**3.5 Microbiota-derived metabolites**

Microbial metabolites are able to affect the metabolic functions of the host and play a key role in the pathophysiology of metabolic diseases. Bacteria of the gut microbiome produce a large number of enzymes that catalyze the depolymerization of complex carbohydrates as well as the degradation of indigestible components of chyme to SCFA (short-chain fatty acids), which are not only energy substrates but can also serve as messengers participating in the immune and systemic inflammatory response [64] and affecting intestinal motility and vascular tone. Many human and animal studies have shown a clear relationship between gut microflora, SCFAs, and obesity.

Bile acids are also one of the most important microbial products with bioactivity in stimulating the secretion of gut hormones, as intestinal bacteria are involved in the deconjugation of bile acids, which are endogenous ligands of the FXR (nuclear Farnezoid receptor), found in various tissues, such as liver, intestines, kidneys, adipose tissue, and immune cells. Bile acid signaling through FXR plays a role in maintaining lipid and glucose homeostasis. Studies have shown that FXR-deficient mice have impaired insulin signaling with impaired regulation of glucose homeostasis and elevated blood cholesterol and triglyceride levels [65]. Among the microbiotaderived metabolites, TMAO (trimethyl N-oxide) should also be mentioned, which is an important modulating factor in various diseases and significantly affects platelet hyperactivity, abnormal plasma lipid levels, obesity, and insulin resistance [66].

However, the main end product of the hydrolysis of indigestible carbohydrates is SCFA, that is, acetic (acetate), propionic (propionate), and butyric (butyric) acids, which are the most common and make up >95% of the total content of SCFAs and are produced in an approximate molar ratio of 60:20:20, reaching a combined concentration of more than 100 mM in the intestinal lumen [67], and act as the main energy supply for intestinal epithelial cells and, therefore, can increase the protection of the mucous barrier [68]. As the primary metabolic end product, gram-negative Bacteroidetes produce acetate and propionate, while the type Firmicutes produce mostly butyrate [69]. Several animal and human studies have found elevated concentrations of SCFAs in feces (particularly propionate) in obese individuals compared to normal-weight subjects [70] and, at the same time, recent data suggest that butyrate and propionate may promote healthy metabolism by activating IGN (intestinal gluconeogenesis) [71], which plays a dual role in maintaining energy homeostasis—regulating food intake and increasing insulin sensitivity. Propionate can directly initiate gut-brain communication by acting as an agonist of FFAR3 (free fatty acid receptor 3) to induce IGN with a positive effect on host physiology [65]. SCFAs are not only involved in energy metabolism but also perform a signaling function by activating GPRs (G-protein bound receptors) or FFAR2 (free fatty receptor 2). As reported, propionic acid is the most powerful activator of this receptor [53]. GPRs are expressed in most cells of the gastrointestinal tract, as well as in adipose tissue and immune cells. High-level expression of this receptor was found in the endocrine L-cells of the ileum and colon, which produce GLP-1 and PYY (peptide YY), and, in this way, SCFAs can modulate the secretion of incretins and regulate the onset of satiety and appetite, thus affecting the metabolic mechanisms of obesity [72].

### **3.6 The role of dietary intervention**

Accumulated data from numerous meta-analyzes shows that macronutrients, especially proteins, fats, and insoluble fiber, have a profound effect on the structure, function, and secretion of gut microbiota-derived metabolites that modulate multiple metabolic and inflammatory pathways. Genetic studies [73] have highlighted the importance of host genotype in determining the relative numbers of certain microbiome groups but found that Bacteroidetes can be influenced by host genetics, meaning that most environmental factors (including diet) determine their relative numbers by epigenetic influence.

Hyperphagia is common in obese individuals and refers to excessive calorie intake compared to the energy needed to maintain body weight, and it has been suggested that Bacteroidetes numbers are sensitive to this condition. Jumpertz et al. conducted an inpatient study of obese and normal body weight subjects, who were randomly assigned to a diet to maintain weight or to a hypercaloric diet (2400 and 3400 kcal/ day, respectively). In subjects with normal body weight, hypercaloric diet results in a decrease in the level of Bacteroidetes in fecal samples by 20% simultaneously with an increase in energy intake by approximately 150 kcal [74]. A similar observation was made in the Finnish monozygotic twin's study, where a hypercaloric diet was also associated with a decrease in the number of Bacteroides [75]. Interestingly, gastric bypass surgery results in an increase in Bacteroides that may be due to a reduction in caloric load rather than weight loss [76].

A diet high in refined and processed foods, red meat, and sugary drinks, combined with low fiber, fruit, and vegetable intake, correlates positively with the development of metabolic diseases, such as diabetes and obesity, both of which are associated with low-grade systemic inflammation and endotoxemia due to decreased commensal microbiota [77]. In obese people, a high-protein, low-carbohydrate diet combined with caloric restriction has been reported to result in increased quantities of branched-chain fatty acids, reduced butyrate, and reduced Roseburia/Eubacterium rectale [78]. On the other hand, a diet with a high percentage of fat and sucrose led to a decrease in the diversity of gut microbiota, metabolic dysfunction, and an increase in the number of opportunistic pathogens [79]. The study by de Wit et al. [80] showed that a diet high in fat (45% energy from fat) with palm oil resulted in reduced fat absorption and increased concentration of fat in the feces compared to a diet with the addition of olive or safflower oil. The increase in the concentration of fecal fat in the palm oil group was accompanied by a decrease in microbial diversity, an increase in the ratio of Firmicutes to Bacteroidetes, and an increase in the expression of lipidrelated genes in the mucosa that can be considered a sign of dysbiosis [80].

Preclinical studies showed that a high-fat diet can increase the proportion of gram-negative bacteria while reducing the number of gram-positive E. rectale/ Clostridium coccoides and Bifidobacterium [81]. There is evidence that the use of emulsifiers to improve the sensory properties of food has increased in the production of low-fat foods, in part due to innovations in specialized products for healthconscious consumers. It has been reported that emulsifiers can potentially increase virulence factors and thus the pro-inflammatory potential of the microbiota and contribute to low-grade inflammation, which may promote colon carcinogenesis [82]. According to epidemiological studies showing that high protein intake from plant sources and dairy products is associated with protection against obesity [83], rats fed dietary soya as a source of protein had a lower body weight than rats fed beef, pork, or turkey [84]. A recent review of human and animal studies examining the effects of

### *Personalized Strategy of Obesity Prevention and Management Based on the Analysis… DOI: http://dx.doi.org/10.5772/intechopen.105094*

soy feeding on the microbiome found that consumption of soy products increased the numbers of Bifidobacterium and Lactobacilli and altered the ratio between Firmicutes and Bacteroidetes [85]. A study of dietary interventions in obese and overweight individuals showed that a large number of gut microbiota taxa increased due to a high-fiber diet with a low content of animal fats that improved the clinical symptoms associated with obesity [86].

Similarly, in a recent randomized clinical trial, obese individuals that were randomly assigned to a Mediterranean diet for a 2-year period displayed an increase in the genera Bacteroides, Prevotella, and Faecalibacterium and the genera Roseburia, Ruminococcus as well as in Parabacteroides distasonis and Faecalibacterium, which are known for their saccharolytic activity and ability to metabolize carbohydrates to short-chain fatty acids [87]. In another study, adherence to a Mediterranean diet characterized by high consumption of vegetables, legumes, and fruits was associated with the enrichment of Bacteroidetes and increased levels of SCFAs in feces. In contrast, nonadherence to the Mediterranean diet was associated with an increase in Ruminococcus and Streptococcus, and higher concentrations of TMAO (trimethylamine N-oxide) [88]. Furthermore, a recent meta-analysis of 12 randomized controlled trials involving 609 overweight and obese adult participants showed that consumption of isolated soluble fiber resulted in a reduction in BMI, body weight by 2.52 kg, fat deposits by 0.41%, fasting glucose by 0.17 mmol/L, and fasting insulin by 15.88 pg./mL compared to placebo treatment [89]. Numerous clinical trials examining the effect of the Mediterranean diet pattern on metabolic syndrome as well as a meta-analysis of findings from eight studies of more than 10,000 participants and five studies have reported positive effects of the Mediterranean diet pattern [90]. Some of these benefits include decreased waist circumference (−0.42 cm), increased serum HDL cholesterol (1.17 mg/dL), decreased serum TGs (−6.14 mg/dL), decreased systolic (−2.35 mm Hg) and diastolic (−1.58 mm Hg) blood pressure, and decreased blood glucose (−3.89 mg/dL) in participants who were instructed to consume a Mediterranean diet pattern compared with those who were not given instructions to change their diet [91].
