Immunonutrition and obesity
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]. It is characterized by a state of low-grade, chronic inflammation, in addition to altered levels of circulating nutrients and metabolic hormones. 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]. Underlining the importance of nutritional behaviour, it depends directly on food nutritional quality. Obesity is considered as a malnutritional status due to the poor quality of the diet. The chance to get healthy foods is largely determined by one’s own profitability. Nowadays, the most vulnerable communities fight disadvantage conditions because of socioeconomic, educational, and environmental disparities. People, who follow a poor quality of diet combined with economic disparity, are at major risk of obesity. The expansion of fat mass, in turn, is linked to various chronic diseases, including cardiovascular disease and diabetes. 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].
Adiposopathy, also known as “sick fat”, is at the basis of obesity condition. It is defined as pathological dysfunction of both anatomical and functional within adipose tissue. It is promoted by an excess of caloric energy intake and a sedentary lifestyle in genetically and environmentally susceptible individuals. This latter may cause or worsen metabolic disease in adverse endocrine and immune response. 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]. 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].
Adipose tissue is not only part of the endocrine system, but it is an active immune organ [40]. 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. On the contrary, during the expansion of adipose tissue like in obesity, inflammation results in adipocyte hypertrophy, cell death, fibrosis and metabolic dysfunction. The inflammatory process, involving both innate and adaptive immune cells, plays an important role in adipose immunometabolism. Among those, macrophages are fundamental for adipose tissue homeostasis and are most thoroughly studied in response to obesity [41].
As a result of the augmentation of the PBF in obesity, there is the proportional increment of adipose tissue macrophages. 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]. 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]. In the cytokine storm milieu in obesity and COVID-19, over 50 adipokines with diverse roles have been identified. Leptin, adiponectin, IL-6 and TNF-α mainly act in adipocyte metabolism, insulin sensitivity and metabolic disorders associated with obesity [44].
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. One of these is the regulatory role between energy metabolism and the immune system, being a pillar in the new concept of immunometabolism. Leptin receptor, expressed overall in the immune system, acts in both innate and adaptive immune system cells. As an adipokine, leptin is responsible for the inflammatory state found in overnutrition. Moreover, in undernutrition status, it plays as crucial mediator of the immunosuppressive state.
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]. In the light of above mentioned, leptin represents a connection between metabolism and the immune response. Its dysregulatory activity would have serious consequences during an eventual infection, such as COVID-19 [46].
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].
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].
The pivotal role of IL-6 in mediating the acute phase response seems to interest the strategical treatment in COVID-19 patients. 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].
TNF-α is a pyrogen cytokine released in the acute phase of inflammation by macrophages and immune cells. It is well known that during influenzae and viral infections, the expression of TNF-α in lung epithelial cells is higher. In patients with COVID-19 and obesity, the IL-6 and TNF-α high serum levels are negatively associated with T-cells. On the contrary, T cell levels are restored by reducing concentrations of both IL-6 and TNF-α. These findings suggested that these cytokines could represent important targets of anti-COVID-19 therapies [48].
Infectious diseases, like COVID-19, are characterized by an increased production of adiponectin. 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].
It seems interesting the possibility to improve the action of adiponectin through diet intervention. A healthy lifestyle and a Mediterranean diet seem to ameliorate adiponectin levels in human, working on omega-3 biochemical pathways [51]. Finally, in light of the above, a possible COVID-19 therapy would combine drug therapy with a personalized immunonutrition [48]. 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].
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].
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.
Moreover, obesity and adiposopathy contribute to the pathways related to appetite regulation, fat storage and alteration of intestinal microbiota. Dysbiosis of gut microbiota can influence the onset and progression of chronic degenerative diseases [56].
The impact of these metabolic abnormalities has undergone intense investigation over the past decade. 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].
There is strong evidence in literature indicating that abundant adiposity negatively impacts on immune system functionality and host defense in individuals with obesity [57].
In people with obesity, the caloric balance surplus is not directly proportional to the high nutritional food components quality [53].
Hence, the overfed malnourished patient may be compared to the underfed malnourishment, because malnutrition is considered the primary cause of immunodeficiency worldwide [58]. Chronic diseases, such as obesity, have been recognized as virulence factors for severe COVID-19. These morbidities are usually coupled to protein-energy malnutrition, which is demonstrated to impair immune cell activation. This process allows longer viral persistence and increased dealing of pro-inflammatory factors [59].
This will allow you to make a personalized emergency intervention, in all the subjects suffering from obesity.
In the onset of COVID-19 era, the nutritional approach might be managed in two different strategies, considering the disease status. 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. The organism fights both the acute inflammatory state triggered by COVID-19 and, in addition, the latent chronic inflammation due to the obesity condition. 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. In this context, immunomodulating diets (IMDs) have been demonstrated to improve immune system response and modulate inflammation cascade [60]. 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.
In the current pandemic panorama, the connection between nutrition science and virology takes a predictable turn. It is worth that nutritional innovation must correlate all the previously treated clinical aspects. 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. This is essentially possible pursuing a balanced diet based on the Mediterranean concept and staying physically active.