The role of gut microbiota in COVID-19 immunonutrition
The human intestine hosts a complex bacterial community called the gut microbiota. The microbiota is specific to each individual despite the existence of several bacterial species shared by most adults. Scientific studies reveal its influence on human health and diseases. 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. 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. 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].
Microbiota plays a crucial role in the maturation, development and functions of both innate and adaptive immune system [156]. The gut microbiota has been shown to affect lung health through a vital crosstalk between gut microbiota and lungs, called the “gut-lung axis”. 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. The immunological health of the gut, primarily mediated by the microbiota, influences lung health via the “gut-lung axis”. In addition, microbial communities inhabiting the mucosal surfaces of the respiratory tract also contribute towards host defense against viral respiratory infections (VRIs). Acute VRIs are associated with microbial dysbiosis in these communities, thus acting the optimal functioning of the immune system. 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]. 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]. 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]. 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]. This point raises an interesting possibility that the new SARS-Cov-2 may also have an impact on the gut microbiota. Indeed, several studies have shown that respiratory infections are associated with a change in the composition of the gut microbiota. Numerous experimental and clinical observations have suggested that the gut microbiota plays a key role in the pathogenesis of sepsis and ARDS [163]. 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).
Fig. 2 Graphical representation of immune homeostasis disequilibrium during SARS-Coronavirus 2 infection. ARDS: acute respiratory distress syndrome; T lymphocyte; IL: interleukin; Th: helper T lymphocyte; TNF: tumour necrosis factor
It is also known that respiratory virus infection causes perturbations in the gut microbiota. Diet, environmental factors and genetics play an important role in shaping gut microbiota which can influence immunity [164]. There is growing evidence that supports the roles of the gut microbiota and diet to shape immunity [165]. Modulating the composition and metabolic capacity of the microbiome for specific dietary components is a promising strategy for influencing immune responses against VRIs. 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].
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. 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].
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]. 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. 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].
Moreover, increased dietary fiber consumption is linked to reduced mortality rates in respiratory-related diseases and improved lung function [162]. Thus, plant-based diets, functional foods, and supplements present a promising strategy for protecting against respiratory infections.
Prebiotics lead the influence of microbiota composition and undergo microbial fermentation to produce SCFAs, such as butyrate, acetate, and propionate [168]. 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).
Fig. 3 Graphical representation of personalized nutritional intervention during COVID-19
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. 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].
Fermented foods such as cultured milk products and yoghurt are enriched in probiotics. 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].
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]. 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. These molecules then interact with other immune cells through other pathways, leading to the activation of the mucosal immune systems. As reported by many reviews specific probiotics have been demonstrated to enhance Th1 and regulatory Treg function [162].
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. Probiotic effectiveness can be species-, dose-, and disease-specific, and the duration of therapy depends on the clinical indication [170].
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]. Some polyphenols influence microbiota composition and also have antioxidant, anti-inflammatory, and anti-viral effects. 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]. In fact, oxidative stress has been implicated in lung tissue injury and epithelial barrier dysfunction in acute respiratory viral infections.
Dietary polyphenols are present in foods such as vegetables, fruits, cereals, tea, coffee, dark chocolate, cocoa powder, and wine. The main groups of dietary polyphenols consist in phenolic acids, flavonoids, tannins, stilbenes and diferuloylmethane [173].
Many evidences revealed the excellent immunomodulatory effects of epigallocatechin-3-gallate (EGCG), abundant in green tea on both innate and adaptive immune responses [174].
Finally, in this context there is an important role explained by postbiotics (also known as metabiotic, biogenic, or metabolite cell-free supernatants). Postbiotics are products or metabolic byproducts secreted by live bacteria or released after bacterial lysis and they provide physiological benefits to the host [175]. 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].
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. 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]. Gut-derived SCFAs have been shown to influence the functions of innate immune cells as well as impact acquired immune components.
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].