-junctional communication [81].

T214

32108-32236

Sentence

denotes

Vitamin A deficiency impairs barrier function, impairs immune responses and increases susceptibility to a variety of infections.

T215

32237-32342

Sentence

denotes

Furthermore, many aspects of innate immunity, in addition to barrier function, are affected by vitamin A.

T216

32343-32567

Sentence

denotes

For example, vitamin A regulates the number and function of NK cells [82], contributes to the phagocytic and oxidative activity of the macrophage burst [79] and controls the maturation of neutrophils and its deficiency [83].

T217

32568-32650

Sentence

denotes

The activity of natural killer cells is therefore reduced by vitamin A deficiency.

T218

32651-32803

Sentence

denotes

The impact of vitamin A on acquired immunity is however clear since it is involved in the development and differentiation of Th1 and Th2 cells [62, 79].

T219

32804-32991

Sentence

denotes

Moreover there is evidence that vitamin A deficiency alters the balance of Th1 and Th2 cells, decreasing the Th2 response, without affecting or, in some cases, enhancing the Th1 response.

T220

32992-33069

Sentence

denotes

This suggests that vitamin A increases the Th1 cell average in immunity [84].

T221

33070-33403

Sentence

denotes

However, studies in several experimental models have shown how the retinoic acid metabolite of vitamin A reduces the responses of Th1-type cells (cytokines, cytokine receptors and the transcription factor T-bet, which promotes Th1), improving responses to Th2-type cells (cytokines and Th2-favoring transcription factor GATA-3) [62].

T222

33404-33546

Sentence

denotes

Indeed, it maintains the normal Th2 response mediated by antibodies by suppressing the production of IL-12, TNF-α and IFN-γ by Th1 cells [85].

T223

33547-33742

Sentence

denotes

Vitamin A appears to be important in the differentiation of regulatory T lymphocytes by suppressing Th17 differentiation, which have implications for the control of adverse immune reactions [86].

T224

33743-33922

Sentence

denotes

It helps regulate the production of IL-2 and the pro-inflammatory TNF-γ, which activates the phagocytic and oxidative action of the macrophages activated during inflammation [79].

T225

33923-34046

Sentence

denotes

It ensures the normal functioning of B lymphocytes, necessary for the generation of antibody responses to the antigen [85].

T226

34047-34233

Sentence

denotes

Retinoic acid appears to promote the movement of T cells to gut-associated lymphoid tissue and, interestingly, some gut-associated immune cells are able to synthesize retinoic acid [87].

T227

34234-34410

Sentence

denotes

Vitamin A deficiency is associated with increased morbidity and mortality in children and appears to predispose to respiratory infections, diarrhea and severe measles [88, 89].

T228

34411-34541

Sentence

denotes

Moreover, supplementing vitamin A in deficient children improves recovery from infectious diseases and reduces mortality [78, 90].

T229

34542-34635

Sentence

denotes

The Recommended Dietary Allowance (RDA) for vitamin A reports a range of 900–700 µg/day [91].

T230

34637-34646

Sentence

denotes

Vitamin C

T231

34647-34757

Sentence

denotes

The role of vitamin C in immunity and in host susceptibility to infection has been scientifically proven [92].

T232

34758-34918

Sentence

denotes

Vitamin C, in fact, is necessary for the biosynthesis of collagen and is essential for maintaining epithelial integrity and protecting against oxidative stress.

T233

34919-35166

Sentence

denotes

It protects cell membranes from damage caused by free radicals, so as to support the integrity of the epithelial barriers [79], also improves keratinocytic differentiation and lipid synthesis as well as fibroblast proliferation and migration [92].

T234

35167-35582

Sentence

denotes

It plays a role in various aspects of immunity, in fact it is involved in the proliferation, function and movement of neutrophils, monocytes and phagocytes [82] and the migration of leukocytes to sites of infection, phagocytosis and bacterial killing, in the activity of natural killer cells and in the function of T lymphocytes (especially CD8 cytotoxic T lymphocytes) and in the production of antibodies [79, 82].

T235

35583-35806

Sentence

denotes

Vitamin C is also involved in apoptosis and elimination of depleted neutrophils from macrophage infection sites [92] and attenuates the formation of extracellular trap (NET), thus reducing the associated tissue damage [92].

T236

35807-35940

Sentence

denotes

Infections have a significant impact on vitamin C levels, due to the increased energy needs required by the body during inflammation.

T237

35941-36080

Sentence

denotes

This nutrient, in fact, promotes the proliferation of lymphocytes, with a consequent increase in the generation of antibodies [79, 85, 92].

T238

36081-36351

Sentence

denotes

It is well known that infections increase oxidative stress and usually activate phagocytes that release ROS, so vitamin C is a well-known antioxidant that can counteract these effects by increasing phagocytosis and ROS generation and improving microbial killing [92–94].

T239

36352-36477

Sentence

denotes

Furthermore, supplementation with vitamin C appears to be able to prevent and treat respiratory and systemic infections [92].

T240

36478-36655

Sentence

denotes

High levels of this nutrient can enhance antimicrobial effects and increase serum levels of complement proteins, also playing an important role in IFN-γ production [85, 92, 95].

T241

36656-36779

Sentence

denotes

Low levels of vitamin C are responsible for an increased susceptibility to severe respiratory infections such as pneumonia.

T242

36780-36970

Sentence

denotes

Indeed, a meta-analysis reported a significant reduction in the risk of pneumonia with vitamin C supplementation, particularly in individuals with a low dietary intake of this nutrient [96].

T243

36971-37182

Sentence

denotes

Vitamin C supplementation has also been demonstrated to reduce the duration and severity of upper respiratory tract infections, such as the common cold, especially in people under increased physical stress [96].

T244

37183-37287

Sentence

denotes

Currently, there are limited recommendations for taking vitamin C supplementation against COVID-19 [97].

T245

37288-37457

Sentence

denotes

Nevertheless, there is sufficient evidence to conduct several clinical trials to assess vitamin C efficacy in COVID-19 prevention and treatment (www.clinicaltrials.gov).

T246

37458-37547

Sentence

denotes

Previously, doses of 1–2 g/day were effective in preventing upper respiratory infections.

T247

37548-37692

Sentence

denotes

As those levels are not attainable through dietary sources, supplementation may be advised for those at a higher risk of respiratory infections.

T248

37693-37767

Sentence

denotes

Doses above 200 mg/day may not be beneficial for healthy individuals [98].

T249

37769-37778

Sentence

denotes

Vitamin D

T250

37779-37901

Sentence

denotes

Many reviews discuss the role of vitamin D and its metabolites in host immunity and susceptibility to infections [99–101].

T251

37902-38128

Sentence

denotes

Vitamin D receptors have been identified in most immune cells, of which some can also synthesize the active form of vitamin D from its precursor, therefore suggesting that might have important immunoregulatory properties [99].

T252

38129-38295

Sentence

denotes

Vitamin D is synthesized at skin level in the presence of UV-light from cholesterol and it is also taken up from the diet (fish, eggs, fortified milk, and mushrooms).

T253

38296-38603

Sentence

denotes

The active form of vitamin D, calcitriol (1,25-dihydroxy vitamin D3), formed following kidney and liver hydroxylation, is most renowned for its regulating role in calcium homeostasis and bone health status, but it has also been shown to regulate the immune system, mainly in the functioning of T-cell [102].

T254

38604-38878

Sentence

denotes

Among the main functions of vitamin D, its ability to improve the integrity of the epithelium has mainly been observed as well as the ability to induce the synthesis of an antimicrobial peptide in epithelial cells and macrophages, thus directly improving host defense [103].

T255

38879-39088

Sentence

denotes

Vitamin D also promotes the differentiation of monocytes from macrophages [95], promotes the movement and phagocyability of macrophages [79], superoxide production and bacterial killing by innate immune cells.

T256

39089-39172

Sentence

denotes

Hence, it promotes the processing of antigen presentation by dendritic cells [104].

T257

39173-39320

Sentence

denotes

Calcitriol regulates the expression of antimicrobial proteins (cathelicidin and defensin), which directly kill pathogens, especially bacteria [99].

T258

39321-39500

Sentence

denotes

It inhibits the production of IFN-γ [71] and reduces the expression of pro-inflammatory cytokines by increasing the expression of anti-inflammatory cytokines by macrophages [105].

T259

39501-39708

Sentence

denotes

Calcitriol modulates antimicrobial proteins (cathelicidin and β-defensin), responsible for modifying the intestinal microbiota, favoring a healthy composition and supporting the intestinal barrier [80, 106].

T260

39709-39961

Sentence

denotes

It also helps protect the lungs against infection, increases the expression of the tight junction protein, E-cadherin and connexion 43 in the intestine, maintains renal-epithelial barrier function and improves corneal epithelial barrier function [104].

T261

39962-40145

Sentence

denotes

The 1,25-dihydroxyvitamin D3 can bind to a specific nuclear receptor (vitamin D receptor, VDR) and its role for both the innate and adaptive immune systems has been highlighted [107].

T262

40146-40250

Sentence

denotes

Moreover, vitamin D has been controversially discussed for its role in influenza prevention and therapy.

T263

40251-40393

Sentence

denotes

As shown in literature, 1,25-dihydroxyvitamin D3 undoubtedly plays a strong role as an immunomodulating agent in adaptive and innate immunity.

T264

40394-40541

Sentence

denotes

Different reviews have also reported that individuals with low vitamin D status have a higher risk of viral respiratory tract infections [99, 108].

T265

40542-40872

Sentence

denotes

Several systematic reviews show that levels of this vitamin are inversely related to respiratory tract infection [109, 110] and underlines that individuals with low vitamin D levels show an increased risk of viral tract infections, concluding that its supplementation can reduce the risk of respiratory tract infections [82, 111].

T266

40873-41063

Sentence

denotes

Some studies on the influenza prevention provide a negative correlation between the enhanced post-immunization vaccine and obese patients, because obesity involves a deficiency of vitamin D.

T267

41064-41251

Sentence

denotes

According to most authors, more randomized controlled trials with large populations are needed to explore the preventive effect of vitamin D supplementation on viral flu infections [107].

T268

41253-41262

Sentence

denotes

Vitamin E

T269

41263-41436

Sentence

denotes

Vitamin E exists mainly in the form of tocopherols present in high amounts in nuts and vegetable oils, whereas tocotrienols are found predominantly in some seeds and grains.

T270

41437-41517

Sentence

denotes

This vitamin is involved in immunity and host susceptibility to infection [112].

T271

41518-41754

Sentence

denotes

A positive association was demonstrated between plasma vitamin E and cell-mediated immune responses, while a negative association was observed among plasma vitamin E and the risk of infections in healthy adults over 60 years of age [8].

T272

41755-41873

Sentence

denotes

It protects cell membranes from damage caused by free radicals and supports the integrity of epithelial barriers [79].

T273

41874-42034

Sentence

denotes

Vitamin E has also been shown to regulate the maturation and functions of dendritic cells, which are important for the innate and adaptive immune systems [112].

T274

42035-42532

Sentence

denotes

The immune response mechanisms in which vitamin E is involved are as follows: (i) maintains or improves the cytotoxic activity of NK cells [82] and reduces prostaglandin E2 (PGE2) production by the inhibition of cyclooxygenase-2 (COX-2) activity, mediated through decreasing of nitric oxide production [64, 112, 113]; (ii) the improvement of immune synapse formation in naive T cells, increasing the percentage of memory experienced with the antigen [112]; (iii) the modulation of Th1/Th2 balance.

T275

42533-42679

Sentence

denotes

Indeed it improves lymphocyte proliferation and T cell mediated functions, optimizes and improves the Th1 response and suppress Th2 response [95].

T276

42680-42830

Sentence

denotes

The role of this vitamin in the prevention of infections such as influenza has been discussed, but more controlled studies in humans are needed [114].

T277

42831-43021

Sentence

denotes

Notably, it is accepted that vitamin E may exert its immune-enhancing effects by scavenging oxygen species to reduce oxidative stress [112] and it may induce anti-inflammatory effects [113].

T278

43022-43206

Sentence

denotes

In particular, it appears to be an important fat-soluble antioxidant that hinders the chain reaction induced by free radicals (chain breaking effect) and protects cells from them [95].

T279

43208-43212

Sentence

denotes

Zinc

T280

43213-43470

Sentence

denotes

Zinc is considered a “guardian” for the body, as it plays an essential role in the functioning of the immune system [115], plays a central role in cell growth and differentiation of the immune system cells that have rapid differentiation and turnover [116].

T281

43471-43759

Sentence

denotes

Most of the studies have recently reported a very interesting evaluation of the function of zinc in antiviral immunity, suggesting how it can play a role in host defense against RNA viruses, inhibiting the RNA polymerase required by RNA viruses (such as coronaviruses) to replicate [117].

T282

43760-43846

Sentence

denotes

The zinc-binding metallothionein seems to play an important role in antiviral defense.

T283

43847-44062

Sentence

denotes

Zinc deficiency has a marked impact on bone marrow, decreasing the number of immune precursor cells, with reduced output of naive B lymphocytes, and causes thymic atrophy, reducing the output of naive T lymphocytes.

T284

44063-44224

Sentence

denotes

Therefore, zinc is essential for cell growth and differentiation of immune cells, helping to modulate the cytokine release and trigger CD8+ T cell proliferation.

T285

44225-44505

Sentence

denotes

Among the main activities of zinc in immune function there are: maintaining skin and mucosal integrity (e.g., cofactor for metalloenzymes required for cell membrane repair) [118]; improving the cytotoxic activity of NK cells [79, 82] and the phagocytic capacity of monocytes [64].

T286

44506-44762

Sentence

denotes

It is involved in the complement activity and in the production of IFN-γ [92, 95]; it is an important anti-inflammatory agent [119] and helps modulate the release of cytokines [95] by attenuating the development of pro-inflammatory Th17 and Th9 cells [64].

T287

44763-44935

Sentence

denotes

Furthermore, by influencing the generation of cytokines such as IL-2, IL-6 and TNF, it has antioxidant effects that protect against ROS and reactive nitrogen species [120].

T288

44936-45089

Sentence

denotes

Zinc also induces the proliferation of cytotoxic T cells [62] and is involved in the production of Th1 cytokines and thus supports the Th1 response [95].

T289

45090-45363

Sentence

denotes

It is essential for the intracellular binding of tyrosine kinase to T cell receptors, which is required for T cell development, differentiation and activation [118] and induces the development of Treg cells and is therefore important for maintaining immune tolerance [120].

T290

45364-45528

Sentence

denotes

Finally, zinc is involved in the production of antibodies [79, 121] and it is important to maintain immune tolerance in recognizing the “self” from “non-self” [64].

T291

45529-45650

Sentence

denotes

Low zinc status impairs many aspects of innate immunity, including phagocytosis, respiratory burst and NK cells activity.

T292

45651-45745

Sentence

denotes

Zinc also supports the release of neutrophil extracellular traps, that capture microbes [122].

T293

45746-45876

Sentence

denotes

Zinc malabsorption also displays severe immune impairments and increased susceptibility to bacterial, viral and fungal infections.

T294

45877-46045

Sentence

denotes

It has widely been suggested that increasing zinc intakes may be useful against COVID-19 infections, by reducing viral replication and lower respiratory symptoms [123].

T295

46046-46257

Sentence

denotes

Recent systematic reviews report a shorter duration of the common cold in adults with a good level of zinc and a reduced incidence of mortality when it is supplemented to adults with severe pneumonia [124, 125].

T296

46258-46338

Sentence

denotes

Further research will be necessary to support a zinc supplementation in advices.

T297

46339-46603

Sentence

denotes

The RDA of zinc, according to the Dietary Recommendation Intake (DRI), is 8–11 mg/day for adults (tolerable upper intake level 40 mg/day), suggesting that a zinc intake of 30–50 mg/day might aid in the RNA viruses control, such as influenza and coronaviruses [98].

T298

46605-46613

Sentence

denotes

Selenium

T299

46614-46742

Sentence

denotes

Selenium is an essential micronutrient that plays a significant role in many physiological processes including immune responses.

T300

46743-46895

Sentence

denotes

The immune system needs an adequate intake of this nutrient mostly through its incorporation into selenoproteins to exerts its biological effects [126].

T301

46896-47069

Sentence

denotes

In fact, it has an important antioxidant role to quench ROS, influencing leukocyte and NK cell function and consequently modulating the host antioxidant defense system [85].

T302

47070-47217

Sentence

denotes

In fact, selenoproteins act as redox regulators and cellular antioxidants, potentially counteracting the ROS produced during oxidative stress [82].

T303

47218-47344

Sentence

denotes

Selenium is involved in T-lymphocyte proliferation and the humoral system [85], especially in immunoglobulin production [127].

T304

47345-47459

Sentence

denotes

It helps improve Th cell counts and maintain antibody levels [85] and also increases the production of IFN-γ [95].

T305

47460-47660

Sentence

denotes

Selenium deficiencies have been associated with viral infections such as influenza, determining adaptive and innate immunity responses and leading to a high level of virus-related pathogenicity [128].

T306

47661-47797

Sentence

denotes

Low concentrations of selenium in humans have been linked to the reduced activity of NK cells and the increase in mycobacterial disease.

T307

47798-47947

Sentence

denotes

Moreover, selenium deficiency has been shown to allow mutations of coxsackievirus, poliovirus and murine influenza virus, increasing their virulence.

T308

47948-48070

Sentence

denotes

Dietary selenium supplementations were suggested as adjuvant therapies of influenza, supporting the immune response [129].

T309

48071-48284

Sentence

denotes

The beneficial effects of a higher selenium status have been supported for some viral infections, although there are some studies that do not conclusively demonstrate effective improvements in anti-viral immunity.

T310

48285-48424

Sentence

denotes

On the contrary, the antioxidant properties of some selenoproteins have been suggested to contribute to boosting anti-viral immunity [129].

T311

48425-48670

Sentence

denotes

Currently, the recommended amounts of adequate selenium intake for adults range between 25 and 100 μg/die [130], with an average of 60 μg/die for men and 53 μg/die for women [131]; the tolerable upper intake level is set at 300–450 μg/die [132].

T312

48671-48775

Sentence

denotes

More research is needed to improve knowledge of selenium metabolism and requirements for optimal health.

T313

48776-48929

Sentence

denotes

The relationships between selenium dietary intake and health status, or risk of disease, are complex and require elucidation to inform clinical practice.

T314

48931-48935

Sentence

denotes

Iron

T315

48936-49034

Sentence

denotes

The role of iron in immunonutrition has been widely discussed and confirmed by many studies [133].

T316

49035-49235

Sentence

denotes

Iron is required for a number of different cellular functions and there is a constant balance between iron uptake, transport, storage, and utilization required to maintain iron homeostasis [134, 135].

T317

49236-49368

Sentence

denotes

As the body lacks a defined mechanism for the active excretion of iron, iron balance is mainly regulated at the point of absorption.

T318

49369-49481

Sentence

denotes

Iron deficiency induces thymus atrophy and has multiple effects on immune function in human subjects [133, 136].

T319

49482-49715

Sentence

denotes

The effects of this micronutrient in modulating the immune system include the regulation of T cell differentiation and proliferation [85], also helping to regulate the interplay between helper T cells and cytotoxic T cells [95, 137].

T320

49716-49888

Sentence

denotes

It also play a role in IFN-γ production and participates in the production of cytokines, in fact it is involved in the regulation of the production and action of cytokines.

T321

49889-50122

Sentence

denotes

It forms highly toxic hydroxyl radicals, involved in the killing of bacteria by neutrophils and it is a component of enzymes critical for the functioning of immune cells (e.g. ribonucleotide reductase involved in DNA synthesis) [95].

T322

50123-50249

Sentence

denotes

The iron-rich state promotes the M2-like macrophage phenotype and negatively regulates the M1 pro-inflammatory response [138].

T323

50250-50373

Sentence

denotes

This nutrient is necessary for the generation of ROS, that kill pathogens (by neutrophils) during the oxidative burst [85].

T324

50374-50471

Sentence

denotes

Finally, it appears to be essential for the differentiation and growth of epithelial tissue [95].

T325

50472-50611

Sentence

denotes

Iron at doses above the upper threshold has been associated with increased risk of malaria and other infections, including pneumonia [139].

T326

50612-50742

Sentence

denotes

Obviously it should be noted that treatment for anemia in a malarious area must be preceded by an effective anti-malarial therapy.

T327

50743-50866

Sentence

denotes

Notably, iron rich status promotes M2-like macrophage phenotype and negatively regulates M1 pro-inflammatory response [65].

T328

50867-50943

Sentence

denotes

On the other hand, iron overload causes impairment of immune function [140].

T329

50944-51096

Sentence

denotes

Iron excess increases the harmfulness of inflammation and the microorganisms themselves require iron as it can contribute to the growth of the pathogen.

T330

51097-51147

Sentence

denotes

RDA for iron reports a range of 8–18 mg/day [138].

T331

51149-51158

Sentence

denotes

Glutamine

T332

51159-51305

Sentence

denotes

The consumption of high biological value proteins is an essential component for a healthy diet and for the optimal production of antibodies [141].

T333

51306-51429

Sentence

denotes

Proteins, or amino acids, deficiency is known to impair immune function and increase susceptibility to infectious diseases.

T334

51430-51508

Sentence

denotes

In fact, some amino acids modulate both metabolism and immune functions [142].

T335

51509-51748

Sentence

denotes

Most reviews indicate an important role for amino acids in the immunity by regulating the activation of T lymphocytes, B lymphocytes, natural killer cells and macrophages; cellular redox state, gene expression and lymphocyte proliferation.

T336

51749-51941

Sentence

denotes

Evidence shows that the dietary integration of specific amino acids in humans with malnutrition and infectious diseases improves the immune status, thus reducing morbidity and mortality [141].

T337

51942-52135

Sentence

denotes

Glutamine is the most abundant and versatile amino acid present in the body and its level in the immune cells is similar to, or even greater than, glucose in both health and disease conditions.

T338

52136-52323

Sentence

denotes

The biological activities of this nutrient are also associated with the reduced cellular potential of oxygen, which mainly depends on the ratio between reduced/oxidized glutathione [143].

T339

52324-52511

Sentence

denotes

In addition, glutamine is an essential nutrient for lymphocyte proliferation and cytokine production, macrophage phagocytes plus secretory activities and bacterial killing of neutrophils.

T340

52512-52738

Sentence

denotes

In immune cells, glucose is mainly converted into lactate (glycolysis), while glutamine is converted into glutamate, aspartate and alanine undergoing a partial oxidation in carbon dioxide, in a process of glutaminolysis [142].

T341

52739-52824

Sentence

denotes

This unique conversion plays a crucial role in the effective functioning of immunity.

T342

52825-53163

Sentence

denotes

Glutamine is necessary for the expression of a variety of immune system genes [144], in particular through the activation of proteins, such as the ERK and JNK kinases which are involved in the activation of transcription factors, including JNK and AP-1, finally promoting the transcription of genes that participate in cell proliferation.

T343

53164-53353

Sentence

denotes

Besides, a sufficient level of glutamine is important to express the key markers of the cell surface of the lymphocytes and also various cytokines, for example, IL-6, IFN and TNF [143–145].

T344

53354-53680

Sentence

denotes

In healthy subjects with a balanced diet, glutamine supplementation does not increase the effectiveness of immune surveillance or prevent disease episodes, as reported by some reviews, but in some catabolic situations or in a low glutamine intake obtained from the diet, the amino acid supplementation could be required [142].

T345

53682-53690

Sentence

denotes

Arginine

T346

53691-53850

Sentence

denotes

The modulation of metabolism and immune functions, essential in the interaction and susceptibility to infectious diseases, is also regulated by arginine [146].

T347

53851-53980

Sentence

denotes

Arginine is a precursor for the synthesis of proteins, nitric oxide, urea, polyamines, proline, glutamate, creatine and agmatine.

T348

53981-54344

Sentence

denotes

The role and relationships between the pathways of arginine synthesis and catabolism are complex, due to the compartmentalized expression of various enzymes in different organs (e.g. liver, small intestine and kidney) and subcellular compartments (cytosol and mitochondria), as well as changes in gene expression in response to diet, hormones and cytokines [147].

T349

54345-54617

Sentence

denotes

As reported by several studies, arginine is the precursor of macrophages and it is now clear that arginine metabolism of immune cells is particularly involved in cancer, inflammation, infections, fibrotic diseases, pregnancy and the regulation of immune system [148, 149].

T350

54618-54734

Sentence

denotes

Macrophage arginine metabolism influences the outcome of immune responses in which innate immune cells are involved.

T351

54735-54895

Sentence

denotes

Arginine supplementation is reported to increase T lymphocyte response and Th cell numbers, suggesting a possible role in prolonged or repeated infection [150].

T352

54896-55155

Sentence

denotes

The importance of arginine metabolism as a new field of investigation includes that its depletion delays the growth of some types of tumours, while others report that its integration improves anticancer effects, probably by ameliorating immune function [150].

T353

55156-55300

Sentence

denotes

As discussed, vitamins E, C, D, zinc and selenium are important examples of nutrients that play a key role in supporting the immune system [65].

T354

55301-55342

Sentence

denotes

They can work individually or in synergy.

T355

55343-55464

Sentence

denotes

Furthermore, other dietary components are likely to play a role in modulating immunity, but have not yet been identified.

T356

55465-55541

Sentence

denotes

It is clear how nutritional deficiencies can compromise the immune response.

T357

55542-55718

Sentence

denotes

In addition, inflammation related to unhealthy eating habits has reached alarming proportions, particularly concerning chronic non-communicable diseases [100] (Tables 1 and 2).

T358

55719-55781

Sentence

denotes

Table 1 Dietary sources and immune function roles of nutrients

T359

55782-55833

Sentence

denotes

Nutrient Good dietary sources Immune function roles

T360

55834-56258

Sentence

denotes

Vitamin A Milk and cheese, eggs, liver, oily fish, fortified cereals, dark orange or green vegetables (e.g., carrots, sweet potatoes, pumpkin, squash, kale, spinach, broccoli), orange fruits (e.g., apricots, peaches, papaya, mango, cantaloupe melon), tomato juice Normal differentiation of epithelial tissue; retinoic acid ↑ T and B cells with gut-homing specificity and array T cells and IgA + cells into intestinal tissues

T361

56259-56424

Sentence

denotes

Supporting the gut barrier; carotenoids; ↑immunoregulatory actions including ↓ toxic effects of ROS and regulating membrane fluidity and gap-junctional communication

T362

56425-56526

Sentence

denotes

Regulates number and function of NK cells,↑ to phagocytic and oxidative burst activity of macrophages

T363

56527-56555

Sentence

denotes

Downregulates IFN production

T364

56556-56760

Sentence

denotes

Helps to regulate the production of IL-2 and the pro-inflammatory TNF-γ, ↑ microbial action of macrophages; involved in phagocytic and oxidative burst activity of macrophages activated during inflammation

T365

56761-56960

Sentence

denotes

Development and differentiation of Th1 and Th2 cells; ↑ TGF- β-dependent conversion of naïve T cells into regulatory T cells; plays a role in acquisition of mucosal-homing properties by T and B cells

T366

56961-57126

Sentence

denotes

Development and differentiation of Th 1 and Th2 cells; maintains normal antibody-mediated Th2 response by suppressing IL-12, TNF-α, and IFN-γ production of Th1 cells

T367

57127-57329

Sentence

denotes

Normal functioning of B cells, necessary for generation of antibody responses to antigen; required for B cell-mediated IgA antibody responses to bacterial polysaccharide antigens [62, 79–82, 85, 92, 95]

T368

57330-57638

Sentence

denotes

Vitamin C Oranges and orange juice, red and green peppers, strawberries, blackcurrants, kiwi, broccoli, brussels sprouts, potatoes ↑ collagen synthesis and protects cell membranes from damage caused by free radicals; ↑ keratinocyte differentiation; ↑ lipid synthesis; ↑ fibroblast proliferation and migration

T369

57639-57754

Sentence

denotes

Proliferation, function, and movement of neutrophils, monocytes and phagocytes; ↑ NK cell activities and chemotaxis

T370

57755-57809

Sentence

denotes

↑ Phagocytosis and ROS generation; ↑ microbial killing

T371

57810-57895

Sentence

denotes

↑ Apoptosis and clearance of spent neutrophils from sites of infection by macrophages

T372

57896-57949

Sentence

denotes

↓ Extracellular trap (NET) formation, ↓ tissue damage

T373

57950-58012

Sentence

denotes

↑ Antimicrobial effects; ↑ serum levels of complement proteins

T374

58013-58263

Sentence

denotes

Maintains redox homeostasis within cells and protects against ROS and RNS during oxidative burst; regenerates other important antioxidants, such as glutathione and vitamin E, to their active state; modulates cytokine production and ↓ histamine levels

T375

58264-58444

Sentence

denotes

Roles in production, differentiation, and proliferation of T cells, particularly cytotoxic T cells; ↑ proliferation of lymphocytes, ↑ generation of antibodies [79, 85, 92, 95, 120]

T376

58445-58889

Sentence

denotes

Vitamin D Oily fish, liver, eggs, fortified foods (spreads and some breakfast cereals) Regulates antimicrobial proteins (cathelicidin and β-defensin), modifying intestinal microbiota to a healthier composition and supporting the gut, as well as protecting the lungs against infection; ↑ tight junction protein expression, E-cadherin and connexion 43 in the gut; maintains renal epithelial barrier function; ↑ corneal epithelial barrier function

T377

58890-59064

Sentence

denotes

Vitamin D receptor found in, e.g., monocytes, macrophages, and DCs; ↑ differentiation of monocytes to macrophages; calcitriol ↑ movement and phagocytic ability of macrophages

T378

59065-59207

Sentence

denotes

Regulates antimicrobial protein expression (cathelicidin and defensin), which directly kill pathogens, especially bacteria; ↓ IFN-γ production

T379

59208-59415

Sentence

denotes

↑ The oxidative burst potential of macrophages; increases superoxide synthesis; reduces the expression of pro-inflammatory cytokines and increases the expression of anti-inflammatory cytokines by macrophages

T380

59416-59800

Sentence

denotes

Homing of T cells to the skin; ↓ T-cell proliferation; inhibitory effects mainly in adaptive immunity (e.g., Th1-cell activity); stimulatory effects in innate immunity; ↓ the effector functions of T helper cells and cytotoxic T cells; ↑ the production of Tregs; inhibitory effect on the differentiation and maturation of the antigen-presenting DCs, and helps program DCs for tolerance

T381

59801-59833

Sentence

denotes

↓ Antibody production by B cells

T382

59834-59940

Sentence

denotes

↑ Antigen processing; role in the down-regulation of MHC-II) [64, 71, 79–81, 85, 95, 99, 104–106, 151–153]

T383

59941-60120

Sentence

denotes

Vitamin E Many vegetable oils, nuts and seeds, wheat germ (e.g., in cereals) Protects cell membranes from damage caused by free radicals and ↑ the integrity of epithelial barriers

T384

60121-60228

Sentence

denotes

↑ NK cell cytotoxic activity; ↓ PGE2 production by macrophages (thus indirectly protecting T-cell function)

T385

60229-60456

Sentence

denotes

Important fat-soluble antioxidant that hinders the chain reaction induced by free radicals (chain-breaking effect) and protects cells against them; ↑ IL-2 production; ↓ production of PGE2 (indirectly protecting T-cell function)

T386

60457-60674

Sentence

denotes

↑ Lymphocyte proliferation and T-cell-mediated functions; ↑ Th1 response; ↓ Th2 response; helps to form effective immune synapses between Th cells; ↑ proportion of antigen-experienced memory [64, 79, 82, 95, 112, 113]

T387

60675-60888

Sentence

denotes

Zinc Shellfish, meat, cheese, some grains and seeds, cereals, seeded or whole grain breads Helps maintain integrity of skin and mucosal membrane (e.g., cofactor for metalloenzymesrequired for cell membrane repair)

T388

60889-61069

Sentence

denotes

↑ NK cell cytotoxic activity; central role in cellular growth and differentiation of immune cells that have a rapid differentiation and turnover; ↑ phagocytic capacity of monocytes

T389

61070-61127

Sentence

denotes

Involved in complement activity; role in IFN-γ production

T390

61128-61452

Sentence

denotes

Anti-inflammatory agent; helps to modulate cytokine release by dampening the development of pro-inflammatory Th17 and Th9 cells and influencing the generation of cytokines such as IL-2, IL-6, and TNF; has antioxidant effects that protect against ROS and reactive nitrogen species; influences activity of antioxidant proteins

T391

61453-61782

Sentence

denotes

↑ Proliferation of cytotoxic T cells; involved in Th1 cytokine production and thus supports Th1 response; essential for intracellular binding of tyrosine kinase to T cell receptors, required for T cell development, differentiation, and activation; ↑ development of Treg cells and is thus important in maintaining immune tolerance

T392

61783-61989

Sentence

denotes

Involved in antibody production, particularly IgG; involved in antibody response; important in maintaining immune tolerance (i.e., the ability to recognize “self” from “non-self”) [64, 82, 95, 116, 118–121]

T393

61990-62078

Sentence

denotes

Selenium Fish, shellfish, meat, eggs, some nuts especially brazil nuts ↑ IFN-γproduction

T394

62079-62181

Sentence

denotes

Selenoproteins important for antioxidant host defense system, affecting leukocyte and NK cell function

T395

62182-62341

Sentence

denotes

Essential for function of selenoproteins that act as redox regulators and cellular antioxidants, potentially counteracting ROS produced during oxidative stress

T396

62342-62395

Sentence

denotes

Roles in differentiation and proliferation of T cells

T397

62396-62461

Sentence

denotes

↑ Th cell counts and to maintain antibody levels [82, 85, 92, 95]

T398

62462-62684

Sentence

denotes

Iron Meat, liver, beans, nuts, dried fruit (e.g., apricots), wholegrains (e.g., brown rice), fortified cereals, most dark green leafy vegetables (spinach, kale) Essential for differentiation and growth of epithelial tissue

T399

62685-63040

Sentence

denotes

Forms highly-toxic hydroxyl radicals, thus involved in killing of bacteria by neutrophils; component of enzymes critical for functioning of immune cells (e.g., ribonucleotide reductase involved in DNA synthesis); involved in regulation of cytokine production and action; ↑ M2-like macrophage phenotype and negatively regulates M1 pro-inflammatory response

T400

63041-63065

Sentence

denotes

Role in IFN-γ production

T401

63066-63209

Sentence

denotes

Involved in regulation of cytokine production and action; required for generation of pathogen-killing ROS by neutrophils during oxidative burst

T402

63210-63351

Sentence

denotes

Important in differentiation and proliferation of T cells; helps to regulate ratio between T helper cells and cytotoxic T cells [85, 95, 138]

T403

63352-63570

Sentence

denotes

Long chain omega-3 fatty acids (EPA and DHA) Oilyfish Anti-inflammatory and antioxidant properties when enzymatically converted to specialized pro-resolving mediators (SPMs) known as resolvins, protectins, and maresins

T404

63571-63648

Sentence

denotes

↑ Immune system, by helping to resolve the inflammatory response [63, 66, 67]

T405

63649-63730

Sentence

denotes

Table 2 Nutrient’s supplementation suggested in support of respiratory infections

T406

63731-63814

Sentence

denotes

Nutrient Recommended supplementation suggested in support of respiratory infections

T407

63815-63849

Sentence

denotes

Omega 3 fatty acids 2–4 g/day [68]

T408

63850-63882

Sentence

denotes

Vitamin D 20,000–50,000 IU [154]

T409

63883-63909

Sentence

denotes

Vitamin E 135 mg/day [114]

T410

63910-63932

Sentence

denotes

Zinc 30–50 mg/day [98]

T411

63933-63961

Sentence

denotes

Selenium 25–100 μg/day [130]

T412

63962-64007

Sentence

denotes

Arginine and glutamine 25–35 g/day [142, 146]

T413

64008-64032

Sentence

denotes

Vitamin C 1–2 g/day [98]

T414

64033-64062

Sentence

denotes

Vitamin A 900–700 µg/day [91]

T415

64063-64085

Sentence

denotes

Iron 8–18 mg/day [138]

T416

64087-64141

Sentence

denotes

The role of gut microbiota in COVID-19 immunonutrition

T417

64142-64224

Sentence

denotes

The human intestine hosts a complex bacterial community called the gut microbiota.

T418

64225-64344

Sentence

denotes

The microbiota is specific to each individual despite the existence of several bacterial species shared by most adults.

T419

64345-64414

Sentence

denotes

Scientific studies reveal its influence on human health and diseases.

T420

64415-64619

Sentence

denotes

In particular they have shown that the intestinal microbiota can play a causal role in the development of obesity and associated metabolic disorders, leading to the identification of different mechanisms.

T421

64620-64852

Sentence

denotes

In humans, differences are observed in the composition of the microbiota, in the functional genes and in the metabolic activities between obese and lean individuals, that suggest a contribution of the microbiota to these phenotypes.

T422

64853-65067

Sentence

denotes

Finally, the evidence linking intestinal bacteria to host metabolism could allow the development of new therapeutic strategies based on the modulation of the intestinal microbiota to treat or prevent obesity [155].

T423

65068-65193

Sentence

denotes

Microbiota plays a crucial role in the maturation, development and functions of both innate and adaptive immune system [156].

T424

65194-65337

Sentence

denotes

The gut microbiota has been shown to affect lung health through a vital crosstalk between gut microbiota and lungs, called the “gut-lung axis”.

T425

65338-65566

Sentence

denotes

This axis communicates through a bi-directional pathway in which endotoxins, or microbial metabolites, may affect the lung through the blood and when inflammation occurs in the lung, this, in turn, can affect the gut microbiota.

T426

65567-65689

Sentence

denotes

The immunological health of the gut, primarily mediated by the microbiota, influences lung health via the “gut-lung axis”.

T427

65690-65863

Sentence

denotes

In addition, microbial communities inhabiting the mucosal surfaces of the respiratory tract also contribute towards host defense against viral respiratory infections (VRIs).

T428

65864-65994

Sentence

denotes

Acute VRIs are associated with microbial dysbiosis in these communities, thus acting the optimal functioning of the immune system.

T429

65995-66235

Sentence

denotes

Alterations in the microbiota during influenza virus infection contributes to the pathogenesis of secondary bacterial infections, thus increasing the severity of the clinical course in the absence of appropriate immune responses [157, 158].

T430

66236-66450

Sentence

denotes

It is also known that alterations of the immune functions associated with chronic inflammation and related metabolic dysfunctions lead to a compromise of innate and acquired immune functions in the host [159, 160].

T431

66451-66633

Sentence

denotes

Moreover, chronic inflammation and the use of antibiotics are known to accompany disorders in the gut microbiota, resulting in dysbiosis and aggravation of immune dysfunctions [161].

T432

66634-66916

Sentence

denotes

In addition, the prevalence of comorbid conditions (including chronic lung disease, diabetes, hypertension and cardiovascular diseases) and old age predispose to infection, the development of ARDS and pneumonia, factors already observed for other infections such as influenza [162].

T433

66917-67032

Sentence

denotes

This point raises an interesting possibility that the new SARS-Cov-2 may also have an impact on the gut microbiota.

T434

67033-67166

Sentence

denotes

Indeed, several studies have shown that respiratory infections are associated with a change in the composition of the gut microbiota.

T435

67167-67316

Sentence

denotes

Numerous experimental and clinical observations have suggested that the gut microbiota plays a key role in the pathogenesis of sepsis and ARDS [163].

T436

67317-67540

Sentence

denotes

Moreover, it is known that the signals derived from the intestinal microbiota tune the cells of the immune system for pro and anti-inflammatory responses which thus influence the susceptibility to various diseases (Fig. 2).

T437

67541-67646

Sentence

denotes

Fig. 2 Graphical representation of immune homeostasis disequilibrium during SARS-Coronavirus 2 infection.

T438

67647-67773

Sentence

denotes

ARDS: acute respiratory distress syndrome; T lymphocyte; IL: interleukin; Th: helper T lymphocyte; TNF: tumour necrosis factor

T439

67774-67867

Sentence

denotes

It is also known that respiratory virus infection causes perturbations in the gut microbiota.

T440

67868-67993

Sentence

denotes

Diet, environmental factors and genetics play an important role in shaping gut microbiota which can influence immunity [164].

T441

67994-68099

Sentence

denotes

There is growing evidence that supports the roles of the gut microbiota and diet to shape immunity [165].

T442

68100-68270

Sentence

denotes

Modulating the composition and metabolic capacity of the microbiome for specific dietary components is a promising strategy for influencing immune responses against VRIs.

T443

68271-68491

Sentence

denotes

Functional food components including probiotics, prebiotics and other bioactive ingredients of plant origin have been associated with immune benefits, mainly via microbiota modulation and impact on oxidative stress [65].

T444

68492-68718

Sentence

denotes

Several papers, regarding body composition, evaluated the correlation between fat mass and disease risk and then identified a new frontier of gut microbiota composition in the bodyweight decrease and anti-inflammatory effects.

T445

68719-69070

Sentence

denotes

As shown, the prevention of cardiometabolic diseases, considering the relationship with obesity, may be possible reducing the inflammatory state, acting on the gut-microbiota and on the intestinal permeability improving the health of the intestinal flora, with 4P medicine and treatment with probiotics, prebiotics, postbiotics, and polyphenols [166].

T446

69071-69255

Sentence

denotes

Prebiotic from fruits and vegetables is well-established to modulate the gut microbiota and numerous benefits have been reported in chronic inflammatory and metabolic conditions [167].

T447

69256-69434

Sentence

denotes

In fact, dietary fibers are a good source of accessible carbohydrates for microbiota then prebiotics have been studied in the context of modification of the human gut microbiota.

T448

69435-69606

Sentence

denotes

The compounds such as inulin, polydextrose, maize fiber have been shown to improve the immunity, gut diversity, digestion in humans and especially in elderly people [164].

T449

69607-69755

Sentence

denotes

Moreover, increased dietary fiber consumption is linked to reduced mortality rates in respiratory-related diseases and improved lung function [162].

T450

69756-69890

Sentence

denotes

Thus, plant-based diets, functional foods, and supplements present a promising strategy for protecting against respiratory infections.

T451

69891-70048

Sentence

denotes

Prebiotics lead the influence of microbiota composition and undergo microbial fermentation to produce SCFAs, such as butyrate, acetate, and propionate [168].

T452

70049-70308

Sentence

denotes

Overall, it is apparent that diet and personalized nutritional interventions acting in modulation of gut microbiota especially to control dysbiosis state and to some extent even lung microbiota can influence health status such as immunity conditions (Fig. 3).

T453

70309-70397

Sentence

denotes

Fig. 3 Graphical representation of personalized nutritional intervention during COVID-19

T454

70398-70624

Sentence

denotes

In addition, probiotics which are generally defined as “live microorganisms, which, when administered in adequate amounts, confer a health benefit on the host” have been shown to have profound effect on the health of the host.

T455

70625-70929

Sentence

denotes

In the intestine, the probiotics mainly refer to the genera Lactobacillus and Bifidobacterium and include many different strains such as L. johnsonii, L. fermentum, L. reuteri, L. paracasei, L. rhamnosus, L. acidophilus, L. plantarum, B. longum, B. breve, B. bifidum, and B. animalis subsp. lactis [169].

T456

70930-71016

Sentence

denotes

Fermented foods such as cultured milk products and yoghurt are enriched in probiotics.

T457

71017-71196

Sentence

denotes

They have shown good results in modulating inflammatory conditions as well as regulating innate immunity using toll-like receptors and the corresponding signalling pathways [170].

T458

71197-71393

Sentence

denotes

The capacity of probiotics to induce immunomodulation could be mediated either directly through interaction with immune cells or indirectly by supporting the challenged commensal microbiota [171].

T459

71394-71746

Sentence

denotes

Ingested probiotics with diet or through supplementation stimulate the immune system and initiate a complex of signals mediated by the whole bacteria, they then interact with intestinal epithelial cells also with immune cells associated with the lamina propria or other microbial PRRs and trigger the production of an array of cytokines and chemokines.

T460

71747-71881

Sentence

denotes

These molecules then interact with other immune cells through other pathways, leading to the activation of the mucosal immune systems.

T461

71882-72003

Sentence

denotes

As reported by many reviews specific probiotics have been demonstrated to enhance Th1 and regulatory Treg function [162].

T462

72004-72180

Sentence

denotes

It is clear that probiotics have an important role in the maintenance of immunologic equilibrium in the gastrointestinal tract through the direct interaction with immune cells.

T463

72181-72320

Sentence

denotes

Probiotic effectiveness can be species-, dose-, and disease-specific, and the duration of therapy depends on the clinical indication [170].

T464

72321-72566

Sentence

denotes

Additionally, phytochemicals including vitamins, micronutrients, and polyphenols present in fruits and vegetables have been shown a considerable importance in nutritional strategies for addressing the severity of viral respiratory diseases [65].

T465

72567-72686

Sentence

denotes

Some polyphenols influence microbiota composition and also have antioxidant, anti-inflammatory, and anti-viral effects.

T466

72687-72895

Sentence

denotes

The antiviral effect of polyphenols have been demonstrated to be mediated either by direct inhibitory effects on virus replication or through the induction of immunomodulatory and antioxidant responses [172].

T467

72896-73037

Sentence

denotes

In fact, oxidative stress has been implicated in lung tissue injury and epithelial barrier dysfunction in acute respiratory viral infections.

T468

73038-73168

Sentence

denotes

Dietary polyphenols are present in foods such as vegetables, fruits, cereals, tea, coffee, dark chocolate, cocoa powder, and wine.

T469

73169-73294

Sentence

denotes

The main groups of dietary polyphenols consist in phenolic acids, flavonoids, tannins, stilbenes and diferuloylmethane [173].

T470

73295-73469

Sentence

denotes

Many evidences revealed the excellent immunomodulatory effects of epigallocatechin-3-gallate (EGCG), abundant in green tea on both innate and adaptive immune responses [174].

T471

73470-73622

Sentence

denotes

Finally, in this context there is an important role explained by postbiotics (also known as metabiotic, biogenic, or metabolite cell-free supernatants).

T472

73623-73790

Sentence

denotes

Postbiotics are products or metabolic byproducts secreted by live bacteria or released after bacterial lysis and they provide physiological benefits to the host [175].

T473

73791-73977

Sentence

denotes

There are multiple types of postbiotics with varied structures, such as Short Chain Fatty Acids (SCFAs), peptides, enzymes, teichoic acids, exo- and endo-polysaccharides, vitamins [176].

T474

73978-74156

Sentence

denotes

A protective role of postbiotics like SCFAs has been found in the immune system modulation; particularly in regulation of neutrophil migration in acute inflammation in the colon.

T475

74157-74404

Sentence

denotes

The benefits of microbially-fermented SCFAs are suggested to be mediated through the direct actions of G-protein-coupled receptors (GPRs) expressed on the gut epithelium, adipose tissues and immune cells, including monocytes and neutrophils [177].

T476

74405-74534

Sentence

denotes

Gut-derived SCFAs have been shown to influence the functions of innate immune cells as well as impact acquired immune components.

T477

74535-74816

Sentence

denotes

Studying microbiota and therefore the human immune system and its dysregulation, or controlling the effects of postbiotics in the symbiotic status represents an important opportunity to develop new drugs, and combining probiotic supplements, with vaccines and immunotherapies [16].

T478

74818-74829

Sentence

denotes

Conclusions

T479

74830-74918

Sentence

denotes

Immunonutrition has been based on the concept that malnutrition impairs immune function.

T480

74919-75194

Sentence

denotes

Therefore, immunonutrition involves feeding enriched with various pharmaconutrients (Omega 3 Fatty Acids, Vitamin C, Arginine, Glutamine, Selenium, Zinc, Vitamin, E and Vitamin D) to modulate inflammatory responses, acquired immune response and to improve patients’ outcomes.

T481

75195-75388

Sentence

denotes

Finally, we can conclude that personalized immunonutrition for obese patients should be the first therapeutic choice to reduce the risk of infections and the disease course in COVID-19 patient.

T482

75389-75527

Sentence

denotes

In particular, the nutritional approach might be managed in two different strategies, considering the disease status of the obese patient.

T483

75528-75631

Sentence

denotes

First, immunonutrition can decrease the risk of infections, reducing characteristic inflammation state.

T484

75632-75763

Sentence

denotes

In addition, immunonutrition would be fundamental to support the immune response and protein synthesis in severe phase of COVID-19.

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