**5.3 Western diet and Mediterranean diet: examples of detrimental and beneficial dietary profiles**

The scientific literature describes the diet as the most characterized factor capable of shaping gut microbiota and immune system. Indeed, the nutritional status of an individual and the composition of the diet, in terms of foods, nutrients, and bioactive substances, influence immunity. A recent analysis by Rinninella and colleagues [58] highlighted the effects of different dietary habits on gut microbiota composition, by comparing vegetarian/vegan, gluten-free, ketogenic, low FODMAP (i.e., low in highly fermentable but poorly absorbable carbohydrates and polyols), Western and Mediterranean diets. Overall, restrictive diets (gluten-free, ketogenic, low FODMAP) have been shown to exert negative effects on the intestinal microbiota, in terms of reduction of biodiversity and alteration of eubiosis, impacting also on the integrity of the intestinal epithelium (especially in the case of ketogenic diet), and on inflammatory status. Among the different dietary profiles, the most consistent evidence concerns the Western Diet and the Mediterranean Diet, indeed Western Diet was shown to negatively impact gut microbiota composition and diversity, and to reduce the intestinal mucus layer, thus favoring bacterial translocation and endotoxemia, while Mediterranean Diet was associated to increased bacterial diversity and improved gut barrier function [58]. The Western Diet is typically described as a diet high in calories and rich in ultra-processed foods with high levels of sugars, saturated and trans fats, salt and food additives, while complex carbohydrates, fiber, vitamins and minerals, and other bioactive molecules (such as polyphenols and omega-3 fatty acids) are scarcely present. The main effects of this diet

concern the elevation of plasma glucose and insulin levels, with a consequent increase in the accumulation of lipids in adipose tissue, which induces a rapid weight gain compared to more balanced diets. Furthermore, recent rodent and human studies have established that the Western dietary pattern is associated with elevated levels of inflammatory biomarkers, suggesting a direct or indirect action on the immune system [59]. It is noteworthy that macronutrients in food are part of a complex microstructure from which the physical, sensorial and nutritional properties, and health implications derive. "The complex assembly of nutrients and non-nutrients interacting physically and chemically, that influences the release, mass transfer, accessibility, digestibility, and stability of many food compounds" has been described as food matrix [60]. Therefore, diverse food matrices can differently affect the digestion and absorption processes of food compounds and play a role in the microbial fermentation of unabsorbed components. Ultra-processed foods and beverages are considered an important hallmark of the Western Diet, and high consumption of these foods appears to be correlated with an increased risk of morbidity. Food processing involves applying controlled procedures in order to preserve, destroy, transform, and create edible structures, whose aim is to prolong the shelf -life of foods. Ultra-processed foods are microbiologically safe, highly palatable, ready-to-eat, and highly profitable products composed primarily of ingredients not routinely found in "real foods" (e.g., hydrogenated/de-esterified oils or additives designed to provide the previously mentioned characteristics). The poor and uncomplex matrix of these foods, together with their low fiber content, generates an unfavorable environment in the gut and microbiota, thus leading to dysbiosis and immune alterations. Therefore, the Western Diet, intended also as an incorrect lifestyle, would induce low-grade inflammatory processes, which are a risk factor for the development of various chronic inflammatory diseases, predisposing the individual to metabolic inflammation, through various mechanisms, acting at both levels of microbiota and intestinal permeability [61]. The action on the microbiota leads to the onset of dysbiosis, intended both as taxonomic (shifts in microbial groups composition), but especially as metabolic (changes in microbial function). Moreover, the decreased bacterial diversity makes the microbial ecosystem less resilient and more susceptible to external stressors. The increase in pathogenic bacteria also causes an increase in pro-inflammatory metabolites, which can influence the response at the level of GALT, with which they are intimately linked. When abnormalities occur in these interactions, intestinal permeability can increase and the leaky gut phenomenon occurs, leading to metabolic endotoxemia, as described previously. But metabolic inflammation arises primarily at the level of white adipose tissue, where adipocytes, cells almost entirely formed by a single large lipid droplet, release numerous adipokines, cytokine-like molecules, in response to changes in lipid accumulation and in local and systemic inflammation. Adipokines can be either pro- or anti-inflammatory and play a key role in linking metabolism with immune function [62]. In individuals with normal metabolic status, pro- and anti-inflammatory adipokines are correctly balanced, and Th2 lymphocytes, Treg cells, and macrophages with an anti-inflammatory phenotype predominate in adipose tissue. Treg cells secrete IL-10 and also stimulate IL-10 secretion by macrophages. Eosinophils secrete IL-4 and IL-13, further contributing to the anti-inflammatory and insulin-sensitive phenotype. A long-term hypercaloric diet causes an increase in the number and size of adipocytes, which become hypertrophic and dysfunctional, starting to secrete pro-inflammatory adipokines, especially TNF-α. In addition, circulating immune cells, mainly monocytes, are recruited from the bloodstream in

### *Immune System, Gut Microbiota and Diet: An Interesting and Emerging Trialogue DOI: http://dx.doi.org/10.5772/intechopen.104121*

response to chemotactic signals (particularly monocyte chemoattractant protein 1, MCP-1) produced in adipose tissue, transmigrate there, and differentiate into macrophages secreting high amounts of pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-6. These cytokines act in a paracrine manner, inducing changes in T lymphocyte populations, with a decrease in Treg and an increase in Th1 cells, which in turn secrete pro-inflammatory cytokines, thus generating a vicious circle, where the inflammatory state becomes systemic. Indeed, cytokines and chemokines from adipose tissue can act in an endocrine way and promote inflammation in other tissues, also causing the onset of insulin resistance and other metabolic disorders associated with obesity [63]. Adipocytes in visceral adipose tissue are metabolically very active and very sensitive to lipolysis, so following a prolonged positive caloric balance, very high amounts of free fatty acids (FFAs) are generated and released into the portal system. Insulin resistance results from an excess of circulating FFAs and excess TNF-α in adipose tissue, as both molecules result in functional blockade of the insulin receptor and its associated signal transduction. In particular, FFAs and TNF-α block insulin receptor signaling by activating phosphorylation of the insulin receptor substrate (IRS)-1 at a serine residue. Serine phosphorylation of IRS-1 causes it to detach from the insulin receptor, resulting in functional blockade of the receptor and of insulin signal transmission itself. In addition, TNF-α, secreted by adipocytes and adipose tissue macrophages, also acts by another mechanism, namely by inducing dephosphorylation of IRS-1 at tyrosine residues. Tyrosinedephosphorylation has the same effect as serine-phosphorylation, thus IRS-1 is inactivated and detached from the insulin receptor [64]. It is known that several components characterizing the Western Diet determine an inflammatory state through the activation of the innate immune response, for example, excess cholesterol is considered the main cause of inflammation in the atherosclerotic process. In addition, an excess of free cholesterol crystals causes damage to lysosomes, with subsequent release of the pro-inflammatory cytokines IL-1β and IL-18 through activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, resulting in a systemic response characterized by a chronic low-grade inflammatory state, associated to insulin resistance and the onset of some related diseases, including colorectal cancer [65]. Saturated fatty acids carried through excessive consumption of animal-derived foods also have cytotoxic effects and can activate endoplasmic reticulum stress as well as the NLRP3 inflammasome. More recent theories suggest that saturated fatty acids induce dysbiosis and subsequent release of metabolites that alter intestinal permeability, inducing metabolic endotoxemia [59]. From a taxonomic point of view, an excess of fat causes an increase in the Firmicutes/Bacteroidetes ratio, while some unrefined oils, such as palm oil, may cause a decrease in *A. muciniphila* and *Clostridium leptum*. Through the consumption of red meat, eggs, and high-fat dairy products, dietary introduced L-carnitine and phosphatidylcholine are converted to the pro-atherogenic metabolite TMAO through a two-stage process, including first a fermentation process by the intestinal microbiota in an anaerobic environment, and then an oxidation catalyzed by the hepatic enzyme Monooxygenase containing Flavin 3. TMAO is a metabolite involved in the activation of inflammatory macrophages and the formation of atherosclerotic plaque foam cells, thus contributing to increased cardiovascular risk [59]. Consumption of excessive amounts of red meat also leads to elevated amounts of iron-eme, which has been associated with alteration of certain bacterial groups including *Escherichia coli* and *B. fragilis*. In general, levels of bacterial genera capable of metabolizing plant polysaccharides such as *Roseburia*, *Eubacterium*, *Ruminococcus,* and *Prevotella* are

underrepresented in individuals on the Western Diet, whereas the relative abundance of bile-tolerant microorganisms increases [44]. The concept of Mediterranean Diet has been developed to describe the eating habits followed by the populations of the Mediterranean basin, mainly Greece and Southern Italy. The Mediterranean Diet is based on the consumption of fruits, vegetables, legumes, dried fruits, fish, olive oil, and whole grains which together provide a combination of complex carbohydrates, polyunsaturated fatty acids, and bioactive molecules such as polyphenols and other antioxidants. It is also characterized by a low consumption of proteins of animal origin. A large number of epidemiological studies have shown that the Mediterranean Diet is associated to increased life expectancy, improved quality of life, and lower prevalence of diseases related to chronic inflammation, such as coronary heart disease, type 2 diabetes, and some forms of cancer. These beneficial properties are mediated by different mechanisms, including lipid-lowering, antiinflammatory, and anti-oxidant effects. Accumulating evidence suggests that such activities are not ascribable to single foods or nutrients, but to interactions and synergistic activities of different nutrients and bioactive compounds from a variety of diverse foods with intact matrices [66]. Among the many molecules found in these foods, omega-3 polyunsaturated fatty acids, polyphenols, as well as fiber, can be mentioned. In particular, omega-3 contributes to balancing the Firmicutes/ Bacteroidetes ratio and to increase bifidobacteria and Lachnospiraceae [67], while some polyphenols, e.g., resveratrol or hydroxytyrosol, have been described as modulators of bacterial groups beneficial for human health [68]. Some nutritional intervention trials based on Mediterranean Diet have been proposed as a therapeutic approach to improve the composition of the microbiota and the state of the immune system, opening the perspective of a possible use of this dietary habit to modulate the microbiota, directing it towards a healthy profile. In fact, it has been demonstrated that adherence to the Mediterranean Diet correlates with a state of eubiosis, in which members of the phylum Bacteroidetes and beneficial bacteria belonging to the clostridia group increase, while Proteobacteria and Bacillaceae decrease. In addition, increased levels of lactic acid bacteria (mainly lactobacilli and bifidobacteria) have been observed, together with a more general increase in biodiversity and stability of the intestinal microbiota, suggesting a greater resilience to possible perturbations. A study focused on obese subjects also showed that an intervention with Mediterranean Diet increased the abundance of SCFA-producing gut bacteria *Roseburia* and *Oscillospira* [69]. In conclusion, the Mediterranean Diet, rich in foods of plant origin, provides polyphenols, high-quality fats (monounsaturated such as oleic acid and polyunsaturated with high content of omega 3), micronutrients, such as vitamins and trace elements, and dietary fiber that, carried by an adequate and complete dietary matrix, exert their beneficial properties in maintaining the eubiosis of the intestinal microbiota and its metabolites, together with the integrity of the intestinal barrier and immune tolerance. In contrast, the Western Diet and ultraprocessed foods, characterized by low levels of dietary fiber or micronutrients, have a plethora of nutritional components, including refined carbohydrates, poor quality fats (trans fatty acids and an excessive omega 6/omega 3 ratio due to refined oils), unhealthy salt and additives (mainly sweeteners), and finally excessive consumption of red and processed meats. In addition, they comprise a poor food matrix that causes detrimental effects on the intestinal barrier, leading to increased permeability, dysbiosis, and altered metabolite profiles, resulting in local inflammation, systemic endotoxemia, and chronic inflammation. **Figure 4** summarizes these observations.

*Immune System, Gut Microbiota and Diet: An Interesting and Emerging Trialogue DOI: http://dx.doi.org/10.5772/intechopen.104121*

**Figure 4.**

*Comparison of "Mediterranean" and "Western" dietary profiles. The main effects on gut integrity, immune status and microbiota composition are schematically represented.*
