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HUMAN GUT MICROBES AND ITS INFLUENCE ON METABOLISM
Jamshid Raxmatovich Nurov
Bukhara state medical institute, department of oncology and medical radiology
This review presents the current understanding of the intestinal microbiota and its effect on the metabolism of the body. The information about the structure of the intestinal barrier and functions of its cellular elements is given. The dependence of the structure of microbial community on nutrients entering the gastrointestinal tract is shown. The influence of microbial imbalance on the production of free fatty acids, amino acids and other biologically active compounds in the gut, and the delivery of them into the human body may influence the course of pathological processes. We discuss the possibility of nutrients and metabolites accumulated by intestinal microflora to modulate the permeability of the intestinal barrier, influence the formation of pro-inflammatory cytokines which are specific for local and systemic immune response.
Keywords: intestine, microbiome, metabolism
There are complex and diverse relationships between the gut microbiome and the host organism. It is known that the composition of the nutrients consumed affects the structure and availability of substrates of the microbial community. It has been proved that the metabolome of the human gut microbiome makes a significant contribution to the functioning of physiological mechanisms or, on the contrary, is one of the factors of the development of pathological processes in tissues and organs [1, 5].
Age differences in the composition of the intestinal microflora are largely determined by the quality and quantity of incoming nutrients. For example, the intestinal microbiomes of infants breastfed and artificially fed differ significantly [45]. Similarly, the gut microbiome of vegetarians differs from that of those who consume a European ("Western") diet [2, 3, 4].
Intestinal epithelial cells simultaneously absorb and excrete compounds necessary for maintaining homeostasis, and also act as a barrier to various pathogens and their toxins. Therefore, its anatomical and physiological integrity is extremely important, as well as the cooperation of cells and components of the intestinal mucosal barrier. Mucosa covers the intestinal wall along its entire length and consists of three layers, which, starting from the outer layer, are represented by: (I) the main membrane (lamina propria); (II) the mucosal muscle layer and (III) the epithelium covering the intestinal villi and crypts [5, 46]. Enterocytes, which are the main structural component of mucosa
ABSTRACT
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(more than 80% of all cells), include goblet cells, Paneta cells, absorbing and enteroendocrine cells. Goblet cells (from 16% to 50% of all cells) secrete mucins (mucus). Paneta cells synthesize and secrete lysozyme, cytokines, including tumor necrosis factor alpha (TNFa) and cryptidins into the intestinal lumen, which perform a protective function. Enteroendocrine cells and Paneta cells form and secrete gastrointestinal hormones and bicarbonates [15, 26, 44]. Tuft cells also express cyclooxygenases 1 and 2 (COX1 and COX2) [26].
The gastrointestinal tract is the site of localization of intestinal-associated lymphoid tissue (GALT) [27], organized into Peyer plaques scattered throughout the intestine and surrounded by specialized follicle-associated epithelium (FAE). FAE contains small-sized M-cells, specialized enterocytes, which are localized in the intestinal lumen and present antigen to dendritic cells, B- and T-lymphocytes in lamina propria and trigger an immune response [33, 47].
Enterocytes of the intestinal tract are able to be renewed every 4-5 days, which makes them one of the most proliferating tissues of the body [39]. The epithelium of the small intestine forms luberki- new crypts and villi, the structural features of which make it possible to have the maximum possible absorbent surface in contact with nutrients and electrolytes. Multipotent stem intestinal cells and progenitor cells are located in crypts, proliferate, and then migrate to the tops of the villi. Stem cells are surrounded by stromal or mesenchymal cells known as lamina propria, which regulate stem cell functions by secreting growth factors and cytokines [51]. During the transition from crypt to villi, progenitor cells differentiate into goblet-shaped, enteroendocrine or epithelial (enterocytes) cells. Panet cells remain in crypts after differentiation [13]. Enterocytes on the tops of the villi after differentiation on day 4-5 undergo spontaneous apoptosis and exfoliate into the intestinal lumen. The epithelium of the large intestine is devoid of villi and Paneta cells.
The microbiota is represented by intestinal lumen microflora, which includes from 500 to 1000 species of bacteria, among which there are 100-1000 times more anaerobes than aerobes [22]. The microbial community of the intestine includes approximately 1014 bacteria, i.e. the number of microbial bodies is many times greater than the number of cells in the human body. The collective genome of these microorganisms (microbiome) contains millions of genes (one bacterium contains about 2,000 genes) compared to about 20,000-25,000 genes of the human genome [18]. It is obvious that this huge, metabolite-producing community exerts a versatile influence on the biochemical and metabolic functions of the human body [41]. In response to qualitative changes in the diet, the ratio between the dominant groups of representatives of the
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Bacteroidetes microbiome (Bacteroides, Prevotella) and Firmicutes (Eubacterium, Bifidobacterium, Lactobacillus, Clostridium, Atopobium) differs [30, 50].
Among the important metabolic functions of the intestinal microbiome are catabolism of food toxins and carcinogens, synthesis of micronutrients, fermentation of undigested food substances and support for the absorption of electrolytes and trace elements. The production of short-chain fatty acids by the intestinal microbiome has a positive effect on the growth and differentiation of enterocytes and colonocytes. Differences in the metabolic activities of the intestinal microbiome can modulate the energy intensity of nutrients entering the intestine, lipogenesis in adipose tissue and the availability of substrates for the proliferation of microorganisms. Differences in the microbial composition of the intestine and the metabolic characteristics of individual representatives of the microbiome affect the predisposition to metabolic disorders, such as obesity and diabetes [34]. The destruction of the energy balance in the microbiome leads to a violation of lipid metabolism in the macroorganism. Transplantation of intestinal microbiota from obese donors contributes to the accumulation of adipose tissue in recipients [18].
The importance of the gut microbiome for the preservation of gastrointestinal and immune functions, as well as the breakdown and absorption of nutrients has been confirmed in studies on non-microbial animals [20, 28, 53]. Gnotobiont mice have elevated concentrations of phosphocholine and glycine in the liver, as well as bile acids in the intestine [16, 58]. The gut microbiome affects homeostasis in renal tissue by modulating the amount of betaine and choline [16]. Specific differences in bile acid patterns depending on the gut microbiome in rats are shown. The concentration of conjugated bile acids, which accumulate in the liver and myocardium, was increased in antimicrobial rats [52].
The intestinal microbiota prevents colonization of pathogenic species of organisms, contributes to the provision of intestinal cell substrates and affects the state of the mucosal immune system [31]. Excessive appearance of pathogenic species of microorganisms, "dysbiotic flora" causes a reaction from the immune system of mucosa, which can be realized in the form of a chronic inflammatory process in the intestine [32].
Bacterial translocation is a phenomenon in which living microorganisms or their products, or possibly both, cross the intestinal barrier and enter the bloodstream. This is favored by the presence of a huge number of bacteria (>1012/ ml of intestinal juice), 200 m2 of the intestinal surface and one layer of epithelial cells of the intestinal barrier separating the microbial population from the sterile environment of internal organs. From the blood, bacteria enter the mesenteric lymph nodes and then, using the liver or
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spleen as an intermediate organ, enter the systemic circulation [6, 7]. The permeability of the mucosal barrier increases with sepsis, trauma, burns, surgical interventions on large vessels and abdominal organs [35, 38].
In gastric mucosa, there is a chemical sensory system that recognizes the presence of amino acids, and among them glutamate, which stimulates the fibers of the vagus nerve [57]. Nutrients regulate the activity of afferent nerve fibers, which promotes the release of hormone-like peptides, including cholecystokinin, peptide YY, glucagon-like peptide-1, leptin, ghrelin and others [21]. The reaction to glutamate is blocked by a decrease in serotonin concentration and inhibition of type 3 serotonin receptors (5-HT3), as well as nitric oxide synthase. More than 90% of all serotonin in the body is found in enterochromaffin cells of the mucosa of the gastrointestinal tract. Serotonin of enterochromaffin cells provides a paracrine function that specifically reacts to glutamate in the lumen of the stomach, and which is similar to the well-known glucose recognition function in the duodenum. Data indicating possible intercellular communication of gastromucosis cells and vagus nerve using NO and serotonin as mediators were obtained [8].
The sensor of nutrients in the intestinal lumen may be an "intestinal sensory cell", the existence of which was assumed in 1980, but has not been proven to date. According to this hypothesis, nutrient-sensitive cells are located in the stomach or duodenal mucosa and, when interacting with nutrients in the intestinal lumen, release hormone-like compounds that transfer information about the content of nutrients to other organs, including the brain, by endocrine or paracrine means (endocrine or nervous regulation pathway).
Hofer et al. (1996) found cells in the intestine similar to cells containing taste receptors, and suggested that they perform a sensory function [29]. Subsequently, by methods of molecular biology, receptors for various amino acids were found in them. Thus, it has been shown that intra-duodenal infusion of lysine or leucine leads to excitation of the vagus nerve. On the contrary, intra-intestinal infusion of glycine, methionine and some other amino acids leads to depression of afferent nervous activity [42]. In rats, intragastric administration of protein hydrolysates also increases mesenteric afferent activity [8].
Mammals, using specific transporters in the proximal jejunum, absorb simple sugars, including galactose and glucose. Mammalian enzymes hydrolyze disaccharides (sucrose, lactose, mannose) and starch to monosaccharides, but have limited ability to break down other polysaccharides. As a consequence, non-cleaved plant polysaccharides (cellulose, xylan and pectin), as well as partially hydrolyzed starch (in the form of oligosaccharides) are utilized by the microbiota of the distal intestine.
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Microbes, unlike the human body, contain many genes encoding enzymes that utilize carbohydrates: glycoside hydrolases, esterases, glycosyltransferases and polysaccharidliases [12]. At the same time, intestinal bacteria differ in their ability to utilize both food and carbohydrates formed in the body (for example, mucin components) [49, 50]. Bacteriodetes easily assimilate carbohydrates from food, since they have a number of corresponding metabolic pathways. However, in situations of carbohydrate starvation, intestinal bacteria use mucins of the gastrointestinal tract as a source of carbohydrates, thus violating the mucin layer adjacent to epithelial cells. In addition to Bacteroides, Bifidobacterium contain genes encoding glycan-cleaving enzymes [56]. Intestinal microorganisms have developed the ability to break down a number of plant and glycoconjugates (glycans) and glycosaminoglycans formed in the host body, including cellulose, chondroitin sulfate, hyaluronic acid, mucins and heparin. Microbial endoglycosidases release a complex of N-glycans from breast milk and other dairy products [25]. Bifidobacteria growing on breast milk oligosaccharides stabilize intercellular contacts of epithelial cells and promote the secretion of anti-inflammatory cytokine, IL-10 [14]. The biogeography of the microbiome is also important, since specific mechanisms, such as the transport of carbohydrates by phosphotransferase systems, are more active in the small intestine than in the large intestine [60].
Intestinal bacteria, including probiotics, produce a variety of fatty acids that have a positive effect on the macroorganism. Intestinal bacteria generate short-chain fatty acids (acetate, butyrate, propionate) by fermentation of dietary fibers. The number of bifidobacteria in the intestine affects the spectrum of fatty acids in the liver and adipose tissue [43]. It has been shown that antimicrobial mice do not produce short-chain fatty acids, which negatively affects the energy metabolism of the macroorganism [40]. Acetate is the dominant short-chain fatty acid in humans and probably plays a significant role in modulating the activity of 5'-AMP-activated protein kinase and infiltration of adipose tissue by macrophages [11]. Propionate modulates energy homeostasis, promoting, in contrast to ketone bodies, the activation of sympathetic neurons [37]. Propionate can be used for de novo glucose synthesis or lipid synthesis, as well as as an energy source for macroorganism cells.
Short-chain fatty acids can function as signaling molecules, stimulating the secretion of regulatory peptides by mammalian cells and serve as an energy source for intestinal epithelial cells. In particular, they stimulate the secretion of glucagon-like peptide 1 (GLP-1) through the G-protein-coupled FFAR2 receptor (free fatty acid receptor) in the colon mucosa [54]. By stimulating the secretion of GLP-1, bacterial short-chain acids inhibit the release of glucagon, enhance glucose-stimulated release of insulin from pancreatic b cells, which favors glucose homeostasis. Short-chain fatty
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acids promote the secretion of peptide YY, a hormone-like compound secreted by the epithelial cells of the ileum and colon after eating and thus possibly suppress appetite [59]. A diet with a high fat content and the addition of butyrate prevents and reduces insulin resistance in obese mice. When fed a diet containing an insufficient amount of dietary fiber, the titer of butyrate-producing bacteria decreases and the amount of this fatty acid in the intestine decreases [24].
The administration of antibiotics changes the structure of the intestinal microbiome and its metabolic capabilities [11]. In mice, fat deposition and the level of incretin GIP-1 increases. Taxonomic changes occur in the microbiome, the titer of Lachnospiraceae and Firmicutes increases, the number of Bacteroidetes decreases. Dysbiosis affects the metabolism of carbohydrates into short-chain fatty acids (the level of acetate, propionate and butyrate increases) and the regulation of lipid and cholesterol metabolism in the liver changes [54].
The quality of food proteins is determined by both the content and bioavailability of amino acids. Bioavailability is the amount of free amino acids that is formed during protein breakdown and absorbed in a form suitable for intracellular protein synthesis [19, 22]. Therefore, the bioavailability of amino acids depends not only on the activity of proteolytic enzymes, but also on the subsequent absorption and potential utilization of intracellular amino acids.
Proteins and peptides of food are hydrolyzed to amino acids by lumen proteinases and peptidases. Meanwhile, more than 90% of fecal nitrogen is bacterial in nature. The amino acid composition of faeces is closer to that of microbial protein than to food proteins, and therefore it is believed that the excretion of amino acids does not depend much on the qualitative composition of dietary proteins. Food components reaching the large intestine are broken down by the microbiota, nitrogen-containing compounds are either absorbed or converted into microbial biomass with an amino acid profile more or less independent of its original composition [11].
Although nitrogen-containing compounds can be absorbed from the intestinal lumen by colonocytes, this is not observed with respect to free amino acids (with the possible exception of newborns) [23]. Most of the carbon skeletons of amino acids entering the large intestine are irreversibly lost either due to microbial metabolism or excretion with feces, although their nitrogen can be absorbed and used by the macroorganism.
The gut microbiota is capable of both splitting and synthesizing amino acids. Bifidobacteria and lactobacilli possess amino acid decarboxylases, which allows them to produce biogenic amines. Among the bioactive molecules synthesized by microbes are anti-inflammatory compounds that inhibit the action of TNFa. The signaling
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molecules include biogenic amine histamine, identified in the TNF-inhibiting fraction isolated from Lactobacillus reuteri breast milk and intestines [10]. Histamine is formed from histidine by histidine decarboxylase, present in some bacterial species, including probiotic lactobacilli. One of the components of the intestinal microbiome, L. reuteri, is able to convert L-histidine into histamine, which suppresses the production of TNFa through type 2 histamine receptors located on the membranes of the intestinal epithelium [55]. In addition, the products of microbial metabolism of amino acids are GABA and putrescine [36]. Identification of these bacterial bioactive metabolites indicates the immunomodulatory effect of microbiome metabolites. In particular, anti-inflammatory amino acid metabolites generated by bifidobacteria and lactobacilli can reduce the pathological manifestations of obesity and diabetes [9, 10, 17].
Thus, the composition of the intestinal microflora can influence the state of health. The nutrients and metabolites produced by the intestinal microbiota are able to modulate the permeability of the intestinal barrier, influence the formation of proinflammatory cytokines characteristic of the local and systemic immune response. Experimental and clinical studies indicate that the intestinal microflora participates in the development of obesity and diabetes mellitus, modulating energy metabolism and the sluggish inflammatory process characteristic of these conditions in insulin-dependent tissues
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