Analysis of Changes in the Intestinal Microbiota of Patients with Infectious and Somatic Pathology Текст научной статьи по специальности «Фундаментальная медицина»

ANALYSIS OF CHANGES IN THE INTESTINAL MICROBIOTA OF PATIENTS WITH INFECTIOUS AND SOMATIC PATHOLOGY

I.V. Belova1*, A.G. Tochilina1, I.V. Soloveva1, S.B. Molodtsova1, D.B. Gelashvili2, V.S. Kropotov1

1 Academician I.N. Blokhina Nizhny Novgorod Scientific Research Institute of Epidemiology and Microbiology (Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing), 71 Malaya Yamskaya St., Nizhny Novgorod, 603950, Russia;

2 Lobachevsky State University of Nizhny Novgorod, 23 Prospekt Gagarina, Nizhny Novgorod, 603022, Russia.

* Corresponding author: [email protected]

Abstract. The paper presents an analysis of literature data on the characteristics of microbiocenoses across a wide range of infectious and somatic pathologies, as well as the results of our research on changes in the composition of the gastrointestinal tract microbiota in patients with various diseases. It is demonstrated that the microbiota responds consistently to any pathological changes occurring in the host organism, primarily manifested as a disruption in the balance between anaerobic (bifidobacteria, lactobacilli, bacteroids, clostridia, etc.) and aerobic components of the microbioce-nosis. The predominance or suppression of specific types of microorganisms is primarily influenced by the composition of the individual's indigenous microbiota, rather than the specific pathology associated with dysbiosis.

Keywords: microbiota, dysbiosis, disease markers.

List of Abbreviations

AEI - acute enteric infection BFP - bacterial food poisoning HAI - healthcare-associated infections CABSI - catheter-associated bloodstream infection

OPM - opportunistic pathogenic microorganisms

COVID-19 - coronavirus disease 2019 ACE2 - angiotensin-converting enzyme 2 SCFA - short-chain fatty acid RVI - rotavirus infection ART - antiretroviral therapy MAIT - mucosa-associated invariant T-cell MDR-TB - multidrug-resistant tuberculosis SIBO - small intestinal bacterial overgrowth syndrome

LPS - Lipopolysaccharide

IBD - inflammatory bowel disease

UC - ulcerative colitis

NUC - non-specific ulcerative colitis

CRC - colorectal cancer

BA - bile acid

AH - arterial hypertension

LDL - low-density lipoproteins

CHD - coronary heart disease

TMAO - trimethylamine-N-oxide

CKD - chronic kidney disease

CNS - central nervous system

GI tract - gastrointestinal tract

AD - Alzheimer's disease

ASD - autism spectrum disorders

Introduction

As scientists acquire new knowledge about the roles and functions of individual microorganism species in the macroorganism's vital activities through modern, advanced technologies and hightech research methods, the idea of detecting and utilizing the presence of specific species/genera/types of bacteria in a patient's microbiota as specific markers for certain diseases is increasingly highlighted in scientific publications. Numerous studies analyze changes in the microbiota state in various infectious and somatic diseases in humans (Alesh-kin et al., 2015). These studies compare the species composition of the microbiota between healthy individuals and patients, revealing "characteristic features": variations in the frequency of isolation of certain microorganisms, alterations in the number of representatives of specific species, the appearance or disappearance of certain taxa from the microbio-cenosis, et cetera. Furthermore, for several microorganisms that constitute the core of the microbiota and are traditionally used as criteria for assessing its condition, mechanisms of their involvement in the pathogenesis of various diseases have been established, reinforcing the concept of specific markers for individual pathologies. For instance, in acute infectious diseases (acute enteric infection (AEI), bacterial food poisoning (BFP), healthcare-associated infections (HAI), catheter associated bloodstream infection (CABSI)), at the onset of the infectious process, the state of the human microbiota corresponds to the individual's age, health status (in-

eluding the presence or absence of chronic somatic or infectious diseases, autoimmune and allergic conditions), and dietary habits. In AEI caused by pathogenic microorganisms, the direct causative agent of the disease is identified in the patient's large intestine microbiocenosis through bacteriological, virological, or molecular genetic methods. AEI, where the etiological factor is opportunistic pathogenic microorganisms (OPM) -representatives of the resident intestinal microbi-ota - occurs against the backdrop of general health. Clinical manifestations develop rapidly, with the OPM pathogen excreted in large quantities (more than 1x105 CFU/g), against the background of minimal shifts in the anaerobe/aerobe ratio. With etiotropic treatment (antibiotics, phages), rapid recovery is observed. A natural decline in the number and imbalance in the species composition of microorganisms during the disease course is noted in bacterial etiology diarrhea, where pathogenic or opportunistic flora becomes predominant, displacing normoflora representatives due to active reproduction and metabolism, as well as treatment with antibacterial drugs. A natural decrease in the number and imbalance of the species composition of microorganisms during the course of the disease occurs with diarrhea of bacterial etiology, when pathogenic or opportunistic flora becomes predominant. This predominance displaces representatives of the normal flora due to active reproduction and metabolism, as well as due to treatment with antibacterial drugs.

In foodborne toxic infections and viral processes, the cytotoxic effect on the intestinal epithelium prevails. The alteration of the microbiota composition occurs secondarily due to epithelial dysfunction, destruction of the mucin layer, increased motility, and, in viral diseases, the unjustified prescription of antibacterial drugs (Ruzhentsova et al., 2017). HAIs, including CABSIs, develop against the background of existing pathology, most often chronic, and are accompanied by dysbiosis in individuals with weakened immunity.

Dysbiotic disorders are characterized by an increase in the number of OPMs, a decrease in the number of beneficial organisms (e.g., Bifidobacterium spp., Akkermansia spp, or Faecalibacterium spp.), a reduction in species richness and diversity, and a disruption in the functional activity of the mi-crobiota. This disruption includes increased production of harmful metabolites such as hydrogen sulfide, and changes in the metabolic pathways of various substrates, resulting in the formation of uncharacteristic metabolites, etc.

In coronavirus disease 2019 (COVID-19), the virus compromises the integrity of the mucosal epithelium in both the respiratory and gastrointestinal tracts, initiating a cascade of immune responses that result in the production of numerous pro-inflammatory cytokines. The infection begins with the attachment of the SARS-CoV-2 virus to angiotensin-con-verting enzyme type 2 (ACE2) receptors on epithelial cells, followed by viral entry into target cells (Sanders et al., 2019). Since ACE2 receptors are distributed throughout the upper respiratory tract, upper esophagus, and the gastrointestinal epithelium from the stomach to the colon, SARS-CoV-2 infection can occur via both airborne and alimentary routes. Damage to the epithelial integrity by the virus triggers immune reactions that produce a large quantity of pro-inflammatory cytokines. This infection process is also marked by increased intestinal permeability, caused by structural disruptions in the tight junctions between intestinal epithelial cells. Consequently, pathogenic and opportunistic microorganisms can enter the bloodstream, leading to systemic infection and inflammation.

The normal intestinal microbiota, which maintains immune homeostasis, plays a crucial role in protecting the body from various infections, including COVID-19, by interacting with organs through the "gut-lung" axis. Additionally, endotoxins and microbial metabolites present in lung tissues due to the infectious process can influence the composition of the intestinal microbiota (Wu et al., 2020).

A study of the intestinal microbiocenosis in patients with COVID-19 revealed a distinct microbial structure characterized by low species diversity and high representation of opportunistic bacteria from the phyla Proteobacteria and Bacteroidetes. There was a notable reduction in beneficial microorganisms such as Bifidobacterium spp., Lactobacillus spp., and Eubacterium spp., alongside a dominance of bacteria from the genera Streptococcus, Rothia, Veillonella, Erysipelatoclostridium, and Actinomyces compared to the microbiota of healthy volunteers (Allali et al., 2021). Additionally, the presence of bacteria from the Lachnospiraceae family, including Fusicatenibacter spp., Anaerostipes spp., Agathobacter spp., and Anaerobutyricum hallii, as well as the relative abundance of Bifidobacterium and Collinsella, was significantly lower than in healthy individuals. Patients with severe COVID-19 exhibited higher levels of proinflammatory blood markers and lower levels of CD8+ T cells. The gut microbiome of these patients showed reduced levels of butyrate-producing bacteria such as Faecalibacterium spp. and Roseburia spp. Decreased butyrate

production exacerbated the inflammatory response in viral pneumonia and contributed to the development of more severe disease forms (Tang et al.,

2020). According to existing literature, a significant decrease in microbial diversity was also observed in other respiratory viral infections (Safina et al.,

2021). Functional analysis of the microbiota, based on short-chain fatty acid (SCFA) production (Zuo et al., 2021), confirmed an increase in opportunistic microorganisms, a decrease in resident microflora, and heightened biosynthetic activity in nucleotide, amino acid, and carbohydrate metabolism pathways.

Dysbiotic disorders of the intestinal microbioce-nosis in COVID-19 were observed even in the absence of pronounced gastrointestinal symptoms. These dysbiotic changes were persistent and prolonged, significantly impacting recovery during the long- and post-COVID periods (Topchiy et al.,

2022).

In rotavirus infection (RVI), the penetration of rotaviruses into epithelial cells causes damage to the cytoskeleton and subsequent rejection from the microvilli. This process accelerates the division and movement of epithelial cells from the base to the tip of the villus, resulting in the appearance of structurally and functionally immature epithelial cells. These immature cells contribute to the accumulation of undigested carbohydrates in the intestinal lumen (Mikhaelova & Levin, 2004). The unabsorbed substances with high osmotic activity lead to impaired reabsorption of water and electrolytes, resulting in watery diarrhea. In the large intestine, these substances are fermented by the intestinal microbi-ota, producing large amounts of organic acids, hydrogen gas, carbon dioxide, methane, and water. This fermentation decreases the pH of the intestinal contents and causes symptoms such as flatulence (Mazankova et al., 2003).

The disruption in acidity, osmolarity, changes in intestinal content composition, increased gas formation, and enhanced intestinal peristalsis lead to the development of dysbiosis in 84.7% of cases during the acute period of rotavirus infection (Lobzin, 2013). The imbalance of normal microflora disrupts local immunity, specifically the production of secretory immunoglobulin A (sIgA), which impacts the rate of pathogen elimination and the speed of symptom relief (Kornienko, 2006). Changes in the intestinal microbiota during the mono-form of rotavirus infection (with an acute onset and hospitalization within the first three days) develop by the 6-8th day of the disease. These changes are characterized by a slight decrease in the total number of normal E. coli

(up to 105 CFU/g) while maintaining sufficient levels of bifidobacteria and lactobacilli (109 CFU/g). Additionally, there is the appearance of atypical (lactose-negative and hemolytic) forms of E. coli and an increased presence of OMPs in significant quantities (up to 104-105 CFU/g). In the mixed form of RVI (virus + bacteria) with a gradual onset and later hospitalization, dysbiotic disorders are detected within the first three days of the disease in 87.8% of patients. Pronounced changes in the mi-crobiota are observed (grade II dysbiosis), including a decrease in the levels of bifidobacteria and lactobacilli (up to 107 CFU/g), total E. coli (up to 105 CFU/g), and an increase in atypical E. coli and OMPs to 106-108 CFU/g. With severe microbiota disorders (grade III dysbiosis), the number of obligate anaerobes decreases to 105 CFU/g, normal E. coli to 103-104 CFU/g, with the isolation of atypical forms of E. coli, and an increase in K. pneumoniae, P. vulgaris, S. aureus to 106-108 CFU/g. The most profound disturbances in the microbiota, a more severe course of rotavirus infection, and the occurrence of acute intestinal infections of mixed viral-bacterial nature are caused by OMP strains with the greatest adhesive activity and persistence ability (Zhelezova & Kvetnaya, 2021).

Evaluation of the biochemical activity of the mi-crobiocenosis representatives during the acute period of the disease in the observed patients indicates suppression of the metabolic activity of the normal microflora. This suppression is manifested by a decrease in the production levels of both individual volatile fatty acids and their total amount. This reduction is attributed to decreased anaerobic metabolism of monosaccharides, resulting from structural and functional disorders of the microbiocenosis and motor-evacuation disorders of the intestine. A decrease in the number of acetic acid producers (obligate anaerobes and E. coli) disrupts lipid metabolism regulation and increases the utilization of acetic acid as an energy substrate. Insufficient production of butyric acid results in impaired regulation of proliferation and differentiation of the intestinal epithelium. The deficiency in propionic acid synthesis (Veillonella spp., Propionibacterium spp., Bac-teroides spp., Fusobacterium spp.), which supports trophic processes in the mucous membrane and blocks pathogen adhesion, leads to disrupted microcirculation and local colonization resistance (Martynova et al., 2014).

In enterovirus infections caused by non-enveloped single-stranded RNA polioviruses (family Pi-cornaviridae) and noroviruses (family Caliciviri-dae), clinical manifestations can range from asymp-

tomatic infections to life-threatening diseases. These variations depend on the properties of the virus itself, the state of the microbiota at the time of viral invasion, and the overall condition of the host organism. Normal gut microbiota can suppress viral infection through various mechanisms (Berger & Mainou, 2018). However, commensal microorganisms can interact with invading viruses in various ways, potentially leading to harmful consequences for the host. Furthermore, viruses can cause significant disturbances in the microbiota, resulting in the development or worsening of intestinal dysbiosis in the host and ultimately leading to an increase in viral infectivity - the ability of the virus to survive in the host body while overcoming non-specific defense mechanisms (Huang, 2020).

An example of the pathological interaction between enteroviruses and microbiota is the increased stability of the virion and enhanced attachment to specific PVR receptors when polioviruses bind to lipopolysaccharides of gram-negative microorganisms. This interaction increases the viral load in the intestine and the host's susceptibility to poliovirus by facilitating recombination and replication of the viral genome, resulting in more diverse and resistant viral populations (Kuss et al., 2011). The ability of the intestinal microbiota to regulate the proliferation of host cells is crucial for the development of no-rovirus infection, as noroviruses target the relatively rare tuft cells of the lamina propria in the proximal small intestine (Manichanh et al., 2012). Additionally, representatives of the intestinal microbiota can suppress the production of inflammatory cytokines and/or the activation of immune cells aimed at eliminating viruses. This was demonstrated in a murine norovirus infection model, where the administration of antibiotics to mice prevented the persistence of noroviruses and promoted the expression of the antiviral cytokine IFN-X (Baldridge et al., 2015). The effect disappeared upon transplantation of microflora from intact mice.

The direct and indirect antiviral effects of micro-biota include enhancing the barrier function of the mucous membrane. Specifically, the microbiome induces the expression of genes encoding mucin 2, a primary component of the glycoprotein network of gastrointestinal mucus (Schroeder, 2019). The involvement of microbiota in maintaining normal mucosal permeability by regulating tight junction proteins, which control intercellular transport between epithelial cells, has also been well-documented. Dysbiotic changes in the microbiota can lead to increased permeability, observed in many diseases. Notably, Lacticaseibacillus casei and Bifidobacte-

rium adolescentis are involved in regulating this function, suggesting the potential for restoration through probiotics (Nagpal & Yadav, 2017; Bron et al., 2017). Symbiotic microorganisms that are part of the microbiota, such as Streptomycetes, Lactobacillus delbrueckii, Enterococcus faecium, Bacillus spp., and others, synthesize antimicrobial peptides and bacteriocins with antiviral activity. Some bacte-riocins prevent viruses from penetrating human cells by blocking coreceptors, while others reduce cytopathic effects and viral release, thereby inhibiting the late stages of the viral cycle. Lactobacilli and bifidobacteria can prevent viruses from attaching to host cells by altering receptor configurations and by capturing and binding viral particles. Additionally, normal microbiota microorganisms can modulate the antiviral innate and adaptive functions of leukocytes by stimulating dendritic cells to produce interferon-alpha (IFN-a), which activates the cytotoxic activity of natural killer cells and promotes the synthesis of antiviral immunoglobulins by B lymphocytes (Ashton et al., 2021).

In HIV infection, the gastrointestinal tract (GI tract) and liver are significantly affected, ranking third after the central nervous system and lungs among target organs involved in the pathological process at various stages of the disease. In 70% of patients, HIV infection manifests clinically as long-term diarrheal syndrome, leading to dehydration, exhaustion, and being one of the main causes of death in this pathology (Musaboev et al., 2011). HIV impacts various intestinal cells, causing degenerative changes in the crypts and partial atrophy of the microvilli, thereby disrupting parietal digestion and absorption. Concurrently, resident microorganisms directly contribute to the development and maintenance of pathological inflammation, which persists even during antiretroviral therapy (ART). HIV causes rapid and profound damage to CD4+ T cells in the lamina propria of the mucosa, affecting overall intestinal homeostasis. Structural damage to the mucosa during primary HIV-1 replication leads to a "leaky gut," facilitating the translocation of microorganisms from the intestine into the bloodstream, where they activate the immune system and contribute to the progression of HIV infection (Mudd & Brenchley, 2016). Besides the mor-phofunctional disruption of the intestinal wall, its resistance decreases, leading to dysbiosis and an infectious process prone to persistent progression and recurrence. Superimposed infections often play a more significant role than the immunodeficiency virus itself.

Disturbances in the intestinal microbiocenosis in HIV infection are detected in 94% of patients, man-

ifesting as a decrease in the quantitative content of obligate intestinal microflora, primarily anaerobes such as bifidobacteria. Alongside this quantitative imbalance, there is a significant alteration in the qualitative composition of the microbiota. Lactose-deficient and hemolytic E. coli appear (up to 20%), or lactose-negative Escherichia are detected in significant quantities (105 CFU/g). More than half of the patients exhibit excessive growth of opportunistic microbes, with S. aureus and Candida fungi being the most prominent (Khasanova et al., 2013). The stage of the disease is crucial when studying the microbiocenosis: atypical microbiota is observed in the early stages, and microbial translocation begins at the end of the acute phase, from 21-28 days to 200 days after infection (Dubourg, 2017). The underlying mechanism involves macrophages initially limiting the circulation of most microbial metabolites in the lamina propria of the gastrointestinal mucosa during the acute phase of HIV infection. However, towards the end of the acute phase, the number of regulatory Th17 cells in the mucosa decreases, leading to damage to the epithelial barrier. HIV-infected patients, compared to non-HIV individuals, also show a low level of intestinal CD13+ myelomono-cytic cells, including dendritic cells, macrophages, and granulocytes, disrupting the removal of micro-bial products from the intestine and allowing them to enter the bloodstream (Zakharova, 2018). The exacerbation of dysbiotic disorders and the increase in severe microbiota disturbances occur against a backdrop of increasing immunosuppression due to the failure of the immune system in HIV patients. Changes in the intestinal microbiocenosis are one of the factors contributing to increased intestinal wall permeability, microbial translocation, activation of inflammatory reactions, and the progression of HIV infection. Conversely, correcting the microbiota in HIV-infected patients with probiotics leads to a reduction in the severity of diarrheal and dyspeptic syndromes and stabilization of CD4 cell counts (Khasanova et al., 2013; Anukam et al., 2008).

When characterizing changes in microbioceno-ses in tuberculosis infection, it is essential to note that the human microbiota can influence the initial resistance of the host to various pathogens, including M. tuberculosis (Namasivayam et al., 2018). Certain microorganisms, such as Helicobacter he-paticus, when integrated into the gastrointestinal microbiota, trigger processes (development of dysbiosis with a predominance of Bacteroides spp. and a decrease in Firmicutes, followed by an increase in IL-10 levels) that ultimately lead to a disruption of the immune response, reduced vaccina-

tion efficacy against M. tuberculosis, and significant lung tissue destruction if infected with mycobacteria (Majlessi et al., 2017). In contrast, the presence of other species, such as Helicobacter pylori, reduces the risk of developing active tuberculosis compared to controls (Perry et al., 2010). Resistance to mycobacterial infection also depends on the mi-crobiota's ability to regulate the number and functional activity of bacterial-reactive innate T-cell subpopulations, particularly mucosa-associated invariant T-cells (MAITs). Stable activation of these cells during primary contact with M. tuberculosis prevents the development of tuberculosis (Na-masivayam et al., 2018). The composition of the mi-crobiota can influence the activity of current infections as well. For instance, a microbial community dominated by SCFA-producing bacteria (e.g., Prevotella spp.) and reduced production of IFN-y and IL-17A by lymphocytes is associated with the reactivation of latent tuberculosis, transitioning the infectious process to the active phase and disease progression (Segal et al., 2017).

Among the causes of dysbiosis in tuberculosis infection are the mycobacteria themselves, their toxins, and prolonged antibiotic therapy with antituberculosis drugs. Mycobacteria enter into competitive relationships with the indigenous microflora, disrupting key functions such as immunomodulation and the synthesis of proteins and vitamins. Mycobacterial toxins cause loss of appetite, nausea, vomiting, and digestive disorders. Antibacterial anti-tuberculosis therapy exacerbates dysbiosis, promoting allergization and toxic damage to hepatocytes, sharply reducing the liver's detoxifying properties. As a result, both during treatment (acute effects) and after cessation of therapy (long-term effects), patients experience persistent changes in the taxonomic composition and a reduction in microbi-ota representatives, which can last from one to eight years (in MDR-TB) after recovery (Wang et al., 2020).

Changes in the intestinal microbiota composition in tuberculosis infection are characterized by decreased species diversity and metabolic functions due to reductions in the number and amount of Bacteroides spp. (phylum Bacteroidota), a decrease in the number of representatives of the genus Lachno-spira (order Clostridiales, phylum Firmicutes=Ba-cillota) and the genus Prevotella, increased number of species from the phyla Actinomycetota, Pseudo-monadota, and Bacillota (Lachnospiraceae (An-aerostipes spp., Blautia spp.) u Erysipelotricha-ceae). These changes correlate with the activation of proinflammatory immune mechanisms associ-

ated with tuberculosis severity (Naidoo et al., 2021). In children with pulmonary tuberculosis, there is an increased number of proinflammatory bacteria Prevotella spp., opportunistic Enterococcus spp., and a decreased number of Bifidobacteriaceae, Ru-minococcaceae, Bacteroidaceae, Faecalibacterium ruminococcaceae, and Faecalibacterium prausnitzii (order Clostridiales, phylum Bacillota). The addition of co-infections in tuberculosis shifts the microbiota balance towards decreased species diversity and increased opportunistic microflora, exacerbating the disease. Dysbiotic disorders from long-term anti-tuberculosis therapy are marked by reductions in immunologically important bacterial species, including representatives of the Rumino-coccaceae and Lachnospiraceae families (SCFA producers, regulators of IL-1 and IFN-y expression, which are fundamental for the regulation of homeo-stasis and intestinal barrier function), Bacteroides spp. (polysaccharide producers that regulate regulatory T-lymphocyte activity for mucosal tolerance), Lactobacillus spp. (modulating innate and adaptive immunity by binding to receptors involved in the recognition of bacterial and viral pathogens), Bifidobacterium spp. (inducing a decrease in the activity of Th17 cells), and Prevotella spp. (involved in the Th17-mediated inflammatory response). Markers of persistent dysbiosis include decreased species representation of phylum Bacillota (Clos-tridiales, Ruminococcus, Faecalibacterium) and increased numbers of Actinomycetota and Pseudo-monadota (Escherichia spp., Salmonella spp., Yersinia spp., Helicobacter spp.) (Li et al., 2019).

In gastrointestinal tract diseases, the pathological process often extends to adjacent sections, leading to combined lesions. For instance, gastric ulcers and duodenal ulcers frequently co-occur with esophagitis, gastritis, and gastroduodenitis. Typically, the upper digestive tract biotopes are sparsely populated by microbiota, a condition maintained by the acidic pH of the stomach, the secretory activity of the pancreas and liver, small intestine motility, and the structural integrity of the GI tract. However, pathological conditions that disrupt these protective mechanisms can result in small intestinal bacterial overgrowth syndrome (SIBO) (Plotnikova et al., 2013), characterized by an increase in bacterial populations and a shift in species composition towards Enterobacterales, Enterococcus spp., and Bac-teroides spp. The excessive growth of bacteria involved in bile acid deconjugation leads to the formation of unconjugated or insoluble compounds, reducing fat absorption and causing diarrhea. Additionally, deconjugated bile acids are toxic and can

damage enterocytes, impairing the absorption of fats, carbohydrates, and proteins. The excessive growth of bacteria that metabolize carbohydrates to form SCFAs and gas is clinically accompanied by flatulence without diarrhea (Plotnikova & Zakha-rova, 2015).

In the stomach, dysbiosis manifests as an increase in the total number of microorganisms and the appearance of of species atypical for a particular biotope with pronounced pathogenic properties, such as hemolytic, lecithinase, catalase, and urease activity. In peptic ulcer disease, the affected mucosa contains not only streptococci, staphylococci, lacto-bacilli, H. pylori, but also various types of pepto-cocci, pseudomonads, corynebacteria, representatives of Enterobacterales, and other opportunistic microorganisms in quantities one to two orders of magnitude higher than normal levels (Chervinets et al., 2022a).

The pancreas, anatomically connected to the GI tract through a system of ducts, is associated with the intestinal microbiota (Thomas & Jobin, 2020). Pancreatic dysfunction, leading to enzyme deficiencies, contributes to the development of SIBO (Pietzner et al., 2021). In acute pancreatitis, the massive release of inflammatory cytokines and hypovolemia impairs microcirculation, resulting in mucosal ischemia, decreased intestinal barrier function, and translocation of intestinal bacteria and their toxins into the bloodstream. This exacerbates local and systemic inflammation. Lipopolysaccha-ride (LPS) from gram-negative bacteria stimulates the inflammatory cascade, activates toll-like receptors, and modulates the TGF-pi pathway, promoting increased collagen production and pancreatic fibrosis. These conditions lead to a decrease in some Bacillota and Actinomycetota representatives (including bifidobacteria) and an increase in entero-cocci, individual representatives of the phyla Pseu-domonadota, Enterobacterales, and Bacteroidota (Schepis et al., 2021).

In inflammatory bowel diseases (IBDs), including ulcerative colitis (UC), non-specific ulcera-tive colitis (NUC), and Crohn's disease, defects in the immune system and disruption of the mucosal barrier function are influenced by heredity (Fiocchi, 2012), environmental factors, diet, lifestyle, including bad habits (smoking, drugs, etc.), and microbiota disturbances (Cosnes et al., 2011). Increased permeability of the mucosal barrier to microorganisms, toxins, and other antigens leads to persistent intestinal inflammation, which exacerbates existing barrier dysfunctions, thus perpetuating a "vicious circle" (Macdonald, 2011).

A crucial factor in the development of IBD, leading to homeostasis dysregulation, is the increase in the number of opportunistic bacteria combined with a decrease in anaerobic representatives of the indigenous microflora (Sartor, 2003), a general reduction in microbial and functional diversity, and a decrease in bacteria with anti-inflammatory properties or an increase in those with pro-inflammatory properties (Corridoni et al., 2012). Several studies have indicated that IBD is associated with an increased presence of phylum Pseudomonadota, adhesive-invasive E. coli (AIEC), Campylobacter concisus, Clos-tridium difficile, Bacteroides fragilis, Bacteroides vulgatus, Klebsiella pneumoniae, Fusobacterium varium, Ruminococcus gnavus, and Mycobacterium avium paratuberculosis (MAP) (Ahmed et al., 2016). Concurrently, there is an elevated content of glucose, glycerophosphorylcholine, arginine, and lysine in the intestinal mucosa (Balasubramanian et al. , 2009); alanine, glycerol, isoleucine, leucine, lysine, valine, and glutamate in feces; and formate, glycine, glycolate, guanidoacetate, methylhistidine, and citrate in urine (Williams et al., 2009). Furthermore, studies have described a decrease in the number of Bacillota phylum representatives, including butyrate-producing bacteria like Roseburia hominis and Faecalibacterium, as well as the anti-inflammatory Faecalibacterium prausnitzii, and Bifidobacterium adolescentis (Ahmed et al., 2016). This is associated with reduced synthesis of SCFAs (Shiomi et al., 2011) and amino acids (Odze, 2015) in the colon mucosa: alanine, choline, formate, gluta-mine/glutamate, isoleucine, leucine, valine, lactate, myoinositol, and succinate (Balasubramanian et al., 2009); in feces: acetate, butyrate, methylamine, tri-methylamine; and in urine: 4-cresol sulfate, citrate, hippurate, trimethyllysine (Williams et al., 2009). These alterations in metabolite composition in the intestine lead to further disruption of the functional interaction within the microbial-tissue complex and the maintenance of chronic inflammation.

The severity of dysbiotic disorders significantly influences the course of IBD. Dysbiosis characterized by elevated levels of Pseudomonadota and Streptococcus spp., as well as dysanaerobiosis with a predominance of gammaproteobacterial - marked by an imbalance between obligate and facultative anaerobes and a significant increase in bacteria with reduced diversity - is associated with severe UC. In patients with mild forms of UC, the imbalance between the aerobic and anaerobic components of the microbiota is less pronounced, and the fecal micro-biota contains higher levels of Ruminococcus spp. and Akkermansia spp. (Sitkin et al., 2018). Dysbio-

sis marked by the appearance or increased levels of enterotoxigenic strains of Bacteroides fragilis, adherent-invasive E. coli (AIEC), or Fusobacterium nucleatum may indicate an elevated risk of colorectal cancer (CRC) in patients with IBD (Yang & Jobin, 2017). The presence of dysbiosis with increased levels of Ruminococcus gnavus (Bacillota, Clostridia) and Enterococcus spp., and decreased levels of Blautia spp. (butyrate-producing bacteria) and Dorea spp. (Bacillota, Clostridia), promotes the development of Clostridium difficile infection even in the absence of antibiotic triggers (Sitkin et al., 2018). Conversely, the absence of dysbiotic changes - such as a decrease in the levels of Fae-calibacterium prausnitzii or Roseburia inulinivo-rans, and reduced diversity of fecal microbiota -can serve as a non-invasive biomarker for a successful response to therapy in patients with IBD (Ahmed et al., 2016). Additionally, literature indicates that the use of "beneficial bacteria" (probiotics) improves the condition of patients with IBD (Cor-ridoni et al., 2012).

In autoimmune and allergic diseases (such as food allergies, eczema, and atopic dermatitis), disturbances in the qualitative and quantitative composition of the microbiota influence the formation of the immune response. According to the "hygienic concept" of allergy development formulated in 1989, excessive hygiene reduces the diversity of antigens encountered by the body, leading to an imbalance between Th1 and Th2 immunity in children, resulting in an improper immune response and subsequent allergies (Mazurina et al., 2020). Further studies have shown that the allergic immune response cannot be fully explained by the imbalance of Th1 and Th2 helper differentiation, leading to the "old friends" or "microbiota" hypothesis. This hypothesis posits that the key antigens for "tuning" the immune system are aerobic and anaerobic representatives of the normal mi-crobiocenosis, with which humans have coexisted for a long time. Children with an aerobic-anaerobic imbalance towards the suppression of the anaerobic microbiota, particularly lactobacilli and bifidobacteria, are more prone to food allergies. Increased levels of E. coli are closely associated with a high risk of developing eczema, and C. difficile is linked to the risk of developing eczema and atopic dermatitis. Observations also indicate a relationship between the rise in allergic, autoimmune, and inflammatory diseases and the increase in obesity in developed countries. It is noted that obesity exacerbates the course of allergic pathologies.

The so-called "Western lifestyle" characterized by the consumption of more meat, fast carbohydrates, and sugar, which leads to the depletion of the species composition of the microbiota, is identified as a contributing factor to both allergic diseases and obesity. Reduced microbial contact at an early age and insufficient stimulation of the child's immune system in the intestinal mucosa contribute to the disruption of normal protective immunity formation and the development of an allergic phenotype. This disruption in oral tolerance and the onset of chronic inflammation can lead to various allergic reactions, including food allergies and food intolerance associated with irritable bowel syndrome. Early-age intestinal dysbiosis increases the risk of developing asthma later in life.

The link between allergopathology and obesity is explained by the role of the intestinal microbiocenosis in maintaining body weight control and energy metabolism, in addition to its interaction with the immune system. Changes in the composition of the microbiota affect two primary causes of obesity: energy consumption and storage, and the development of insulin resistance, which leads to chronic inflammation characteristic of obesity (Musso et al., 2010).

Infants at high risk for atopy or asthma exhibit deficiencies in commensal bacterial taxa, such as Faecalibacterium spp., Akkermansia spp., and Lachnospira spp. (Nikonov & Popova, 2019). Supplementation with SCFAs and Lactobacillus john-sonii culture improves conditions by reducing T-cell activity, decreasing the number of IL-4-produc-ing T-cells, and lowering the level of circulating immunoglobulin E. Current data suggest that these improvements are associated with metabolites of lac-tobacilli, particularly ©-3 fatty acids like do-cosahexaenoic acid. This indicates that early manipulation of the gut microbial community could be a novel strategy for preventing allergic sensitization and excessive weight gain.

In oncological diseases, the state of the microbiota is of significant importance. On one hand, it has been proven that microorganisms can provoke on-cogenesis through the production of toxic, carcinogenic metabolites and immunosuppressive actions. On the other hand, the microbiota can stimulate antitumor immunity through selective activation of T cells (Morkunas et al., 2020). Dysbiotic changes in the microbiota are a negative factor in the development of oncological diseases. OPMs can initiate on-cogenesis in three distinct ways: damaging DNA and inducing mutagenesis, producing oncogenic signals, and causing disturbances in the immune response system.

Some OPM metabolites, such as E. coli colibac-tin, Bacteroides fragilis toxins, and superoxide and hydrogen peroxide produced by Enterococcus fae-calis, are capable of destroying or damaging DNA molecules (Lee, 2021). Helicobacter pylori cyto-toxin, Fusobacterium nucleatum adhesin A, and Bacteroides fragilis toxin Bft, by affecting various components of the Wnt/p-catenin signaling pathway that controls cell proliferation, differentiation, migration, and apoptosis, activate the production of P-catenin. In cancer, this promotes the proliferation and survival of tumor cells, enhances their migratory and invasive abilities, and leads to tumor metastasis (Liu & Zhang, 2022). Microbiota-induced immune response system disorders in cancer are primarily associated with a large number of microbial metabolites (SCFAs, bile acids, tryptophan, inosine, niacin, B vitamins, etc.) involved in regulating immune system responses. Literature data indicate that 50% of metabolites in human plasma are of micro-bial origin. Microbial metabolites play a role in stimulating the growth of immune cells, influencing the production of y-interferon (IFN-y), and affecting local dendritic cells, which in turn activate the transformation of naive (not exposed to the antigen) T cells into regulatory lymphocytes (T-reg) or T-helper cells (Th) producing various interleukins, such as IL-10, which regulates local anti-inflammatory cytokines, and IL-17, which promotes increased Paneth cell-mediated production of antimicrobial peptides (Gopalakrishnan et al., 2018). As a result of microbiota imbalance, barrier function is disrupted, and inflammation is activated through exposure to bacterial endotoxins. Changes in metabolite levels, both decreases and increases, lead to dysregulation of the immune response, particularly hyperactivation of the immune system via proin-flammatory cytokines (e.g., interleukin 6 (IL-6)) (Bhatt et al., 2017).

The anticancer effect of microbiota is based on the production of tumor-suppressive metabolites, such as butyrate, which act through multiple immune reactions, maintenance of barrier function, direct effects on immune cells to prevent inflammation (induction of regulatory T cells, or production of immunosuppressive cytokines like IL-10 to weaken the response of immune cells), and antagonistic activity against pathogenic bacteria. Representatives of normobiota, such as Lactobacillus johnsonii and Enterococcus hirae, are capable of potentiating the antitumor effect by regulating the immune response (Bhatt et al., 2017).

The effect of intestinal microbiota on the immune system can be both local and systemic, due to

the activation of immune signals or the induction of differentiation of immune system cells. The composition of the gut microbiota can influence the response to certain immunotherapeutic agents used in oncology, such as immune checkpoint inhibitors. Studies have shown that anti-CTLA activity is associated with Bacteroides spp., while the anti-PD-Ll effect depends on Bifidobacterium spp. (Longhi et al., 2020). To date, 11 strains of microorganisms representing the gut microbiota (Parabacteroides spp., Alistipes senegalensis, Bacteroides spp., Eu-bacterium limosum, bacteria of the Ruminococca-ceae family, Phascolarctobacterium faecium, and Fusobacterium ulcerans) have been described that have the ability to affect immune checkpoint inhibitors by inducing IFN-y + CD8 + T cells (Khan et al., 2020). Conversely, immunotherapy can also alter the composition of the gut microbiota. Anti-CTLA-4 treatment can cause a decrease in Bacteroi-dales and Burkholderiales and an increase in Clos-tridiales, while Bacteroides fragilis remains relatively unchanged (Roy, 2017). Similarly, in a study using anti-PD-1 in melanoma, the abundance of different members of the gut microbiota changed after the end of therapy, with responders showing an increase in Clostridiales/Ruminococcaceae and non-responders showing an increase in Bacteroidales (Gopalakrishnan et al., 2018). Other immunotherapies, such as allogeneic stem cell transplantation (allo-HSCT), also result in changes in the abundance of Enterococci, Streptococci, and Proteobac-teria (Nguyen et al., 2021). It has been hypothesized that the same metabolic end products of different microbial communities may shape the immune response in patients receiving checkpoint inhibitor therapy by affecting T-cell homeostasis or through other, as yet undiscovered mechanisms. Metabolic products may also be both a potential therapeutic target for modulating the immune response and a bi-omarker for identifying patients with solid tumors (Nomura et al., 2020).

In addition to immunotherapy, the species composition of the microbiota of cancer patients is also affected by nutrition, antibacterial drugs, chemotherapy, and radiation therapy. Chemotherapy causes a significant imbalance in the qualitative and quantitative composition of the microbiota and, as a consequence, a change in its functional activity, leading to a disruption of the barrier function, activation of inflammatory processes, and an increased susceptibility of patients to pathogens (Deleemans et al., 2019).

A decrease in the integrity of the intestinal epithelium as a result of radiation therapy leads to the

translocation of microbiota to the mesenteric lymph nodes, where the amount of microbial LPS increases. The development of mucositis, ulcerative-necrotic lesions of the mucous membranes, complicates radiation therapy, jeopardizing antitumor treatment and the patient's prognosis. There is also evidence suggesting that the intestinal microbiota may influence the therapeutic effects of radiation therapy. A preclinical study demonstrated that the presence of intestinal microbiota is responsible for increased radiosensitivity of the intestinal endothe-lium (Grigorievskaya et al., 2023).

Dysbiotic disturbances in the composition of the intestinal microbiota, provoked by the administration of antibacterial drugs, decrease the activity and effectiveness of antitumor therapy and increase its toxicity (Iida, 2013). The use of antibiotics in cancer treatment is currently under discussion. On one hand, there are cancers associated with specific types of microorganisms (e.g., colorectal cancer and Fusobacterium nucleatum found in tumor tissues and metastatic lesions); it has been shown that the elimination of these bacteria with antibiotics reduced cancer cell proliferation and overall tumor growth (Bullman et al., 2017). Other studies have demonstrated that continuous oral administration of broad-spectrum antibiotics leading to general mi-crobiota depletion reduced tumor growth in models of pancreatic cancer, colon cancer, and melanoma and increased the antitumor activity of radiotherapy (Uribe-Herranz et al., 2020). On the other hand, several studies have proven that microbiota depletion and dysbiosis caused by antibacterial therapy increase tumor growth and progression (Laborda-Il-lanes et al., 2020).

Restoration of beneficial representatives of the microbiota leads to the restoration of its functional activity, for example, the production of short-chain fatty acids, most of which (except acetate) have anti-inflammatory and antitumor effects. Additionally, the consumption of fiber-rich food (a prebiotic factor) enhances the effect of immunotherapy, making diet an integral component of cancer therapy (Li et al., 2021).

In metabolic disorders, which involve disruptions in normal metabolic processes, the intestinal microbiota plays a significant role. The relationship between metabolic pathology and the state of the intestinal microbiota is exemplified by metabolic syndrome, a pathological condition characterized by at least two of the following metabolic, hormonal, and clinical disorders: insulin resistance with reduced carbohydrate tolerance and hyperinsulinemia; dyslipoproteinemia with hypertriglyceridemia and

reduced levels of high-density lipoprotein cholesterol; a tendency to thrombosis with elevated levels of plasminogen activator inhibitor in the blood plasma; arterial hypertension due to increased sympathetic nervous system activity; and generalized obesity with increased secretion of free fatty acids into the portal vein (Grinevich & Radchenko, 2020). Factors contributing to the development of metabolic syndrome include hereditary predisposition to insulin resistance and obesity, combined with low physical activity and overnutrition (Shilov et al., 2003).

In a healthy individual, the rise in glucose levels 20-30 minutes after carbohydrate intake initiates its metabolism, resulting in the formation of mannose, which promotes insulin release from pancreatic P-cells. Insulin facilitates the conversion of glucose into glycogen in the liver and muscles, normalizing blood glucose levels by the 60th minute. When glucose levels drop below normal, glucagon is released to hydrolyze glycogen into glucose and restore blood glucose levels (Shilov et al., 2003). In obese patients, although elevated glucose levels trigger mannose synthesis and insulin release, altered receptors in liver cells and muscle tissue prevent insulin interaction. Consequently, glucose is not converted into glycogen but is metabolized into fatty acids, leading to fat synthesis and deposition. Excess fat is predominantly formed due to excessive carbohydrate intake, accounting for 90% of cases (Aleshin, 2003).

The intestinal microbiota modulates energy balance in the human body by fermenting indigestible dietary fiber and fructooligosaccharides into SCFAs and other metabolites that can be absorbed by the host organism. For instance, colonocytes derive up to 60-70% of their cellular energy from oxidizing SCFA. It is estimated that microbiota-derived SCFA production provides about 10% of the daily caloric requirement in humans. Additionally, propi-onate serves as the main substrate for gluconeogen-esis, while acetate and butyrate are primarily involved in the synthesis of fatty acids and cholesterol (Den Besten et al., 2015).

By acting as signaling molecules via the free fatty acid receptors FFAR2 and FFAR3 (stimulating the secretion of glucagon-like peptide and intestinal gluconeogenesis) and directly enhancing the production of the satiety-promoting anorexigenic pep-tide and leptin hormone, as well as by stimulating GABA and, consequently, hypothalamic neurotransmission, SCFAs contribute to increased tissue sensitivity to insulin and a decrease in appetite (Forbes et al., 2015). In addition, SCFAs (acetate,

propionate, and butyrate) are capable of activating the expression of thermogenic genes, which leads to increased mitochondrial function and the stimulation of oxidative metabolism in the liver. This process ultimately results in a significant increase in energy expenditure and a decrease in fat mass and body weight, despite minor changes in nutrient intake or a high-fat diet (Den Besten et al., 2015).

The involvement of the microbiota in the development of obesity is evidenced by studies showing that germ-free mice, despite a high-carbohydrate diet, did not develop obesity, and undigested polysaccharides were excreted in greater quantities in feces and urine compared to normal animals. Colonization of these animals with a healthy microbiome led to an increase in SCFA excretion and the development of obesity. Conversely, transplantation of the microbiota from an obese donor resulted in a two-fold increase in fat mass. Genetic studies of the microbiota in obese individuals have revealed a greater number of carbohydrate metabolism genes compared to the microbiome of lean individuals (Turnbaugh et al., 2009). Additionally, a metabo-lomic study of feces in obese individuals indicated higher levels of SCFA than in lean individuals, suggesting a higher level of carbohydrate fermentation (Fernandes et al., 2014).

Lipid metabolism, cholesterol balance, and insulin sensitivity also depend on bile acid (BA) metabolism, which involves the intestinal microbiota. BAs have both direct and indirect antimicrobial effects on the intestinal microbiocenosis through the farnesoid receptor FXR, inducing the formation of antimicrobial peptides. This contributes to an increase in the number of microorganisms in the microbiota that can metabolize BAs, such as Clostridia spp., Blautia spp., Erysipelotrichia spp., etc. (Ridlon et al., 2014). Bacterial enzymes deconju-gate bile acids by hydrolyzing the peptide bond between the bile acid core and the amino acid residue of the conjugate, enhancing their lipophilic properties, facilitating their absorption in the intestine, and regulating the enterohepatic circulation of the bile acid pool. Components of microbial cells, such as endotoxin, muramyl dipeptides, zymosan, and other microbial-derived compounds, can increase cholesterol synthesis in the liver, particularly in patients with hypercholesterolemia. An increase in the number and activity of bile-resistant Alistipes spp., Bi-lophila spp. (sulfate-reducing microorganisms), and Bacteroides spp. in the intestine, which deconjugate bound BAs, combined with a decrease in the number of microorganisms that metabolize food plant polysaccharides, such as Roseburia spp., Eubacte-

rium rectale, and Ruminococcus bromii, associated with a diet predominantly consisting of animal food, contributes to the development of various diseases including non-alcoholic fatty liver disease, cholestatic diseases, and inflammatory bowel diseases (Tkachenko et al., 2016).

One of the hallmarks of obesity and metabolic syndrome is a systemic inflammatory response, evidenced by a wide range of inflammatory markers, including C-reactive protein and proinflammatory cytokines (Choi et al., 2013). Normal intestinal microbiota is known to prevent colonization and invasion by exogenous microorganisms that can harm the host macroorganism. Additionally, it stabilizes the mucous membrane by stimulating the regular turnover of mucin glycoproteins, promotes the production of endocannabinoids that reduce inflammation, and maintains the barrier function of the mucous membrane by regulating intracellular tight junction proteins (Everard et al., 2013). In metabolic syndrome, obese individuals are 20% more likely, and type 2 diabetics are 125% more likely than lean individuals to have dysbiosis-induced metabolic endotoxemia, characterized by elevated plasma levels of LPS, which is a component of the cell wall of gram-negative microbes. LPS circulating in the blood can bind to toll-like receptors in both the mucosa and peripheral tissues, triggering a cascade of proinflammatory cytokine synthesis by adipocytes and macrophages in adipose tissue (Clemente-Postigo et al., 2018). A decrease in the number of butyrate-producing bacteria, excess endotoxin, and the development of systemic inflammatory response syndrome lead to a series of intercellular interactions and biochemical transformations, stimulating an increase in endothelial dysfunction, dyslipidemia, hyperinsulinism, and ather-ogenesis, which serve as the basis for the progression of metabolic disorders and the development of systemic arterial hypertension (AH) (Razavi et al., 2019).

In general, the intestinal microbiota in metabolic syndrome is characterized by decreased microbial diversity, reduced numbers of lactobacilli, families Oscillospiraceae (Bacillota), Christensenellacea (Bacillota), Rikenellaceae (Bacteroidota), the genus Bifidobacterium, and Akkermansia muciniphila. Some studies mention the predominance of certain species from Bacillota or Bacteroidota in the microbiota (Drapkina & Shirobokikh, 2018).

Several studies have shown that a low-carbohydrate diet rich in dietary fiber and the use of probi-otics contribute to the normalization of microbiota and overall health: adding probiotics to the diet for

several weeks leads to a significant decrease in blood levels of low-density lipoproteins (LDLs), fibrinogen, IL-6, and markers of lipid oxidative stress (Croci et al., 2021).

In heart diseases, in addition to the well-known clinical and pathobiochemical factors associated with metabolic syndrome, social, behavioral and environmental factors, several additional factors indirectly contribute to the emergence and development of cardiovascular pathology, including viral and bacterial infections, redox imbalance, and intestinal dysbiosis.

When intestinal microbiocenosis is disturbed, there is typically a decrease in the representation of the main (obligate) flora and an increase in the number of opportunistic microorganisms, leading to changes in the metabolic potential of the intestinal microbiota. This disruption in homeostasis results in increased peroxidation and metabolic disturbances in the human body. Under these conditions, intestinal dysbiosis mediates the formation and progression of negative changes in lipid metabolism, acting as one of the triggers of cholesterol aggression.

Additionally, pathogens of various infections are considered potential etiological factors in the development of atherosclerosis of the coronary arteries and other localizations. It has been established that in some cases, pathogens are not eliminated from the body after an illness but persist in tissues for extended periods, manifesting only under adverse conditions such as stress, unhealthy lifestyle, or concomitant pathology. In patients with atherosclerosis, compared to healthy individuals, persistent streptococci, staphylococci, chlamydia, Helicobacter, herpes viruses, respiratory syncytial virus, cytomegal-ovirus, and others are more frequently detected. These pathogens are capable of causing oxidation of lipoproteins, which is a key factor in the development of atherogenesis, and indirectly stimulating the formation of plaques in the walls of blood vessels (Statinova et al., 2013).

One of the factors damaging the vascular endo-thelium is endotoxin - LPS of gram-negative microorganisms - released during their death, growth, and reproduction. Endotoxin is a complex consisting of lipopolysaccharide, protein molecules, and phos-pholipids, with the greatest amount found in the intestine. Although the macroorganism has several barrier and neutralizing protection systems against the pathological effects of LPS, during endotoxe-mia, changes in the vascular wall under the influence of LPS develop rapidly, ultimately leading to desquamation of endothelial cells. Elevated endo-toxin levels in the blood are also a trigger mecha-

nism for the formation of atherosclerotic plaque (Konev, 2012).

Disturbance of intestinal microflora occurs in 90% of patients with cardiovascular (coronary heart disease (CHD)) and metabolic (obesity, dyslipopro-teinemia) diseases. Patients with arterial hypertension have a microbiota depleted in qualitative composition with a quantitative predominance of bacteria of the Prevotella spp. phylotype, but a decrease in Bacteroidetes, Bifidobacterium spp., Roseburia spp. , and other producers of SCFA (Chervinets et al., 2022b). Excessive activation of atherogenic li-pids and an increase in vascular tone, coupled with deterioration of peripheral blood flow, lead to pathological changes in the gastrointestinal mucosa, thereby exacerbating disturbances in the composition of the microbiota. Consequently, the correction of intestinal dysbiosis is an important component in the treatment of patients with chronic heart failure. This intervention ensures colonization resistance of the mucous membrane and improves its reparative processes, leading to a decrease in the amount of bacterial endotoxin entering the internal environment of the body from the intestinal lumen (Arutyunov, 2005).

Among the factors contributing to the development of kidney diseases, which serve as the primary filters in the human body and perform various vital functions, such as toxin removal, blood pressure regulation, and control of the chemical composition of the blood, are systematic hypothermia, poisoning and intoxication, angiopathies of various origins, certain somatic diseases, and previous infections.

The relationship between the human intestinal microbiota and the development of kidney diseases is currently well-studied. Representatives of the intestinal microbiota are involved in the digestion of food through saccharolytic and proteolytic pathways. The saccharolytic pathway catabolizes carbohydrates, forming SCFAs. The proteolytic pathway is responsible for the catabolism of proteins, during which SCFAs and various amines, phenols, and indoles are formed and subsequently excreted from the body through the kidneys (Nallu et al., 2017). When kidney function is impaired, nitrogenous metabolic products accumulate in the GI tract, exerting a selective effect on the microbiota. This leads to an increase in microorganisms with urease, uricase, and indole- and p-cresol-forming enzymes. As a result of the metabolism of nitrogenous substrates in the intestine, uremic toxins such as indoxyl sulfate, p-cresyl sulfate, indole-3-acetic acid, and trimethyl-amine-N-oxide (TMAO) are formed and accumu-

late (Sorokina et al., 2023). Microbial, endogenous, and exogenous uremic toxins from food and ammonia released during the hydrolysis of urea have a detrimental effect on the microbial community, leading to the development of dysbiotic disorders. This initiates the standard response of the microbi-ota to environmental damage: disruption of colonization resistance, increased intestinal wall permeability, translocation of opportunistic microorganisms, and the onset of pro-inflammatory immune reactions, ultimately aggravating both the underlying disease and dysbiosis (Lukichev et al., 2018).

In the microbiota of patients with terminal chronic kidney disease (CKD), dysbiotic disorders are characterized by a decrease in the number of representatives of the families Lactobacillaceae, Bifidobacteriaceae, and Prevotellaceae; butyrate-producing bacteria such as Roseburia, Faecalibac-terium, and Coprococcus; and an increase by two orders of magnitude in the number of species from the phyla Enterobacterales and Enterococcus. There is also an increased content of bacteria from the families Lachnospiraceae, Bacteroidaceae, and some representatives of the family Ruminococca-ceae (Sampaio-Maia et al., 2016). Additionally, in patients with CKD, among the dominant species, there is a large number of producers of urease (Al-teromonadaceae, Clostridiaceae, Cellulomona-daceae, Dermabacteraceae, Halomonadaceae, En-terobacteriaceae, Methylococcaceae, Moraxel-laceae, Micrococcaceae, Polyangiaceae, Xan-thomonadaceae, and Pseudomonadaceae); uricase (Cellulomonadaceae, Micrococcaceae, Dermabac-teraceae, Xanthomonadaceae, and Polyangiaceae); and indole- and p-cresyl-forming enzymes (i.e., those possessing tryptophanase: Clostridiaceae, Verrucomicrobiaceae, and Enterobacteriaceae) (Wong, 2014).

Patients receiving hemodialysis treatment exhibit higher levels of inflammatory biomarkers, including Interleukin-6 and MCP-1, which are positively correlated with indoxyl sulfate and p-cresyl sulfate, as well as other uremic toxins, compared to patients on peritoneal dialysis. An increase in the number of Pseudomonadota (especially Gammap-roteobacteria), Actinomycetota, and Bacillota (especially the Clostridia subtype) is observed in their microbiota (Borges et al., 2016). Conversely, children on hemodialysis show a significantly higher number of Bacteroidota and lower numbers of Pseudomonadota and butyrate-producing bacteria compared to healthy controls (Wong, 2014). Overall, patients with end-stage chronic kidney disease (CKD) receiving dialysis treatment exhibit lower

intestinal colonization with Bifidobacterium spp. and Lactobacillus spp. (Sampaio-Maia et al., 2016). The composition of the microbiota in CKD is also influenced by treatment modalities. For instance, increased numbers of iron-oxidizing bacteria are associated with oral iron supplementation, and an increase in Enterobacteriaceae is linked to enhanced absorption of glucose from the dialysate used in peritoneal dialysis.

In nephrolithiasis (the formation of kidney stones from calcium, phosphate, oxalates and other food components), the presence of Oxalobacter for-migenes in the intestinal microbiota is significant as they can degrade oxalates in the intestinal tract, thereby reducing their excretion in the urine (Siva et al., 2009). There is an inverse relationship between recurrent kidney stones and intestinal colonization by Oxalobacter formigenes, which consistently reduces the concentration of oxalate available for absorption in the intestine. In patients with nephro-lithiasis, Bacteroides spp. are more frequently isolated, whereas Prevotella spp. are found more commonly in healthy individuals. Another component of kidney stones, cyanuric acid, is transformed from melamine by representatives of the genus Klebsiella, particularly Klebsiella terrigena (Zheng et al., 2013).

In arterial hypertension of renal origin, some studies have identified an increased content of Bacillota and Bacteroidota, coupled with a general decrease in species richness (Li et al., 2017). The involvement of microbiota in the pathogenesis of this disease is associated with the production of SCFAs and their stimulatory effect on the Olf78 receptor, expressed in the juxtaglomerular apparatus of the kidneys and mediating the secretion of renin. Additionally, the microbiota's ability to metabolize cho-line and phosphatidylcholine to form trimethyla-mine, which is converted into TMAO, plays a role in the development of atherosclerosis (Chen et al., 2019).

The mechanisms of interaction between the normal microbiota of the GI tract and the central nervous system (CNS) in CNS disorders have been extensively detailed in studies on the functioning of the gut-brain axis. The gut-brain axis is a bidirectional communication system wherein the brain modulates the functions of the GI tract and, conversely, the GI tract and gut microbiota influence brain activity through neural, endocrine, and immu-nological mechanisms, interconnected at the organismal, organ, cellular, and molecular levels (Bulga-kova et al., 2020). Experiments on mouse models have elucidated the mechanisms by which microbe-

ota influence the development of the nervous system and CNS. It has been demonstrated that alterations in hippocampal neurogenesis in gnotobionts (germ-free animals) and mice treated with antibiotics to eliminate microbiota lead to impaired spatial and object recognition. Gnotobionts also exhibit impaired myelination of the cerebral cortex and blood-brain barrier function. The influence of microbiota on the synthesis of intestinal and circulating serotonin, anxiety, hyperactivity, and cognitive functions in mice has been established. Furthermore, it has been proven that intestinal microbiota controls the differentiation and function of immune cells in the macroorganism (Sampson et al., 2016).

In Parkinson's disease (shaking palsy), characterized by bradykinesia, tremor at rest, rigidity, and postural instability (a loss of stability when holding the body in a standing position or changing positions), the pathology is primarily based on the degeneration of dopamine neurons in the substantia nigra zone due to the accumulation of the protein alpha-synuclein. It has been found that this protein is deposited in the olfactory bulbs and neurons of the enteric nervous system long before the manifestation of motor disorders associated with Parkinson's disease. Possible causes that trigger the process of alpha-synuclein accumulation include immune-inflammatory reactions that occur in response to bacterial pathogens or the toxins they produce on the enteric nervous system. Chronic constipation, diagnosed in patients both with the clinical manifestations of the disease and during the prodromal period, contributes to an increase in the concentration of microbial toxins. Additionally, the inability of the microbiota to produce neuronal dopamine-specific nutrients can also impact the development of this disease. Regarding changes in the structure of the microbiota, some authors indicate an increase in microorganisms of the phyla Enterobacterales, Verru-comicrobiaceae, and Akkermansia, and a decrease in representatives of the Prevotellaceae family (Tyutina et al., 2020). However, other researchers, as systematized in a table by Dinan & Dinan (2022), focus on different phyla when characterizing the mi-crobiota in Parkinson's disease. This suggests that these findings reflect an imbalance in the microbiota of specific individuals rather than specific changes related to the disease itself.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive loss of memory, language, and cognitive abilities due to the excessive production of beta-amyloid peptide resulting from impaired regulation of proteolysis of the amyloid precursor protein. Microbial LPS, neu-

roactive molecules, and toxins that contribute to increased permeability of the intestinal epithelium and blood-brain barrier, thereby provoking neuroin-flammatory reactions and neurodegenerative brain damage, are also involved in the development of AD (Askarova et al., 2020). A decrease in the number of bacteria from the phyla Bacillota and Actino-mycetota (particularly Bifidobacterium) and an increase in bacteria from the phyla Bacteroidota and Pseudomonadota are characteristic of patients with AD in the United States. In contrast, qualitative changes in the gut microbiome of Chinese patients were characterized by a decrease in Bacteroidota, with Bacillota levels not differing significantly from those in healthy individuals (Lozupone et al., 2012). Consequently, it has been concluded that the functional composition of the microbiota, rather than the taxonomic one, plays a more critical role in disease development.

In the development of multiple sclerosis (a chronic autoimmune inflammatory disease of the CNS characterized by the formation of inflammatory foci, destruction of myelin sheaths, and damage to demyelinated axons, manifesting in impaired motor functions, sensitivity, balance, visual impairment, sphincter function, fatigue, depression, and cognitive changes), several factors are of great importance. These include genetic predisposition, past viral infections such as those caused by the Epstein-Barr virus, vitamin D deficiency, stress, and the state of the intestinal microbiota (Preiningerova et al., 2022). An inadequate immune response directed at one's own nerve cells is also considered a contributing factor to the disease, with its formation dependent on the correct development of the microbiota, as described in the hygiene hypothesis (Bach, 2020).

Microbiota imbalance leads to increased permeability of the intestinal wall and the blood-brain barrier, resulting in the sensitization of Th17/Th1 cells with antigens. Activated T cells migrate to the CNS and trigger neuroinflammation and autoimmune reactions involving astrocytes and microglia (resident macrophages of the central nervous system) (Abdu-rasulova, 2018). It has been found that representatives of the intestinal microbiota can influence as-trocytes in the brain and, with the help of some of the metabolic derivatives of tryptophan (indole, in-doxyl-3-sulfate, indole-3-propionic acid, and in-dole-3-aldehyde), limit inflammation and neurodegeneration. Altered microbiota, characterized by a decrease in the number of microorganisms producing tryptophan, on the contrary, contributes to the progression of the disease (Rothhammer et al., 2016).

Changes in the composition of the microbiota in multiple sclerosis are primarily characterized by a decrease in diversity. As for the predominance or decrease in the number of individual representatives of the microbial community, the data obtained in different studies are inconsistent: some showed virtually no differences in the microbiota of patients and healthy individuals, while others indicated an increase in the number of Akkermansiaceae and Methanobacteriaceae and a decrease in the number of Bacteroidota and Clostridia, among others (Di-nan & Dinan, 2022; Preiningerova et al., 2022).

In autism spectrum disorders (ASDs), complex mental development disorders characterized by social maladjustment, inability to socially interact, communicate, and stereotypical behavior (repetition of monotonous actions), psychopathological symptoms are often accompanied by gastrointestinal disorders (chronic abdominal pain, constipation, diarrhea, etc.), correlating with their severity (Blagon-ravova et al., 2021). It is believed that their common pathogenetic link is the inflammatory process caused by dysbiotic changes in the microbiota, leading to a violation of the barrier function, penetration of bacterial metabolites and LPS into the bloodstream, and the subsequent immune response (Navarro et al., 2016). Chemokines and proinflammatory cytokines (interleukin-ip, -6, -8, -12p40, tumor necrosis factor-a, and transforming growth factor-P) released as a result of immune system activation affect brain development in early ontogenesis and can impact the functioning of the CNS (Blagon-ravova et al., 2021). In particular, high levels of cytokines can cause disruption of neuronal and synaptic development and modulate the synthesis of neuropeptides (Doenyas, 2018). Elevated LPS levels contribute to increased activity in the brain regions responsible for emotion control and are inversely correlated with socialization indicators (Haba et al., 2012).

Impaired secretion and metabolism of some important neurotransmitters are of great significance in the development of ASD (Marler et al., 2016). Thus, changes in the cognitive and affective spheres in this disease are apparently associated with a high concentration of serotonin in the blood plasma due to its increased production in the intestine, and insufficient synthesis of serotonin from tryptophan in the brain. The level of tryptophan in the CNS can also decrease due to its increased consumption in the intestine by indole-producing microorganisms or due to insufficient intake of amino acids from food caused by dysbiotic disturbances of the microbiota (Kraneveld et al., 2016).

Additionally, the level of p-cresol and p-cresyl sulfate in early ontogenesis is important in the pathogenesis of ASD: an increase in the concentration of these microbial metabolites synthesized by C. difficile, for example, is associated with the severity of behavioral symptoms and cognitive impairment (Gabriele et al., 2014).

Children with ASD exhibit an imbalance in SCFA production: acetic and propionic acids are produced in greater quantities, while butyric acid is produced in lesser quantities compared to healthy children. Excess propionic acid, produced by Clostridium spp., Bacteroides spp., and Desulfovibrio spp., can modulate genes associated with ASD and induce biological, chemical, and pathological changes typical for autism (MacFabe, 2015). Intestinal dysbiosis in pregnant women, leading to excess propionic acid, causes gliosis and neuroinflammation, contributing to CNS developmental disorders in the child (Abdelli et al., 2019). Butyric acid, in contrast to propionic acid, helps reduce behavioral disorders by inhibiting histone deacetylase and positively modulating gene expression affecting neurotransmitter synthesis (Kratsman et al., 2016).

An increased number of proteolytic microorganisms in the microbiota of children with ASD results in abnormalities in protein and peptide metabolism and elevated excretion of free amino acids (glycine, serine, threonine, alanine, histidine, glutamine, tryptophan) (Ming et al., 2012). The etiopathogene-sis of ASD also involves disturbances in folate metabolism, which are normally synthesized by representatives of the phyla Actinomycetota, Bacteroidota, Bacillota, Pseudomonadota, Fusobacteriota, and Verrucomicrobiota de novo or from para-ami-nobenzoic acid (Engevik et al., 2019). Despite numerous studies, identifying specific features of mi-crobiota changes in ASD has not been possible (Blagonravova et al., 2021). However, there is evidence of the positive effect of probiotic therapy on improving behavior associated with ASD (Hsiao et al., 2013).

Synthesizing the literature data on the involvement of microbiota in various pathological processes' development, the following conclusion can be made: an increase in the aerobic component of the microbial community, including opportunistic microorganisms, triggers a standard pathogenetic mechanism. This includes decreased colonization resistance, increased intestinal wall permeability, and translocation of bacteria, their metabolites, and cell wall components into the vascular system. They spread throughout the organism, triggering immune response cascades that exacerbate pathological pro-

cesses in organs and tissues affected by etiological and concomitant factors. Regarding the composition of the microbiota in various diseases, our findings indicate that changes in microbial communities manifest similarly across different pathologies when focusing on larger phyla (types or orders). There is a decrease in anaerobic microorganisms (lactobacilli, bifidobacteria, bacteroids) and an increase in aerobes (Pseudomonadota, particularly Enterobacterales, and Bacillota representatives, such as staphylococci and enterococci). Some studies note that changes in the microbiota vary depending on the region of the research, while others report discrepancies with previously published data. Specific types of microorganisms described as markers of certain diseases often do not belong to the core microbiota and were either not looked for or not considered in studies of microbiocenoses in other diseases.

To confirm our findings, we analyzed our own data obtained from long-term studies of the micro-biota in individuals with various pathologies.

The microbiota of children diagnosed with bacteriologically confirmed dysentery (84% caused by S. sonnei and 16% by S. flexneri) at the onset of the disease was characterized by the predominance of anaerobic flora, including high titers of bifidobacteria, lactobacilli, and bacteroides corresponding to age norms. In 100% of cases, representatives of the genus Shigella and E. coli in amounts ranging from 10-5 to 10-7 CFU were detected, of which 2% were hemolytic. Among OPMs of the order Enterobacterales, genera such as Klebsiella, Enterobacter, and Citrobacter were identified. Associations of OPMs comprising more than three species were rarely detected. Under the influence of the infection and subsequent antibiotic therapy, 25 days after the onset of the disease, children exhibited pronounced dysbiotic conditions. These conditions were marked by a decrease in the number of anaerobic components (Bacteroides spp., Bifidobacterium spp., Lactoba-cillales) below the physiological norm, and in some cases, the complete disappearance of representatives of these phyla. Correspondingly, there was an increase in the proportion of the aerobic component: the frequency of detection of hemo-lytic E. coli, K. pneumoniae, Citrobacter spp., co-agulase-negative Staphylococcus spp., S. aureus, C. albicans, and non-fermenting Gram-negative bacteria increased. Additionally, the frequency of detection of OPM in significant quantities (>10-5 CFU/g) in associations of three species or more also increased (Fig. 1 and 2).

— —Bifidobacterium spp. Day 1 —■— Bifidobacterium spp. Day 25 Lactobacillales Day 1 x Lactobacillales Day 25 ж Bacteroides spp. Day 1 • Bacteroides spp. Day 25

Fig. 1. Changes in the anaerobic component of the microbiota in children with dysentery on the 1st and 25th day from the onset of the disease

Fig. 2. Change in the frequency of of aerobic OPM isolation in children with dysentery on the 1st and 25th day from the onset of the disease

Our data on changes in the microbiota in children with bacteriologically confirmed dysentery also support the general rule: microbiota imbalance is characterized by a shift towards the aerobic component of the microbiota.

The microbiota of patients with terminal CKD receiving hemodialysis treatment was studied

in more detail. However, due to the fact that the assessment of the microbiota state was carried out in accordance with the Industry Standard "Intestinal Dysbacteriosis" (Standardization system in healthcare of the Russian Federation, 2003), which provide normal values only for key phyla, some of the isolated types of microorganisms remained out-

side the analysis, as their presence or absence in the microbiota of healthy individuals is not indicated.

In analyzing the obtained data, a decrease in the content of Bifidobacterium spp. in the intestinal microbiota was found: representatives of the genus were found in 75% of those examined, and in 43.7% of these cases, the identified amount of bifidobacteria was significantly below the norm. Each patient had 12 species of bifidobacteria isolated, with B. longum predominating in the species structure at 43.75%.

An in-depth study of the microbiota in patients with CKD undergoing hemodialysis showed that among the representatives of the Actinomycetota phylum in the colon microbiocenosis, representatives of the genus Bifidobacterium spp. were found in 75% of those examined, and in 43.7% of these cases, the detected amount of bifidobacteria was significantly lower than normal (Fig. 1). Each patient had 1-2 species of bifidobacteria isolated, with B. longum predominating in the species structure at 43.75%. Other representatives of this phylogenetic type were also found with varying frequencies. Specifically, Collinsella aerofaciens was found in 31.25% of cases, Eggerthella lenta in 18.75%, and Actinocorallia libanotica in individual cases.

Suppression of lactoflora was also noted: representatives of the order Lactobacillales were isolated in only 31.25% of those examined, and in sufficient quantities (107-108 CFU/ml) in only 18.75% of patients (Fig. 3). Each patient had 1-3 species of lac-tobacilli isolated, with L. gasseri being the leading species.

In addition, the phylum Bacillota was represented by bacteria of the genera Eubacterium (E. limosum), Bacillus (B. acidicola), Clostridium spp. (C. innocuum, C. spiroforme), Staphylococcus spp. (S. aureus and a group of coagulase-negative staph-ylococci), and Streptococcus spp.

The phylum Bacteroidota was represented by the genera Parabacteroides spp. (P. distasonis) and Bacteroides spp. In the microbiota of one examined person, 1-5 different species of bacteroides were also found, most often B. vulgatus, B. uniformis, B. ovatus, B. thetaiotaomicron, and B. fragilis. The content of representatives of this phylum in the mi-crobiota of the examined persons corresponded to the age norm.

The phylum Pseudomonadota was represented by various genera and species of the order Entero-bacterales, as well as microorganisms from the group of non-fermenting Gram-negative bacteria (Fig. 3), including Enterobacter asburiae, Enterobacter kobei, Citrobacter youngae, Serratia lique-faciens, and Raoultella planticola.

It was found that in the absence or suppression of lacto- and bifidoflora, the number and species diversity of microorganisms of the genera Bacteroides, Clostridium, Collinsella, Eggerthella, etc., increased. This is explained from the perspective of the theory of functional redundancy of microbiota, which suggests the possibility of performing similar metabolic functions by phylogenetically different microorganisms, i.e., the possibility of replacing some species with others without loss of function. On the other hand, in pathological conditions in humans, the mechanism of functional redundancy of microbiota can lead to a worsening of the course of the disease (Belova et al., 2020).

Microbiota in pulmonary tuberculosis is characterized by pronounced and sharply expressed dysbiotic changes: approximately half of the examined patients exhibited a decrease in the number of bifidobacteria, lactobacilli, and bacteroides below the physiological norm, sometimes leading to their complete absence. There was an increased frequency of isolation and higher counts of coagulase-negative staphylococci, yeast-like fungi of the genus Candida (mainly C. albicans), non-fermenting Gram-negative microorganisms including Pseudomonas spp., Corynebacterium spp., as well as Klebsiella spp. and Enterobacter spp. (Fig. 4). In one-third of the examined patients, associations of four or more microorganisms were detected in significant quantities (>105 CFU/g).

In the colon microbiota of patients with gas-troduodenal pathology (gastritis, gastroduodeni-tis, etc.), bifidobacteria were detected in 100% of cases, though in reduced quantities (106-107 CFU/ml) in 37.5% of patients. B. longum (75%), B. adolescentis (62.5%), and B. bifidum (33.3%) were isolated with the highest frequency. Representatives of the Lactobacillaceae family were detected in 70.8% of the examined patients, but in 29.1% of cases, their numbers were less than 107 CFU/ml. In 21% of patients, lactobacilli were absent in the microbiota of the colon lumen. The most frequently detected bacteria in feces were L. gasseri (45.8%), L. paracasei and L. vaginalis (29.1%), L. oris (25%), L. crispatus and L. salivarius (20.8%). Bacteroides spp. were isolated in reduced quantities in 91.6% of patients, with amounts of 108 CFU/ml in 41.6% of cases. The most frequently detected bacteria were B. uniformis and B. ovatus (33.3%), and B. vulgatus and B. thetaiotaomicron (25%). E. coli was detected in all examined patients, with reduced quantities (106 CFU/ml and less) in 41.6% of cases. Lactose-negative E. coli were detected in 4.2% of cases. Enterococci were detected in 50% of

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Bifidobacteirum spp. Lactobacillus spp. Leuconostoc lactis Bacteroides spp. Enterococcus spp. Clostridium spp.

E.coli E.coli hem Klebsiella spp. Enterobacter spp. Citrobacter spp. Staphylococcus spp. CoNS S.aureus Streptococcus spp. Candida spp. nonalbicans C.albicans

Non-fermenting Gram-negative bacteria Corynebacterium spp.

0%

0%

0%

12,5 25%

25%

25%

0%

18,75%

31,25

31,25

31,25

7,50% %

42,8

50%

43,75%

5%

75

93,

5%

100%

Fig. 3. Frequency of isolation of various representatives of the normal microbiota of the human colon in patients with CKD receiving programmed hemodialysis

0,00% 10,00% 20,00% 30,00% 40,00% 50,00% 60,00% 70,00% 80,00% 90,00%

Bifidobacterium spp. Lactobacillus spp.

L.lactis Bacteroides spp. Enterococcus spp. Fusobacterium spp. Clostridium spp.

E.coli E.coli hem Klebsiella spp. Enterobacter spp. Hafnia spp. Proteus spp. Morganella spp. Providencia spp. Citrobacter spp. Staphylococcus spp. CoNS Streptococcus spp. Pediococcus spp. Candida spp. nonalbicans C.albicans

Non-fermenting Gram-negative bacteria Myroides spp. Corynebacterium spp.

Bacillus spp.

Fig. 4. Frequency of isolation of various representatives of normal microbiota of the human colon in patients with pulmonary tuberculosis

cases within normal values (105-108 CFU/ml), with E. faecalis (33.3%) and E. faecium (16.6%) being the most frequently isolated from feces. Various types of Clostridia were isolated in 52.6% of the examined patients, with numbers not exceeding 10 CFU/g, which corresponds to normal values. In isolated cases, C. innocuum (106 CFU/g) and C. perfringens (107 CFU/g) were detected in increased quantities. S. aureus was detected in 12.5% of patients. Coagulase-negative staphylococci were isolated in 41.2% of cases, and in significant quantities (more than 105 CFU/g) in 12.5% of cases. OPM of the Enterobacterales order were detected in significant quantities (>105 CFU/g) in 45.8% of patients, with Enterobacter cloacae (16.6%) and Klebsiella pneumoniae (12.5%) being the most frequently isolated. Proteus mirabilis, M. morganii, Raoultella ornithinolytica, and Citrobacter freundii were detected in smaller quantities and less frequently. Yeast-like fungi of the genus Candida were de-

tected in the microbiota of the colon lumen in 70.8% of those examined. C. kefyr and C. lusitaniae were detected in the highest quantities (105-107 CFU/g). C. albicans was detected with a higher frequency (54.2%), but in smaller quantities (102-104 CFU/g). In isolated cases, C. crusei, C. tropicalis, C. guiller-mondii, C. parapsilosis, C. dublinensis, and C. gla-brata were identified. Among the gram-negative non-fermenting bacteria, P. aeruginosa, Acineto-bacter lwoffii, and Comamonas testosteroni were detected in significant quantities (>105 CFU/g) in isolated cases. Collinsella aerofaciens, Eggerthella lenta, Streptomyces lavendulae were detected in significant quantities (106-107 CFU/g), as well as various types of streptococci (S. lutetiensis, S. pleo-morphus, S. salivarius, S. sanguinis, S. gallolyticus, S. vestibularis, S. parasanguinis). Although these types of streptococci were found in isolated cases, the overall frequency of isolation of bacteria of the genus Streptococcus was 45.8% (Fig. 5).

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Bifidobacterium spp. Lactobacillaceae Bacteroides spp.

E.coli E.coli lact Enterococcus spp. Clostridium spp. S.aureus

Staphylococcus spp. CoNS Enterobacter spp. Klebsiella spp. Proteus spp Morganella spp.

Raoultella spp. Citrobacter spp. Candida spp. nonalbicans C. albicans

Non-fermenting Gram-negative bacteria Streptococcus spp.

Fig. 5. Frequency of isolation of various representatives of the normal microbiota of the human large intestine in patients with gastroduodenal pathology

As can be seen from our data, the composition of the colon microbiota is almost identical in patients with different nosological forms of disease. All patients exhibit dysbiotic disorders of varying degrees, characterized by suppression of the anaerobic component, an increase in the number and frequency of excretion of the aerobic part of the microbiocenosis, and with each pathology, the same species or genera of microorganisms are consistently detected. It should be noted that during bacteriological examination of feces, a wider range of bacteria and fungi is isolated than that presented in the discussion and figures. For instance, in cases of gastroduodenal pathology, other phyla such as Anaerococcus spp., Micrococcus spp., Peptoniphilus spp., Veillonella spp., Weissella spp., Actinocoralia spp., Bacillus spp., Aeromonas spp., Corynebacterium spp., and others are also isolated from patients' feces. Similar examples can be given for other diseases. However, since the frequency of detection of such microorganisms is quite low (isolated cases within a statistically significant sample size), it would be incorrect to suggest that they characterize the microbiocenosis of the large intestine in a specific disease.

It should also be noted that this work presents only a few examples of our own studies on the mi-crobiota in people of different ages and health conditions, although we have conducted many more. We have studied the process of formation and the state of the microbiota in pregnant women at risk for gonorrheal inflammatory diseases and intrauterine infections, in women with inflammatory diseases of the pelvic organs, in patients with Helicobacter-as-sociated diseases, in children with gastroduodenal pathology and allergies, in frequently ill preschool children, in medical university students, and others. The total number of individuals examined exceeds 3,000, and more than 10,000 bacteriological analyses were performed. In each pathology, dysbiotic disorders in the microbiota manifest similarly: the number and frequency of isolation of lactobacilli

and bifidobacteria decrease, while the frequency of detection of staphylococci and representatives of the Enterobacteriaceae family in significant quantities increases. The number and frequency of detection of Enterococcus spp. vary in the microbiota of the examined groups without being tied to any specific pathology. The same can be said about coryne-bacteria, bacilli, fusobacteria, hemolytic, and lactose-negative forms of E. coli. Additionally, a wide range of bacteria and fungi characteristic of individual microbiocenoses of specific individuals, rather than the sample as a whole, are isolated. The absence of specific changes is indirectly confirmed by the results of microbiota correction in various pathological conditions. The administration of pro-biotics containing only strains of lactobacilli and bifidobacteria leads to replenishment of these phyla in the patient's own microflora and the restoration of the GI tract microbiocenosis as a whole, regardless of the pathology.

Summing up, the microbiota is a key factor in maintaining homeostasis and exerts a multifaceted effect on the macroorganism through symbiotic, evolutionarily mediated relationships between the microbiota and internal organs: the microbiota-gut-brain axis, the microbiota-gut-kidney axis, the mi-crobiota-gut-lung axis, etc. Changes in the state of the microbiota can be considered indicators of the state of the macroorganism. Any pathological process developing in the human body inevitably causes disturbances in the metabolic and regulatory properties of microbial communities, manifested by the formation of dysbiosis, characterized by an imbalance in the ratio of anaerobic (bifidobacteria, lactobacilli, bacteroids, clostridia, etc.) and aerobic components. These changes in the microbiota are not specific to individual nosologies, and the predominance or suppression of any microbiota representatives are primarily due to the individual characteristics of the microbiocenosis composition of each particular individual.

References

ABDELLI L.S., SAMSAM A. & NASER S.A. (2019): Propionic acid induces gliosis and neuroinflammation through modulation of PTEN/ AKT pathway in autism spectrum disorder. Sci. Rep. 9(1), 8824. https://doi.org/10.1038/s41598-019-45348-z. ABDURASULOVA I.N. (2018): Intestinal microbiota in multiple sclerosis - a new pathogenetic target?

Bulletin of the Russian Military Medical Academy 53, 8-10. (In Russ.) AHMED I., ROY B.C., KHAN S.A., SEPTER S. & UMAR S. (2016): Microbiome, Metabolome and Inflammatory Bowel Disease. Microorganisms 4(2), 20. https://doi.org/10.3390/microorganisms4020020. ALESHIN S. (2003): Metabolic syndrome X: a high-risk condition. Orthomolecular Medicine 2003. (In Russ.)

ALESHKIN V.A., AFANASYEV S.S., KARAULOV A.V. et al. (2015): Microbiocenoses and human health: monograph. Moscow: Dynasty, 548 pp. (In Russ.)

ALLALI I., BAKRI Y., AMZAZI S. & GHAZAL H. (2021): Gut-lung axis in COVID-19. Interdiscip. Perspect. Infect. Dis. 2021, 6655380. DOI: 10.1155/2021/6655380.

ANUKAM K.C., OSAZUWA E.O., OSADOLOR H.B. et al. (2008): Yogurt containing probiotic Lactobacillus rhamnosus GR-1 and L. reuteri RC-14 helps resolve moderate diarrhea and increases CD4 count in HIV/AIDS patients. J. Clin. Gastroenterol. 42, 239-243.

ARUTYUNOV G.L. (2005): Intestinal biocenosis and cardiovascular continuum. Cardiovascular insufficiency 5(5), 224-229. (In Russ.)

ASKAROVA S., UMBAYEV B., MASOUD AR., KAIYRLYKYZY A., SAFAROVA Y., TSOY A., ... & KUSHUGULOVA A. (2020): The links between the gut microbiome, aging, modern lifestyle and Alzheimer's disease. Frontiers in cellular and infection microbiology 10, 104.

BACH J.F. (2020): Revisiting the Hygiene Hypothesis in the Context of Autoimmunity. Front. Immunol. 11, 615192.

BALASUBRAMANIAN K., KUMAR S., SINGH R.R. et al. (2009): Metabolism of the colonic mucosa in patients with inflammatory bowel diseases: An in vitro proton magnetic resonance spectroscopy study. Magn. Reson. Imaging 27, 79-86.

BALDRIDGE M.T., NICE T.J., MCCUNE BT., YOKOYAMA C.C., KAMBAL A., WHEADON M. et al. (2015): Commensal microbes and interferon-lambda determine persistence of 285 enteric murine norovirus infection. Science 347(6219), 266-9.

BELOVA I.V., KHRULEV A.E., TOCHILINA AG., KHRULEVA N.S., LOBANOVA N.A., ZHIRNOV V.A., MOLODTSOVA S.B., LOBANOV V.N. & SOLOVIEVA I.V. (2020): Colon microbiocenosis and its correction in patients receiving programmed hemodialysis. Sovremennye tehnologii v medicine 12(5), 62-70, https://doi.org/10.17691/stm2020.12.5.07. (In Russ.)

BERGER A.K. & MAINOU B.A. (2018): Interactions between Enteric Bacteria and Eukaryotic Viruses Impact the Outcome of Infection. Viruses 10(1).

BHATT A.P., REDINBO M R. & BULTMAN S.J. (2017): The role of the microbiome in cancer development and therapy. CA Cancer J Clin. 67(4), 326-44. doi: 10.3322/caac.21398.

BLAGONRAVOVA A S., ZHILYAEVA T V. & KVASHNINA D.V. (2021): Dysbiosis of intestinal microbiota in autism spectrum disorders: new horizons in search for pathogenetic approaches to therapy. Part 1. Features of intestinal microbiota in autism spectrum disorders. Journal of microbiology, epidemiology and immunobiology 98(1), 65-72. https://doi.org/10.36233/0372-9311-62. (In Russ.)

BORGES N.A., BARROS A.F., NAKAO LS. et al. (2016): Protein-bound uremic toxins from gut microbiota and inflammatory markers in chronic kidney disease. J Ren Nutr. 26, 396-400. doi: 10.1053/j.jrn.2016.07.005.

BRON P.A., KLEEREBEZEM M., BRUMMER R.J., CANI P.D., MERCENIER A., MACDONALD T.T. et al. (2017): Can probiotics modulate human disease by impacting intestinal barrier function? Br. J. Nutr. 117, 93-107. Doi: 10.1017/S0007114516004037.

BULGAKOVA S., ROMANCHUK N. & POMAZANOVA O. (2020): Psychoneuroimmunoendocrinology and immune homeostasis: gut-brain axis, obesity and cognitive function. Bulletin of Science and Practice 6(12), 124-154. https://doi.org/10.33619/2414-2948/61/15 (In Russ.)

BULLMAN S., PEDAMALLU CS., SICINSKA E., CLANCY T.E., ZHANG X., CAI D., NEUBERG D., HUANG K., GUEVARA F., NELSON T., CHIPASHVILI O., HAGAN T., WALKER M., RAMACHANDRAN A., DIOSDADO B., SERNA G., MULET N., LANDOLF S., RAMON Y CAJAL S., FASANI R., AGUIRRE A.J., NG K., ELEZ E., OGINO S., TABERNERO J., FUCHS C S., HAHN W.C., NUCIFORO P. & MEYERSON M. (2017): Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science 358(6369), 1443-8. doi: 10.1126/science. aal5240.

CHERVINETS V.M., CHERVINETS YU.V. & GANZYA D.V. (2022a): Mikrobiota esophagus, stomach and duodenal estate in normal and pathology. Experimental and Clinical Gastroenterology 4, 169-178. https://doi.org/10.31146/1682-8658-ecg-200-4-169-178 (In Russ.)

CHERVINETS V.M., CHERVINETS YU.V. & KRAVCHUK E.S. (2022b): Intestinal imbalance in young people as a marker of chronic somatic diseases. Experimental and Clinical Gastroenterology 4, 153-159. https://doi.org/10.31146/1682-8658-ecg-200-4-153-159 (In Russ.)

CHOI J., JOSEPH L. & PILOTE L. (2013): Obesity and C-reactive protein in various populations: A systematic review and meta-analysis. Obes. Rev. 14, 232-244. doi: 10.1111/obr.12003.

CLEMENTE-POSTIGO M., OLIVA-OLIVERA W., COIN-ARAGÜEZ L., RAMOS-MOLINA B., GIRALDEZ-PEREZ R.M., LHAMYANI S., ALCAIDE-TORRES J., PEREZ-MARTINEZ P.,

EL BEKAY R., CARDONA F. et al. (2018): Metabolic endotoxemia promotes adipose dysfunction and inflammation in human obesity. Am. J. Physiol. Endocrinol. Metab. 2018.

CORRIDONI D., PASTORELLI L., MATTIOLI B. et al. (2012): Probiotic bacteria regulate intestinal epithelial permeability in experimental ileitis by a TNF-dependent mechanism. PLoS ONE 7, e42067.

Cosnes J., Gower-Rousseau C., Seksik P. & Cortot A. (2011): Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology 140, 1785-1794.

CROCI S., D'APOLITO L.I., GASPERI V., CATANI M.V. & SAVINI I. (2021): Dietary Strategies for Management of Metabolic Syndrome: Role of Gut Microbiota Metabolites. Nutrients 13(5), 1389. doi: 10.3390/nu13051389

DELEEMANS J.M., CHLEILAT F., REIMER R.A., HENNING J.W., BAYDOUN M., PIEDALUE K.A., MCLENNAN A. & CARLSON L.E. (2019): The chemo-gut study: investigating the long-term efects of chemotherapy on gut microbiota, metabolic, immune, psychological and cognitive parameters in young adult Cancer survivors; study protocol. BMC Cancer 19(1), 1243. doi: 10.1186/ s12885-019-6473-8.

DEN BESTEN G., BLEEKER A., GERDING A. et al. (2015): Short-Chain Fatty Acids Protect Against High-Fat Diet-Induced Obesity via a PPARy-Dependent Switch From Lipogenesis to Fat Oxidation. Diabetes. 64, 2398. doi: 10.2337/db14-1213.

DINAN K. & DINAN T.G. (2022): Gut Microbes and Neuropathology: Is There a Causal Nexus? Pathogens 11(7), 796.

DOENYAS C. (2018): Gut microbiota, inflammation, and probiotics on neural development in autism spectrum disorder. Neuroscience 374, 271-86. https://doi.org/10.1016/j.neuroscience.2018.01.060.

DRAPKINA O.M. & SHIROBOKIKH O.E. (2018): Role of Gut Microbiota in the Pathogenesis of Cardiovascular Diseases and Metabolic Syndrome. Rational Pharmacotherapy in Cardiology 14(4), 567-574. DOI: 10.20996/1819-6446-2018-14-4-567-574. (In Russ)

DUBOURG G. (2017): Microbiome of HIV-infected people. Microbial Pathogenesis 106, 85-93.

ENGEVIK M.A., MORRA C.N., ROTH D., ENGEVIK K., SPINLER J.K., DEVARAJ S. et al. (2019): Microbial metabolic capacity for intestinal folate production and modulation of host folate receptors. Front. Microbiol. 10, 2305. https://doi.org/10.3389/fmicb.2019.02305.

EVERARD A., BELZER C., GEURTS L., OUWERKERK J.P., DRUART C., BINDELS L.B., GUIOT Y., DERRIEN M., MUCCIOLI G.G., DELZENNE N.M. et al. (2013): Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc. Natl. Acad. Sci. USA 110, 9066-9071. doi: 10.1073/pnas.1219451110.

FERNANDES J., SU W., RAHAT-ROZENBLOOM S., WOLEVER T.M.S. & COMELLI E M. (2014): Adiposity, gut microbiota and faecal short chain fatty acids are linked in adult humans. Nutr. Diabetes. 4, e121. doi: 10.1038/nutd.2014.23.

FIOCCHI C. (2012): Genes and "in-vironment": How will our concepts on the pathophysiology of inflammatory bowel disease develop in the future? Dig. Dis. 30, 2-11.

FORBES S., STAFFORD S., COOPE G., HEFFRON H., REAL K., NEWMAN R., DAVENPORT R., BARNES M., GROSSE J. & COX H. (2015): Selective FFA2 Agonism Appears to Act via Intestinal PYY to Reduce Transit and Food Intake but Does Not Improve Glucose Tolerance in Mouse Models. Diabetes 64, 3763. doi: 10.2337/db15-0481.

GABRIELE S., SACCO R., CERULLO S., NERI C., URBANI A., TRIPI G. et al. (2014): Urinary p-cresol is elevated in young French children with autism spectrum disorder: A replication study. Biomarkers 19(6), 463-70. https://doi.org/10.3109/1354750X.2014.936911.

GLUSHHENKO V.A. & IRKLIENKO E.K. (2019): Cardiovascular morbidity - one of the most vital problems of modern health care. Medicine and health care organization 4(1), 56-63. (In Russ.)

GOPALAKRISHNAN V., HELMINK B.A., SPENCER C.N., REUBEN A. & WARGO J.A. (2018): The Infuence of the Gut Microbiome on Cancer, Immunity, and Cancer Immunotherapy. Cancer Cell 33(4), 570-80. doi: 10.1016/j. ccell.2018.03.015.

GRIGORIEVSKAYA Z.V., PETUKHOVA I.N., BAGIROVA N.S., AGINOVA V.V. & KONONETS P.V. (2023): Role of the microbiota in oncogenesis. Siberian journal of oncology 22(2), 129-142. https://doi.org/10.21294/1814-4861-2023-22-2-129-142 (In Russ.)

GRINEVICH V.B., RADCHENKO V.G. (2020): Gut microbiota and metabolic syndrome. Experimental and Clinical Gastroenterology 183(11), 11-19. https://doi.org/10.31146/1682-8658-ecg-183-11-11-19 (In Russ.)

HABA R., SHINTANI N., ONAKA Y. et al. (2012): Lipopolysaccharide affects exploratory behaviors toward novel objects by impairing cognition and/or motivation in mice: Possible role of activation of the central amygdala. Behav. Brain Res. 228(2), 423-31. https://doi.org/10.1016Zj.bbr.2011.12.027.

HARPER A., VIJAYAKUMAR V., OUWEHAND A.C., TER HAAR J., OBIS D., ESPADALER J., ... & DAY R. (2021). Viral infections, the microbiome, and probiotics. Frontiers in Cellular and Infection Microbiology 10, 596166.

HSIAO E.Y., MCBRIDE S.W., HSIEN S. et al. (2013): Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopment disorders. Cell 155(7), 1451-63. https://doi.org/10.1016/j.cell.2013.11.024.

HUANG P.-N. (2020): Microbiota and Enteric Viruses Infection. Medicine in Microecology 3, 100006. https://doi.org/10.1016/j.medmic.2020.100006.

IIDA N., DZUTSEV A., STEWART C.A., SMITH L., BOULADOUX N., WEINGARTEN R A., MOLINA DA., SALCEDO R., BACK T., CRAMER S., DAI RM., KIU H., CARDONE M., NAIK S., PATRI A.K., WANG E., MARINCOLA F.M., FRANK K.M., BELKAID Y., TRINCHIERI G. & GOLDSZMID R.S. (2013): Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342(6161), 967-70. doi: 10.1126/science.1240527.

KHAN M.A.W., OLOGUN G., ARORA R., MCQUADE J.L. & WARGO J.A. (2020): Gut Microbiome Modulates Response to Cancer Immunotherapy. Dig Dis Sci. 65(3), 885-96. doi: 10.1007/s10620-020-06111-x.

KHASANOVA G R., ANOKHIN V A., BIKKININA O.I., SHAKHBAZOVA E.N., KOTLYAR E.Y. & NAGIMOVA F.I. (2013): Changes of intestinal microbiota in patients with HIV. Kazan medical journal 94(1), 34-39. (In Russ.)

KONEV YU.V. (2012): The role of endotoxin (LPS) in the pathogenesis of metabolic syndrome and atherosclerosis. Experimental and clinical gastroenterology 11, 11-22. (In Russ.)

KORNIENKO E.A. (2006): Current issues of intestinal microflora correction in children: methodological manual. Moscow, 48 pp. (In Russ.)

KRANEVELD A.D., SZKLANY K., DE THEIJE C G. & GARSSEN J. (2016): Gutto-brain axis in autism spectrum disorders: Central role for the microbiome. Int. Rev. Neurobiol. 131, 263-87. https://doi.org/10.1016/bs.irn.2016.09.001.

KRATSMAN N., GETSELTER D. & ELLIOTT E. (2016): Sodium butyrate attenuates social behavior deficits and modifies the transcription of inhibitory/excitatory genes in the frontal cortex of an autism model. Neuropharmacology 102, 136-45. https://doi.org/10.1016/j.neuropharm.2015.11.003.

KUSS S.K., BEST G.T., ETHEREDGE C A., PRUIJSSERS A.J., FRIERSON J.M., HOOPER L.V. et al. (2011): Intestinal microbiota promote enteric virus replication and systemic 266 pathogenesis. Science 334(6053), 249-52.

LABORDA-ILLANES A., SANCHEZ-ALCOHOLADO L., DOMINGUEZ-RECIO M.E., JIMENEZ-RODRIGUEZ B., LAVADO R., COMINO-MÉNDEZ I., ALBA E. & QUEIPO ORTUNO M.I. (2020): Breast and Gut Microbiota Action Mechanisms in Breast Cancer Pathogenesis and Treatment. Cancers (Basel) 12(9), 2465. doi: 10.3390/cancers12092465.

LEE M.H. (2021): Harness the functions of gut microbiome in tumorigenesis for cancer treatment. Cancer Commun (Lond) 41(10), 937-67. doi: 10.1002/cac2.12200.

LI B., GONG T., HAO Y., ZHOU X. & CHENG L. (2021): Mining the Gut Microbiota for Microbial-Based Therapeutic Strategies in Cancer Immunotherapy. Front. Oncol. 11. doi: 10.3389/fonc.2021.721249.

LI J., ZHAO F., WANG Y. et al. (2017): Gut microbiota dysbiosis contributes to the development of hypertension. Microbiome 5, 14. doi: 10.1186/s40168-016-0222-x.

LI W., ZHU Y., LIAO Q. et al. (2019): Characterization of gut microbiota in children with pulmonary tuberculosis. BMC Pediatr. 19, 445.

LIU J. & ZHANG Y. (2022): Intratumor microbiome in cancer progression: current developments, challenges and future trends. Biomark Res 10(1), 37. doi: 10.1186/s40364-022-00381-5.

LOBZIN YU.V. (2013): Clinic, epidemiology and prevention of rotavirus infection: Methodological recommendations. St. Petersburg: NIIDI, 48 pp. (In Russ.)

LONGHI G., VAN SINDEREN D., VENTURA M. & TURRONI F. (2020): Microbiota and Cancer: The Emerging Benefcial Role of Bifdobacteria in Cancer Immunotherapy. Front Microbiol 11. doi: 10.3389/fmicb.2020.575072.

LOZUPONE C A., STOMBAUGH J.I., GORDON J.I., JANSSON J.K. & KNIGHT R. (2012): Diversity, stability and resilience of the human gut microbiota. Nature 489, 220-230. 10.1038/nature11550.

LUKICHEV B.G., RUMYANTSEV A SH. & AKIMENKO V. (2018): Colonic microbiota and chronic kidney disease. Message one. Nephrology 22(4), 57-73. https://doi.org/10.24884/1561-6274-2018-22-4-57-73. (In Russ.)

MACDONALD T.T. (2011): New cytokine targets in inflammatory bowel disease. Gastroenterol Hepatol 7, 474-476.

MACFABE D.F. (2015): Enteric short-chain fatty acids: Microbial messengers of metabolism, mitochondria, and mind: Implications in autism spectrum disorders. Microb. Ecol. Health Dis. 26, 28177. https://doi.org/10.3402/mehd.v26.28177.

MAJLESSI L., SAYES F., BUREAU J.F. et al. (2017): Colonization with Helicobacter is concomitant with modified gut microbiota and drastic failure of the immune control of Mycobacterium tuberculosis. Mucosal Immunol. 10, 1178-1189.

MANICHANH C., BORRUEL N., CASELLAS F. & GUARNER F. (2012): The gut microbiota in IBD. Nature reviews Gastroenterology & hepatology 9(10), 599-608.

MARLER S., FERGUSON B.J., LEE E.B. et al. (2016): Brief report: Whole blood serotonin levels and gastrointestinal symptoms in autism spectrum disorder. J. Autism Dev. Disord. 46(3), 1124-30. https://doi.org/ 10.1016/j .neuroscience.2015.11.010.

MARTYNOVA G.P., KOGAN N.V. & SOLOVYEVA I.A. (2014): Disturbance of metabolic activity of intestinal microflora and local immunity of rotavirus infection. Children infections 13(2), 5-8. (In Russ.)

MAZANKOVA L.N., BOROVIK T.E. & ROSLAVTSEVA E.A. (2003): Osmotic diarrhea in children and principles of pathogenetic treatment. Current Pediatrics 2(4), 47-53. (In Russ.)

MAZURINA S.A., GERVAZIEVA V.B. & SVERANOVSKAYA V.V. (2020): Intestinal microbiota and allergic diseases. Journal Infectology 12(2), 19-29. https://doi.org/10.22625/2072-6732-2020-12-2-19-29. (In Russ.)

MIKHAELOVA E.V. & LEVIN D.Y. (2004): Rotavirus infection in children: modern conceptions of etiology, pathogenesis and prophylaxis of the disease. Infectious diseases 2(4), 70-75. (In Russ.)

MING X., STEIN T.P., BARNES V., RHODES N. & GUO L. (2012): Metabolic perturbance in autism spectrum disorders: A metabolomics study. J. Proteome Res. 11(12), 5856-62. https://doi.org/10.1021/pr300910n.

MORKÜNAS E., SKIECEVICiENE J. & KUPCINSKAS J. (2020): The impact of modulating the gastrointestinal microbiota in cancer patients. Best Pract Res Clin Gastroenterol. 2020, 48-49. doi: 10.1016/j.bpg.2020.101700.

MUDD J.C. & BRENCHLEY J.M. (2016): Gut mucosal barrier dysfunction, microbial dysbiosis, and their role in HIV-1 disease progression. J. Infectious Diseases 214(suppl 2), 58-66.

MUSABOEV E.I. et al. (2011): Diarrheal syndrome in HIV infection. Infection, immunity and pharmacology (Tashkent) 4-5, 123-125. (In Russ.)

MUSSO G., GAMBINO R. & CASSADER M. (2010): Obesity, diabetes, and gut microbiota. Diabetes Care 33, 2277-2284.

NAGPAL R. & YADAV H. (2017): Bacterial translocation from the gut to the distant organs: An overview. Ann. Nutr. Metab. 71, 11-16. Doi: 10.1159/0004799.

NAIDOO C.C., NYAWO G.R., SULAIMAN I. et al. (2021): Anaerobe-enriched gut microbiota predicts proinflammatory responses in pulmonary tuberculosis. EBioMedicine 67, 103374.

NALLU A., SHARMA S., RAMEZANI A. et al. (2017): Gut microbiome in chronic kidney disease: challenges and opportunities. Transl. Res. 179, 24-37.

NAMASIVAYAM S., SHER A., GLICKMAN M.S. & WIPPERMAN M.F. (2018): The Microbiome and Tuberculosis: Early Evidence for Cross Talk. mBio 9, e01420-18.

NAVARRO F., LIU Y. & RHOADS J.M. (2016): Can probiotics benefit children with autism spectrum disorders? World J. Gastroenterol. 22(46), 10093-1102. https://doi.org/10.3748/wjg.v22.i46.10093.

NGUYEN C.L., DOCAMPO M.D., VAN DEN BRINK M R. & MARKEY K.A. (2021): The role of the intestinal microbiota in allogeneic HCT: clinical associations and preclinical mechanisms. Curr Opin Genet Dev. 66, 25-35. doi: 10.1016/j.gde.2020.11.007.

NIKONOV E L. & POPOVA E.N. (2019): Microbiota. Moscow: Media Sphere, 255 pp. http://gastro-rsmu.ru/wp-content/uploads/2017/06/mikrobiota.pdf. (In Russ.)

NOMURA M., NAGATOMO R., DOI K. et al. (2020): Association of Short-Chain Fatty Acids in the Gut Microbiome With Clinical Response to Treatment With Nivolumab or Pembrolizumab in Patients With Solid Cancer Tumors. JAMA Netw Open 3(4). doi: 10.1001/jamanetworkopen.2020.2895.

ODZE R.D. (2015): A contemporary and critical appraisal of "indeterminate colitis". Mod. Pathol. 28, S30-S46.

PERRY S., DE JONG B.C., SOLNICK J.V. et al. (2010): Infection with Helicobacter pylori is associated with protection against tuberculosis. PLoS ONE 5, e8804.

PIETZNER M., BUDDE K., RÜHLEMANN M., VÖLZKE H., HOMUTH G., WEISS F.U., LERCH MM. & FROST F. (2021): Exocrine Pancreatic Function Modulates Plasma Metabolites Through Changes in Gut Microbiota Composition. J. Clin. Endocrinol. Metab. 106, e2290-e2298.

PLOTNIKOVA E.YU., KRASNOVA M.V., BARANOVA E.N. & BORSCH M.V. (2013): Uninvited guests: bacterial overgrowth in the small intestine. What to do? Consilium medicum. Gastroenterology 1, 36-42. (In Russ.)

PLOTNIKOVA E.YU. & ZAKHAROVA YU.V. (2015): Diagnostics and treatment of bacterial overgrowth syndrome. Russian Medical Journal 13, 767. (In Russ.)

PREININGEROVA J.L., JIRASKOVA ZAKOSTELSKA Z., SRINIVASAN A., TICHA V., KOVAROVA I., KLEINOVA P., ... & KUBALA HAVRDOVA E. (2022): Multiple sclerosis and microbiome.

Biomolecules 12(3), 433.

RIDLON J.M., KANG D.J., HYLEMON P.B. & BAJAJ J.S. (2014): Bile acids and the gut microbiome. Curr Opin Gastroenterol 30(3), 332-8.

ROTHHAMMER V., MASCANFRONI I D, BUNSE L., TAKENAKA M C., KENISON J E. et al. (2016): Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nature medicine 22(6), 586-597.

ROY S. & TRINCHIERI G. (2017): Microbiota: a key orchestrator of cancer therapy. Nat Rev Cancer 17(5), 271-85. doi: 10.1038/nrc.2017.13.

RUZHENTSOVA T.A., PLOSKIREVA A.A. & GORELOV A.V. (2017): Correction of dysbiotic disorders developing in acute enteric infections in children. RMJ 5, 362-366. (In Russ.)

SAFINA D.D. & ABDULKHAKOV S R. (2021): Coronavirus infection and gut microbiota. Kazan Medical Journal 102(4), 518-527. DOI: 10.17816/KMJ2021-518. (In Russ.)

SAMPAIO-MAIA B., SIMOES-SILVA L., PESTANA M. et al. (2016): The role of the gut microbiome on chronic kidney disease. AdvApplMicrobiol. 96, 65-94. doi: 10.1016/bs.aambs.2016.06.002.

SAMPSON T.R., DEBELIUS J.W., THRON T. et al. (2016): Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease. Cell 167(6), 1469-1480.e12. doi: 10.1016/j .cell.2016.11.018.

SANDERS J.M., MONOGUE ML., JODLOWSKI T.Z. & CUTRELL J.B. (2020): Pharmacologic treatments for coronavirus disease 2019 (COVID-19). JAMA 323(18), 1824-1836. DOI: 10.1001/jama.2020.6019.

SARTOR R.B. (2003): Targeting enteric bacteria in treatment of inflammatory bowel diseases: Why, how, and when. Curr. Opin. Gastroenterol. 19, 358-365. doi: 10.1097/00001574-200307000-00006.

SCHEPIS T., DE LUCIA S.S., NISTA E C., MANILLA V., PIGNATARO G., OJETTI V., ... & CANDELLI M. (2021): Microbiota in pancreatic diseases: a review of the literature. Journal of Clinical Medicine 10(24), 5920.

SCHROEDER B.O. (2019): Fight them or feed them: How the intestinal mucus layer manages the gut microbiota. Gastroenterol. Rep. 7, 3-12.

SEGAL L.N., CLEMENTE J.C., LI Y. et al. (2017): Anaerobic Bacterial Fermentation Products Increase Tuberculosis Risk in Antiretroviral-Drug-Treated HIV Patients. Cell Host Microbe 21, 530-537.

SHILOV A.M., CHUBAROV M.V., MELNIK M.V. & RYBKINA T.E. (2003): Arterial hypertension and metabolic syndrome X. Russian medical journal 21, 1145.

SHIOMI Y., NISHIUMI S., OOI M. et al. (2011): Gcms-based metabolomic study in mice with colitis induced by dextran sulfate sodium. Inflamm. Bowel Dis. 17, 2261-2274.

SITKIN S.I., VAKHITOV T.YA. & DEMYANOVA E.V. (2018): Microbiome, gut dysbiosis and inflammatory bowel disease: That moment when the function is more im-portant than taxonomy. Almanac of Clinical Medicine 46(5), 396-425. doi: 10.18786/2072-0505-2018-46-5-396-425. (In Russ.)

SIVA S., BARRACK E.R., REDDY G.P. et al. (20019): A critical analysis of the role of gut Oxalobacter formigenes in oxalate stone disease. BJUInt. 103, 18-21. doi: 10.1111/j.1464-410X.2008.08122.x.

SOROKINA YU.A., PRYAZHNIKOVA M.I., SINYUSHKINA S.D., GORINOVA A.V., SUKHANOV S.A., RUDAKOV A.S. & ZANOZINA O.V. (2023): Potential Effect of Pharmacotherapy on the Course

of Kidney Diseases in Intestinal Dysbiosis. Effective pharmacotherapy 19(21), 46-52. DOI 10.33978/2307-3586-2023-19-21-46-52. (In Russ.)

STANDARDIZATION SYSTEM IN HEALTHCARE OF THE RUSSIAN FEDERATION (2003): Protocol for patient management. Intestinal dysbacteriosis: Industry Standard 91500.11.0004-2003. Approved by the Order of the Ministry of Health of the Russian Federation dated 09.06.2003 No. 231. Electronic fund of legal and normative-technical documentation. URL: https://docs.cntd.ru/document/1200119089.

STATINOVA E.A., OMELCHENKO R.YA. & AURSALIDI A O. (2013): Infectious agents in the development of atherosclerosis. Ateroscleroz 9(3-4), 51-64. (In Russ.)

TANG L., GU S., GONG Y. et al. (2020): Clinical significance of the correlation between changes in the major intestinal bacteria species and COVID-19 severity. Engineering 6(10), 1178-84. DOI: 10.1016/j.eng.2020.05.013.

THOMAS R.M. & JOBIN C. (2020): Microbiota in pancreatic health and disease: The next frontier in microbiome research. Nat. Rev. Gastroenterol. Hepatol. 17, 53-64.

TKACHENKO E.I., SITKIN S.I., ORESHKO L S. & MEDVEDEVA O.I. (2016): Trophology aspects of noocpherogenesis. Experimental and Clinical Gastroenterology 2, 4-13. (In Russ.)

TOPCHIY T.B., ARDATSKAYA M D., BUTOROVA L.I., MASLOVSKII L.V. & MINUSHKIN O.N. (2022): Features of the intestine conditions at patients with a new coronavirus infection. Terapevticheskii Arkhiv (Ter. Arkh.) 94(7), 920-926. DOI: 10.26442/00403660.2022.07.201768. (In Russ.)

TURNBAUGH P.J., HAMADY M., YATSUNENKO T., CANTAREL B.L., DUNCAN A., LEY R.E., SOGIN M L., JONES W.J., ROE B.A., AFFOURTIT J.P. et al. (2009): A core gut microbiome in obese and lean twins. Nature 457, 480-484. doi: 10.1038/nature07540.

TYUTINA R.R., PILIPOVICH A.A., GOLUBEV V.L. & DANILOV A.B. (2020): Microbiota and Parkinson's disease (overview). Medical alphabet 1, 10-14. https://doi.org/10.33667/2078-5631-2020-1-10-14. (In Russ.)

URIBE-HERRANZ M., RAFAIL S., BEGHI S., GIL-DE-GOMEZ L., VERGINADIS I., BITTINGER K., PUSTYLNIKOV S., PIERINI S., PERALES-LINARES R., BLAIR I.A., MESAROS C.A., SNYDER N.W., BUSHMAN F., KOUMENIS C. & FACCIABENE A. (2020): Gut microbiota modulate dendritic cell antigen presentation and radiotherapyinduced antitumor immune response. J Clin Invest. 130(1), 466-79. doi: 10.1172/JCI124332.

WANG J., XIONG K., ZHAO S., ZHANG C., ZHANG J., XU L. & MA A. (2020): Long-Term Effects of Multi-Drug-Resistant Tuberculosis Treatment on Gut Microbiota and Its Health Consequences. Front. Microbiol. 11, 53.

WILLIAMS H.R., COX I.J., WALKER D.G. et al. (2009): Characterization of inflammatory bowel disease with urinary metabolic profiling. Am. J. Gastroenterol. 104, 1435-1444.

WONG J., PICENO Y.M., DESANTIS T.Z. et al. (2014): Expansion of urease- and uricase-containing, indole- and p-cresol-forming and contraction of short-chain fatty acid-producing intestinal microbiota in ESRD. Am J Nephrol. 39, 230-237. doi: 10.1159/000360010.

WU Y., GUO C., TANG L. et al. (2020): Prolonged presence of SARS-CoV-2 viral RNA in faecal samples. Lancet Gastroenterol. Hepatol. 5(5), 434-435. DOI: 10.1016/S2468-1253(20)30083-2.

YANG Y. & JOBIN C. (2017): Novel insights into microbiome in colitis and colorectal cancer. Curr Opin Gastroenterol 33(6), 422-7. doi: 10.1097/ MOG.0000000000000399.

ZAKHAROVA YU.V. (2018): Gut bacterial microbiome of HIV-infected people. Journal of microbiology, epidemiology and immunobiology 2, 102-109. (In Russ.)

ZHELEZOVA L.I. & KVETNAYA A.S. (2021): Diagnostics and prediction ofviolations of microbiocenosis of the tolstous in rotasviral diarrhea in children. Poliklin 3, 24-27. (In Russ.)

ZHENG X., ZHAO A., XIE G., CHI Y., ZHAO L., LI H., WANG C., BAO Y., JIA W., LUTHER M. et al. (2013): Melamine-induced renal toxicity is mediated by the gut microbiota. Sci TranslMed. 5, 172ra122.

ZUO T., LIU Q., ZHANG F. et al. (2021): Depicting SARS-CoV-2 faecal viral activity in association with gut microbiota composition in patients with COVID-19. Gut 70(2), 276-284. https://doi.org/10.1136/gutjnl-2020-322294.