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Current issues in the correction of intestinal microbiocenosis

HEALTH COMMITTEE
GOVERNMENT OF ST. PETERSBURG

NORTHWESTERN STATE MEDICAL
UNIVERSITY named after. I.I. MECHNIKOVA

teaching aid

SAINT PETERSBURG

UDC: 616.36-002.2:616.831:615.241.2(07)
Current issues in the correction of intestinal microbiocenosis. Educational and methodological manual. St. Petersburg, 2012.

This educational manual outlines current issues related to disturbances of intestinal microbiocenosis in patients with chronic liver diseases, presents the modern definition, classification, methods of diagnosis and treatment of this condition. The significance of the normal composition of the colon microbiocenosis on the course of the underlying disease is noted.

The educational and methodological manual is intended for general practitioners, therapists, gastroenterologists, infectious disease specialists, dermatologists, surgeons and senior students of medical universities.

The educational manual was developed at the North-Western State Medical University named after. I.I. Mechnikov by Professor V.G. Radchenko, professor V.P. Dobrits, assistant P.V. Seliverstov, graduate students L.A. Teterina, E.A. Chikhacheva.

Reviewers: Head. Department of Propaedeutics of Internal Diseases of Northwestern State Medical University named after. I.I. Mechnikova, professor, PhD. E.I. Tkachenko

Professor of the Department of Internal Medicine and Nephrology of Northwestern State Medical University named after. I.I. Mechnikova, professor, doctor of medical sciences O.A. Sablin

Introduction

In recent years, sufficient knowledge and experience has accumulated in the diagnosis and treatment of most human diseases, including the gastrointestinal tract, which is associated with the development and implementation of the principles of evidence-based medicine, modern diagnostic methods and the production of effective drugs. Thanks to this innovation in medical practice, established views on the pathogenesis, principles of diagnosis and treatment of many gastrointestinal diseases have radically changed.

Today it has been established that the intestinal microflora is an integral part of the human body and performs numerous vital functions and, naturally, is involved in the pathological process occurring at the level of the whole organism.

Thus, indigenous representatives of normal intestinal microflora, which are quite labile and can change quantitatively and qualitatively under the influence of numerous factors, participate in maintaining the health of the host organism. Normal human microflora is an established system of many microbiocenoses, characterized by a certain species composition and occupying one or another biotope in the human body.

Composition and role of intestinal microflora

Indigenous representatives of the normal intestinal microflora participate in maintaining the health of the host organism. The latter is very labile, changing in quantitative and qualitative aspects under the influence of numerous factors. The normal human microflora is considered as a phylogenetically formed system of many microbiocenoses , characterized by a certain species composition and occupying a particular biotope in the human body.

The most representative and complex in the human body is the intestinal microbiocenosis. It includes representatives of 17 families, 45 genera and over 1,500 species of microorganisms (some researchers report 150 thousand species). In 1 g of colon contents, the number of bacteria is 10 12 CFU, while the total number of microbial bodies reaches 10 14 –10 15. It is important that there are 1000 times more anaerobic microorganisms than aerobic ones.

For a long time it was believed that bacteria colonizing the surface of the mucous membrane form a biofilm, which is adjacent directly to the apical part of the epithelium. However, recently it has been shown that consortia of microorganisms form colonies on the apical surface of the epithelium. These microorganisms constitute the so-called normal, or resident (autochthonous), microflora of a particular biotope, in contrast to microorganisms that are found in the lumen of the open intestinal cavity. Normal microflora is immersed in the mucous, or enteral, environment of the body. The composition of the enteral environment includes mucin, waste products of microorganisms (metabolites), low molecular weight food fragments, humoral and cellular components of the immune system. This is a special environment in the hierarchy of internal environments of the body, which has properties intermediate between the properties of the external and internal environments.

Obligate microflora accounts for more than 90% of all bacteria available for cultivation in clinical practice. It is this part of the intestinal microbial spectrum that is classified as permanent (autochthonous) microflora.

In the process of joint evolution, close relationships have developed between the host organism and representatives of the normal microflora, which have left their mark on the physiological characteristics of each of the interacting parties. Microflora is involved in the implementation of almost all the most important functions of the macroorganism. Thus, resident microflora is involved in supplying the cells and tissues of the macroorganism with nutrients.

Based on the provisions of the theory of A.M. Ugolev, the body is supplied with nutrients thanks to 2 streams: the 1st is directly the products of digestion (cavity, parietal, etc.), and the 2nd is metabolites and other waste products of the components of normal microflora. It is the presence of these 2 flows that ensures a constant supply of nutrients to the body, both in terms of assortment (i.e., in composition and ratio of components) and in time.

Taking into account the numerous metabolic functions of microflora, a violation of colonization resistance can be considered one of the most likely triggering factors for various diseases, primarily the liver. When the pathology of any organ manifests itself, it is difficult to identify a decrease in colonization resistance of the intestine as an independent pathogenetic link, since various metabolic disorders are combined into a single dismetabolic process.

There is a controversial opinion about the advisability of attributing short-term changes in the ratio of normal microflora of the digestive tract to dysbacterial reactions, and persistent ones to dysbiosis or dysbacteriosis, although it is more correct to call such changes in human endoecology disorders of the microbiocenosis of the mucous membranes of the gastrointestinal tract (GIT) with clinical or other symptoms of manifestations or without them. The latter is consistent with world literature data.

Intestinal dysbiosis according to OST 91500.11.0004–2003 “Protocol for patient management. Intestinal dysbiosis" is a clinical and laboratory syndrome that occurs in a number of diseases and clinical situations and is characterized by changes in the qualitative and (or) quantitative composition of normal microorganisms, their excessive or insufficient growth, the transition of various species to a state unusual for them, causing metabolic, immunological disorders and various clinical manifestations. In patients with chronic liver diseases (CLD), disturbances in the composition of the normal intestinal microflora are detected in more than 90% of cases, and the severity of the clinical manifestations of the disease is often directly linked to the severity of changes in the intestinal microecology. There are many trigger and predisposing moments for the development of microbial endoecology disorders: due to changes in the quantity and quality of microorganisms (bifidobacteria, lactobacilli, E. coli), against the background of various effects (hypothermia, physical or mental overload, toxic, chemical, medicinal - antibiotics, cytostatics, postoperative and other stress effects), disturbances in the ratio of bacteria in different parts of the gastrointestinal tract, increased proliferation of opportunistic flora and the appearance of pathogenic flora.

Intestinal microflora and liver are the main systems through the interaction of which the body’s detoxification processes are carried out. The microbiota in the biofilm is the first to come into contact with all substances entering the body with food, water, and atmospheric air. It transforms chemicals into non-toxic end products or intermediate compounds that are easily broken down in the liver and removed from the body. Violation of the interaction between the liver and intestines leads to mutual functional and structural changes in them and in the body as a whole. As a result, hepatoenteric regulation of various organic and inorganic compounds can, without exaggeration, be considered a cardinal homeostatic mechanism. The reduced detoxification function of microflora during intestinal dysbiosis increases the load on the enzymatic systems of the liver, which contributes to the occurrence of metabolic and structural changes in it. Contamination of the intestine with opportunistic and pathogenic microflora in CKD accelerates disruption of parietal digestion, inhibits the synthesis of B vitamins, disrupts hepatoenteric circulation with the formation of toxic substances, and increases the permeability of the intestinal wall epithelium to bacteria, toxic products, micro- and macromolecules. In other words, a vicious circle arises that maintains mutually aggravating damage to the intestines and liver. In patients with CKD with impaired intestinal biocenosis, there is an aggravation of morphological changes in the structure of the liver in the form of: manifestations of hepatocyte dystrophy and histological activity of the process, the severity of fibrotic changes, activation of sinusoidal mononuclear cells, disruption of the processes of synthesis and bile flow. In turn, disturbances in the processes of synthesis and excretion of bile components in liver diseases can lead to changes in the qualitative and quantitative composition of the intestinal microbiota and, as a result, to disruptions in the functioning of internal organs and the development of polyvalent clinical manifestations of internal microbial disharmony.

The complexity of pathogenesis, the staged inclusion of individual pathological factors in the development of one or another clinical and laboratory syndrome of the disease, multidirectional changes in the carbohydrate, lipid, protein metabolism of the human body, and the role of the immune system significantly complicate the diagnosis and adequate pharmacological correction of CKD. Despite advances in the study of the etiology and pathogenesis of CKD, the issues of their treatment at the present stage have not been completely resolved. At the same time, clinical manifestations of intestinal dysbiosis are detected in the majority of patients with pathology of the hepatobiliary system, and the severity of CKD does not always correlate with the severity of disorders of the intestinal microecology. Most authors indicate that in liver diseases, the intestinal microbiocenosis is disrupted in more than 50% of cases, however, the frequency of detection of individual degrees of dysbiosis has not been sufficiently studied. According to our data, intestinal dysbiosis is detected in all patients with CKD (CHB, CHB, NAFLD), and dysbiosis of the 1st and 4th degrees was most often detected in CHB and CHB, and dysbiosis of the 2nd and 3rd degrees - in NAFLD. An increase in the content of potentially pathogenic bacteria leads to an increase in the formation of endotoxins, which, penetrating through the intestinal mucosa into the local circulatory system and then through the portal vein into the liver, cause damage to hepatocytes or potentiate the adverse effects of other toxic substances. About 90% of all endotoxins are released facultatively by anaerobic gram-negative bacteria. Specific damaging mechanisms in this case are destruction of cell membranes, disruption of ion transport, fragmentation of nucleic acids, formation of free radical oxidation products, and induction of apoptosis.

In small intestinal bacterial overgrowth syndrome (SIBO), severe consequences are also associated with the fact that microbes can compete with the host for the utilization of nutritional components. This increases the absorption of microbial metabolic products and creates an increased toxic load on the liver. Toxic amines are released after decarboxylation of amino acids by microbes. Bacterial amino acid metabolites (ammonium, amines, phenols, indoles, skatoles) are transferred into the blood and cannot be sufficiently detoxified, especially in liver diseases. Disorders of intestinal absorption lead to serious changes in the body's activity, while malabsorption plays a role in the development of such clinical manifestations as anemia, dystrophy, and polyhypovitaminosis.

Numerous clinical studies have shown that metabolic disorders in the liver, often associated with changes in intestinal microbiocenoses, include both hepatic and intestinal pathogenesis. In the formation of steatosis and steatohepatitis, exogenous risk factors are identified - excessive entry into the hepatocyte from the intestine of lipid hydrolysis products (fatty acids - FA), glucose, fructose, galactose, alcohol, and endogenous - increased concentration and impaired oxidation of fatty acids (FA) in the hepatocyte, formed during lipolysis of peripheral fat, which increases with a deficiency or decrease in tissue sensitivity to insulin, accumulation of triglycerides in hepatocytes, relative or absolute deficiency of apoproteins B, C1–C3, E.

The transformation of steatosis into steatohepatitis is caused by: activation of the production of tumor necrosis factor alpha (TNF-α) by adipose tissue, an increase in the concentration of free fatty acids, which have a direct damaging effect on hepatocyte membranes and activate cytochrome P450-2E1 with an increase in lipid peroxidation, accumulation of reactive oxygen species ( oxidative stress) and the formation of excessive amounts of highly toxic xenobiotics. The presence of bacterial overgrowth in the intestine is essential in the transformation of steatosis into steatohepatitis. Thus, according to the results of a hydrogen breath test, excessive bacterial proliferation in the small intestine is detected in 50–75% of patients. The maximum severity of bacterial growth is observed in non-alcoholic steatohepatitis, resulting in cirrhosis of the liver.

Clinical diagnosis of intestinal microbiocenosis disorders in patients with CKD presents certain difficulties due to the lack of generally accepted methods and criteria. However, clinical practice shows that when treating diseases of internal organs, taking into account the correction of the state of intestinal microbiocenosis, the results improve.

It must be remembered that the intestinal microflora is involved in pathophysiological reactions during the development of most human diseases. That is why timely diagnosis and correction of dysbiotic changes in intestinal microbiocenosis based on modern advances in therapy, medical microbiology, biotechnology, immunology and allergology is an important common task for doctors of different specialties, since the choice of the most adequate treatment tactics largely depends on them.

Signs of disturbance of intestinal microbiocenosis:

Stool disorders (diarrhea, constipation);
Flatulence (a feeling of fullness in the stomach due to increased gas formation, rumbling);
Abdominal pain;
Gastrointestinal dyspepsia syndrome (a feeling of fullness in the stomach, aerophagia, belching, nausea, difficulty defecating, changes in the character of feces);
Symptoms of hypovitaminosis;
Chronic food urticaria;
Maldigestion syndrome.

Stages of clinical development of intestinal dysbiosis

(according to V.M. Bondarenko, 2006)

Stage 1 – compensated (latent): there are no clinical manifestations, the ratios of microflora indicators change; Stage 2 – subcompensated: general condition is impaired, dyspeptic disorders; Stage 3 – decompensated: symptoms of general intoxication and dyspepsia intensify; body weight decreases; skin allergic reactions; trophic disorders appear; generalization of the process with extreme weakening of the body.

Classification of intestinal dysbiosis

There are four degrees:

1st degree: characterized by minor changes in the aerobic part of the microbiocenosis (increase or decrease in the number of Escherichia). As a rule, intestinal dysfunction is not observed.

2nd degree: against the background of a slight decrease in the content of bifidobacteria, quantitative and qualitative changes in Escherichia and an increase in opportunistic bacteria, pseudomonads and fungi of the genus Candida are detected. Transient intestinal dysfunction is observed.

3rd degree: the level of bifidoflora and lactoflora decreases, the number of Escherichia changes sharply. Conditions are created for the manifestation of the aggressive properties of opportunistic microorganisms, and intestinal dysfunction occurs.

4th degree: there is no bifid flora, the amount of lacto flora is significantly reduced, the content of Escherichia coli changes, the number of obligate, facultative and opportunistic microorganisms increases. The normal ratio of the composition of the intestinal microbiocenosis is disrupted. These changes contribute to the development of gastrointestinal dysfunction, which leads to destructive changes in the intestinal wall, bacteremia, sepsis, etc.

Clinical manifestations of intestinal dysbiosis:

Local (intestinal) symptoms and syndromes;
Systemic disorders caused by the translocation of intestinal microflora and its toxins into the internal environment of the macroorganism, impaired absorption processes, immunological disorders, etc.

Effect of dysbiosis on the colon:

Damage to enterocytes;
Increased intestinal permeability;
Change in motor skills;
Reduced protective properties of the mucous membrane;
Translocation of microflora.

Laboratory diagnostic methods

Laboratory methods for diagnosing dysbiosis in CKD can be direct (isolation of living microflora from biological material or biofluids of the patient) and indirect (determination of products associated with the vital activity of microflora).

Direct methods include: culture and electron microscopy of stool, small intestinal aspirate, intestinal and liver biopsies. Indirect methods are: biochemical stool tests, breath tests (hydrogen, C14-glycocholate or C14-D-xylose tests), gas-liquid or thin layer chromatography of feces or small intestinal fluid.

Bacteriological examination of stool. The most common method of laboratory diagnosis in patients with liver diseases is bacteriological culture of stool to study the quantity and quality of microbes. It should be taken into account that this method has a number of generally accepted disadvantages: the length of time it takes to obtain results, the use of expensive culture media, the dependence of the results on compliance with the necessary conditions for taking samples, their storage, transportation times and the quality of transport and culture media, the predominant determination of intraluminal microflora. In addition, the number of cultivated intestinal anaerobic bacteria does not exceed 7–50% of their estimated true number, so it is quite difficult to determine the microbiocenosis of the small intestine. The listed objective difficulties of research do not provide a complete picture of the autochthonous (resident) microflora inhabiting the glycocalyx. Quite often they forget about the low sensitivity of this method and the possibility of obtaining false negative results. Its main disadvantage is the inability to differentiate between organic and functional pathology of the gastrointestinal tract, which led to a change in microbiocenosis, in order to carry out not symptomatic, but etiopathogenetic treatment.

Microbiological criteria for intestinal dysbiosis:

an increase in the number of opportunistic microorganisms of one or more species in the intestine with a normal number of bifidobacteria;
an increase in one or several types of opportunistic microorganisms with a moderate decrease (by 1–2 orders of magnitude) in the concentration of bifidobacteria;
reduction in the content of obligate representatives of the microbiocenosis (bifidobacteria and/or lactobacilli) without a recorded increase in the amount of saprophytic or opportunistic intestinal microflora;
moderate or significant (<10 7) снижение содержания бифидобактерий, сочетающееся с выраженными изменениями в аэробной микрофлоре: редукцией лактобацилл, появлением измененных форм кишечной палочки, обнаружением одного или нескольких представителей условно-патогенных микроорганизмов в высоких титрах (до 10 7 –10 8 КОЕ/г).

Dysbiosis is characterized by the presence of at least 3 criteria that are persistently preserved in 3-fold analysis.

Coprogram indirectly indicates dysbiotic disorders, and the changes detected depend on the presence and type of a particular intestinal dyspepsia.

Bile acids excreted by the liver in the proximal parts of the small intestine perform their main physiological function - they participate in the digestion and absorption of lipids. In the distal parts of the small intestine, transformations of the bile acids themselves occur: deconjugation, dehydroxylation and their reabsorption.

The main physiological site of absorption of bile acids is the terminal ileum, where there is a specific active transport system, which in general ensures a constant circulation of bile acids. In a healthy person, 95% of bile acids are reabsorbed during each cycle and only 5% is lost in the feces. In the presence of an inflammatory process and dysbiosis in the ileum, fecal losses of bile acids increase significantly.

Bile acids in the colon inhibit absorption and increase secretion of water and electrolytes, which causes secretory (cholagogenic) diarrhea. Thanks to the enterohepatic circulation, primary conjugated and deconjugated, as well as secondary bile acids enter the hepatocyte. In this case, deoxycholic acid binds to glycine or taurine and circulates along with primary bile acids. Lithocholic acid, in addition, is conjugated with sulfates, which sharply reduces its absorption and entry into the enterohepatic circulation. Excessive absorption and entry into circulation of deoxycholic acid promotes the formation of gallstones, while lithocholic acid leads to damage to hepatocytes.

With partial damage to the ileum (less than 100 cm), impaired absorption of bile acids leads to so-called biliary diarrhea. With more extensive lesions (more than 100 cm), absolute deficiency of bile acids develops due to interrupted enterohepatic circulation, which is the cause of steatorrhea.

In patients with symptoms of dysbiosis, the cholesecretory function of the liver is impaired, which is associated with a violation of the enterohepatic circulation of bile acids and the conjugating ability of the liver. Bile acids have a stimulating effect on the growth and function of normal intestinal microflora. The biosynthesis of bile acids is controlled by a negative feedback type by a certain amount of bile acids returning to the liver in the process of enterohepatic circulation. Bile acids stimulate intestinal motility and have a bacteriostatic effect. With a decrease in the flow of bile into the intestines, the microflora undergoes significant changes. The total concentration of bile acids in the blood and their ratio change significantly in liver diseases.

Free bile acids, formed as a result of increased deconjugation processes in the proximal parts of the small intestine under the influence of intestinal bacteria, mainly Bacteroides, are a factor damaging the intestinal mucosa. Unabsorbed in the small intestine, long-carbon chain FAs in the colon also cause hypersecretion of water and sodium and, consequently, diarrhea. At the same time, the concentration of conjugated bile acids involved in lipid absorption is significantly reduced.

Malabsorption in the small intestine is characterized by steatorrhea, expressed to a greater or lesser extent, and represented by FA during diarrhea or FA salts during normal evacuation of chyme through the intestines or constipation.

Digestive insufficiency in the large intestine is accompanied by fermentative dyspepsia, in which a large amount of digested fiber is formed. The amount of feces is significantly increased, the nature of the stool is pasty, foamy, the reaction of feces is sharply acidic, a large amount of starch, digested and undigested fiber, iodophilic flora, fatty acids is determined, the amount of secreted organic acids is increased. In a preparation with Lugol's solution, starch located intra- and extracellularly and normal iodophilic flora (clostridium) are revealed.

When fermentation processes predominate in the intestines, the sharply sour smell of feces attracts attention. Intestinal dysbiosis in patients with CKD, leading to fermentative dyspepsia, is characterized by the appearance of mucus with leukocytes and columnar epithelium, while the mucus is usually mixed with fecal detritus and the appearance of pathological iodophilic flora (small cocci, small and large rod flora). With dysbiosis occurring with putrefactive dyspepsia, the amount of feces is increased, the stool is liquid, an alkaline reaction of the feces is noted, it contains a lot of muscle fibers, starch, undigested fiber, and iodophilic flora. Putrefactive dyspepsia (colitis) - crystals of triple phosphates indicate a shift in pH to the alkaline side and an increased process of putrefaction in the large intestine.

PCR diagnostics. Molecular genetic methods allow the identification of microorganisms by determining the unique base sequence of deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) of the microbes being studied; In recent years, the method of determining the types of microorganisms using polymerase chain reaction (PCR diagnostics) has become widespread. The PCR method is based on the complementary completion of a section of genomic DNA or RNA of the pathogen, carried out in vitro using the enzyme thermostable DNA polymerase. Using PCR diagnostics, some representatives of microflora with intracellular or membrane localization, which are difficult to cultivate in nutrient media, are determined. The method is distinguished by ease of execution, the possibility of full automation, speed of obtaining results, and a small amount of pathological material required for research. However, the information content of the study is high only in relation to a limited range of opportunistic and pathogenic microorganisms and viruses. This method has a number of disadvantages, such as frequent false-positive results and the impossibility of adequate quantitative assessment. In terms of sensitivity, PCR is the most advanced as a diagnostic method (several orders of magnitude higher than other tests). The specificity of the method is also high, but so far most test systems are not reliable enough to supplant classical methods in diagnosing even absolute pathogens.

Gas-liquid chromatography of feces (GLC). Allows you to evaluate substances associated with the vital activity of microorganisms (precisely those that are not determined during routine bacteriological testing, which requires special conditions for cultivating anaerobes). The method allows you to quickly and accurately assess the state of indigenous microflora. In addition, a distinctive feature of the developed method is that as a result, material has been accumulated not only to verify the generic composition of microorganisms, but also a clinical database of FA content (taking into account their physiological effects) in many biological substrates for various gastrointestinal pathologies has been compiled, and an adequate forecasting system has been developed and monitoring the clinical course, severity, stage of the pathological process and the development of complications in gastrointestinal pathology, effective treatment regimens have been developed taking into account the individual “metabolite” status of the patient. That is, the use of a new methodological approach allows the clinician not only to correctly assess the state of the microbiocenosis, but also to identify the pathology that led to its disruption and differentiated treatment.

Gas chromatography with mass spectrometry. The composition of the parietal intestinal microbiota can be analyzed using gas chromatography combined with mass spectrometry (GC-MS) . It is in the mucous layer that encloses the intestinal mucosa that the absorption of food chyme coming from the stomach and essential nutrients by the epithelial cells of the intestinal wall occurs, as well as the synthesis by microorganisms of a large number of biologically active substances (enzymes, vitamins, antibiotics, immunostimulants), as well as toxins and metabolites harmful to humans. The microflora of feces is a product of these processes, in which the proliferation of microorganisms continues, but under different conditions compared to the upper parts of the intestine and reflects the cavity rather than the parietal microflora, which is more stable. The method is based on identifying the presence of microorganisms by chemical substances specific to them - markers from among FAs, aldehydes and sterols that are part of their cell wall. Specificity means that such substances are contained only in the lipids of microorganisms and are not found in their habitat. Therefore, with a sufficiently sensitive analytical method, they can be detected and quantified directly in their habitat, avoiding the need to pre-cultivate them in artificial media. The essence of the analysis is to extract higher FAs from the sample to be studied (clinical material: blood, urine, feces), separate them on a chromatograph in a high-resolution capillary column, and analyze the composition in dynamic mode on a mass spectrometer. The method of detecting microorganisms using FA markers is similar to the genetic method (PCR, determination of the nucleotide sequence of 16sRNA, etc.), since the composition of FAs is determined in DNA and is reproduced by replication of a genome region with transfer RNAs and subsequent synthesis of FAs in mitochondria using messenger RNAs. Both methods show that there are more eubacteria, bacteroides and clostridia, together and individually, by an order of magnitude than bifidobacteria. To diagnose dysbiotic changes or infection of the small intestine, blood is examined using GC-MS. 40 µl of blood is enough – i.e. literally one microdrop. Such an amount can be obtained by collecting blood from a fingertip during a standard clinical blood test, which significantly simplifies the collection of material and reduces the time required to complete the analysis.

Thus, in order to obtain a complete picture of microflora disturbances in both the small and large intestines, it is necessary to combine diagnostic methods and monitor them, which allows for a rational design of the therapy and timely correction over time.

Therapeutic measures

For patients with CKD with clinical manifestations of microbiocenosis disorders, it is advisable to correct microbiocenosis in several directions. This is etiotropic therapy, measures to restore impaired metabolic function of the liver, activate cells of the reticuloendothelial system and eliminate disorders of the intestinal microbiocenosis. Due to close cooperation, the listed approaches are equally important. Disruption of the enzymatic systems of liver cells, imbalance of mechanisms for controlling their functions due to changes in cooperation in the microbiota - sinusoidal mononuclear cells - hepatocyte system do not leave hope for achieving a positive metabolic effect without drug intervention.

Their successful implementation is possible with long-term use of bile acid preparations, probiotics and prebiotics. The complex of these drugs is characterized by the absolute absence of a hepatotoxic effect, which is important in many respects. To correct impaired liver function in CKD, bile acid preparations belonging to the group of hepatoprotectors (ursodeoxycholic acid - ursofalk) are used. They initiate the restoration of the physiological functions of hepatocytes, have membrane-stabilizing, antioxidant activity, and also enhance the production of bile (choleretic effect) and ensure sufficient flow of bile from the liver into the biliary tract (cholekinetic effect), which contributes to the normalization of digestive processes.

It is advisable to correct violations of intestinal microbiocenoses in several directions: elimination of adverse external influences; complete functional nutrition; therapy of the underlying disease; correction of intestinal microbiocenosis disorders. Currently, there are 3 areas of correction of intestinal microbiocenosis disorders:

selective decontamination (antibiotics, intestinal antiseptics);
“stimulation” of strains of normal microflora (prebiotics),
replacement therapy (probiotics - Bifistim).

The positive effect of microbiocenosis-correcting agents on the human body is mediated by inhibition of growth, reproduction and colonization of pathogenic and opportunistic microorganisms, creation of optimal conditions for the development of endogenous obligate microorganisms, immunomodulation, direct influence on the physiological functions and biochemical reactions of the body. In order to inhibit the growth, reproduction and colonization of pathogenic and opportunistic microorganisms, antibacterial drugs are used, however, the possibility of suppressing the symbiont microbiota and the increase in the number of resistant forms leads to a limitation of their use. The absolute indications are bacteremia and the threat of enterogenous sepsis due to dysbiosis. The drugs of choice in this case are broad-spectrum antibiotics, to which microbes found in the blood are sensitive. Relative indications for antibiotic therapy may be chronic diarrheal diseases with excessive bacterial growth of pathogenic microbial flora in the lumen of the small intestine (post-resection short small intestine syndrome, adhesive disease, celiac disease with torpid course). On the other hand, the indication for the prescription of antimicrobial drugs is a persistent increase in the amount of opportunistic microflora of more than 10 4 -10 5 per gram, accompanied by severe intestinal and general somatic disorders. It is recommended to use intestinal antiseptics with less pronounced adverse effects on the symbiont microbial flora than antibiotics.

Prebiotics are a large number of compounds that selectively stimulate the growth and/or metabolism of one or more groups of microorganisms living in the intestine, ensuring the normal composition of the intestinal microbiocenosis. The following have a prebiotic effect: oligo-, mono- and polysaccharides (lactulose, xylitol, pectin, inulin); soluble and insoluble dietary fiber (psyllium, fibergam); plant and microbial extracts (yeast, potato, corn, rice); amino acids (valine, arginine, glutamic acid); antioxidants (superoxide dismutase, rexod, vitamins A, C, E, carotenoids); polyunsaturated fatty acids (eicosapentaenoic acid), etc. Prebiotics have a beneficial effect on various body functions and do not have side effects with long-term use.

Probiotics – preparations or food products containing live strains of normal intestinal microflora. An important mechanism of their action is the antagonistic effect against pathogenic strains of intestinal microflora, caused by the action of metabolites of normal bacteria, the main of which are short-chain fatty acids and lactic acid.

The following requirements apply to microorganisms on the basis of which probiotics are created:

1) the microorganism must be identified to a species based on pheno- and genotypic characteristics, the genetic characteristics of the strain must be examined, including extrachromosomal factors of heredity;

2) the strain must belong to a species that does not cause human diseases, i.e. must be avirulent, apathogenic, safe for humans;

3) the properties of the strain must be stable during cultivation, during production and long-term use in laboratory animals;

4) the strain must exhibit antagonistic activity towards pathogenic and opportunistic microorganisms, while not inhibiting representatives of normal microflora; chromosomal resistance to therapeutic doses of antibiotics is desirable;

5) strains must be stable in biological properties at all stages of the process of obtaining drugs and when stored within regulated periods.

Microbiological criteria for selecting a therapeutically active probiotic include:

high viability of the bacterial strain of the probiotic and rapid transition of the strain from anabiosis to a metabolically active state;
antagonism to pathogenic pathogens of the patient’s diseases (bacteria, viruses, fungi, mycoplasmas, etc.);
absence of antagonism and symbiosis with normal beneficial human microflora;
absence of antagonism of normal microflora to the probiotic strain;
adhesive ability of probiotic strains and their short residence time in the human body.

Currently, drugs and food additives containing various microorganisms are used: bifidobacteria ( Bifidobacterium bifidum, B. infantis, B. longum, B. breve, B. adolescentis, B. lactis, B. animals), lactobacilli ( Lactobacillus GG, L. acidophilus, L. plantarum, L. casei spp. rhamnosus, L. brevis, L. helveticus, L. delbrueckii spp. bulgaricus, L. gasseri, L. femientum, L. lactis), lactococci (Lactococcus spp. Withremonis L. lactis spp. Lactis), Escherichia coli ( Escherichia coli), enterococci ( Enterococcus faecium, E. faecalis), streptococci ( Streptococcus salivarium spp. thermophilus, S. faecium, S. cremoris, S. lactis), propionibacteria ( Propionibacterium acnes), bacilli ( Bacillus subtilis), Saccharomyces mushrooms ( Saccharomyces boulardii). Probiotics can contain either a monoculture or several types of microorganisms (symbiotics).

The most promising direction in the treatment of intestinal dysbiosis in patients with CKD is the use of the symbiotic Bifistim for adults, which meets all of the above requirements. The composition of the drug includes a freeze-dried microbial mass of living bifidobacteria of the following strains: Bifidobacterium bifidum, Bifidobacterium longum, Bifidobacterium adolescentis, the concentration of microorganisms is not less than 10? CFU/g. Also contains vitamins (A, D?, C, K, E, B?, B?, B?, B??, niacin, biotin, folic acid, calcium pantothenate), pectin, MCC, calcium hydrogen phosphate, fructose, natural flavoring additive "Orange".

The drug Bifistim Lacto contains a freeze-dried microbial mass of live lactobacilli L. acidophilus, bifidobacteria strains Bifidobacterium adolescentis, concentration of at least 10? CFU/g and oligofructose, pectin, MCC, calcium, fructose.

All microorganisms that make up Bifistim have a synergistic effect in relation to each other. This combination of beneficial bacteria, vitamins and dietary fiber maintains and regulates the physiological balance of intestinal microflora, eliminating the manifestations of intestinal disorders, and produces substances that improve the processes of absorption and assimilation of biologically active substances. The vitamin complex helps restore the body's natural defenses, and is also an additional factor that ensures the balance of normal microflora. Dietary fiber (MCC, pectin) and oligofructose perform a prebiotic function, stimulating the growth and reproduction of bacteria that improve digestion processes, and also promote active detoxification of the body.

Propertiesbifidobacteria and lactobacilli included in the drug Bifistim:

have high antagonistic activity against a wide range of pathogenic and opportunistic intestinal microorganisms, including: staphylococci, Proteus, enteropathogenic Escherichia coli, Shigella, some yeast-like fungi,
restore the balance of intestinal microflora,
normalize the digestive and protective functions of the intestines,
activate metabolic processes,
increase nonspecific resistance of the body,
helps improve liver function,
reduce the risk of developing diarrhea caused by antibiotics and various toxicants,
reduces blood cholesterol levels,
reduce allergic manifestations of lactose intolerance,
prevent the development of cancer,
production of organic fatty acids,
synthesize amino acids, proteins, vitamins B and K, acids: pantothenic, nicotinic, folic, lactic, acetic, formic and succinic,
participate in the utilization of food substrates and activation of parietal digestion and stimulate intestinal motility,
participation in mineral metabolism helps to enhance the absorption processes of calcium, iron, vitamin ions through the intestinal walls,
have an immunomodulatory effect: they regulate the functions of cellular and humoral immunity, prevent the degradation of secretory Ig A, stimulate interferon formation and produce lysozyme.

Indications for use:

In general, combined probiotics have better adhesion and stimulate the growth of indigenous flora to a greater extent.

Thus, there is a close multi-level relationship between the development of CKD and structural changes in the intestinal microflora, which largely determine the severity of liver disease and require an integrated and step-by-step approach to the diagnosis and treatment of these conditions using high-tech drugs.

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Man and his environment form a single ecological system, which is in biological equilibrium with respect to macro- and microorganisms (MO). It is well known that normal microflora (normoflora, or microbiota) populating the human intestine is important for regulating the optimal level of metabolic processes in the body and creating high colonization resistance of the gastrointestinal tract (GIT) to opportunistic MOs. However, in recent years there has been a tendency towards a significant increase in the number of various pathological conditions accompanied by a violation of the microecological balance of the intestine, which requires appropriate pharmacological correction, which is often also called biotherapy. For the first time, the significant role of normal intestinal microflora in human life and maintaining his health was pointed out in his works by the outstanding Russian scientist I.I. Mechnikov. He believed that a lactic acid diet helps reduce the number of pathogenic MOs, calling lactic acid products “longevity products.” It was I.I. Mechnikov was the first to propose maintaining normal intestinal microflora at an optimal level with the help of microorganisms and their metabolic products.

Biotherapies include terms such as “probiotics,” “prebiotics,” and “probiotic products.” Over the years, there have been several interpretations of the term “probiotic.” D.M. Lilly, R.J. Stillwell first used this term in 1965 to refer to the metabolites produced by some MOs to stimulate the growth of others. The term “probiotics” literally means “for life” (in relation to a living organism), in contrast to the term “antibiotics” - “against life”. R. Parker proposed the term “probiotics” to denote natural adjuvants - living microorganisms, the introduction of which into the macroorganism helps maintain and restore the biological balance of its normal flora and has a positive effect on it. R. Fuller used the term “probiotics” to mean living MOs, which, when introduced into animal feed or human food (yogurt), have a positive effect on the body by improving the intestinal microflora. G.R. Gibson, M.B. Robefroid called probiotics live MO (for example, strains of live bacteria in yogurt), which must be present in products in sufficiently large quantities, remain stable and viable both during storage and after administration to the body; adapt to the host’s body and have a beneficial effect on its health. These same authors first proposed to introduce, along with the term “probiotics,” the term “prebiotics.” Unlike probiotics, prebiotics are substances or dietary ingredients that selectively stimulate the growth and biological activity of microorganisms in the intestine, positively affecting the composition of the microbiocenosis. In this article, we will focus on the characteristics of probiotic preparations only.

The total number of MOs living in various biotopes of the human body reaches a value of about 1015, i.e. the number of microbial cells is approximately two orders of magnitude greater than the number of the macroorganism’s own cells. The most significant part (about 60%) of the microflora populates various parts of the gastrointestinal tract, approximately 15-16% in the oropharynx. The urogenital tract, excluding the vaginal section (9%), is rather poorly populated (2%). The rest of the MO falls on the skin. The digestive canal contains more than 500 different types of MO with a biomass of 2.5-3 kg. Together, the macroorganism and microflora constitute a single ecological system, which is in a state of homeostasis, or eubiosis. The most important among the representatives of microflora are lactobacilli (Lactobacillus acidophilus) and bifidumbacteria (Bifidumbacterium bifidum), which form the basis of the obligate (indigenous) flora. This group also includes bacteroides, clostridia, enterococci and Escherichia coli. The species composition of these MOs in humans is genetically determined, and their content in the intestine is relatively constant. At birth, a person does not have Lactobacillus acidophilus in the intestines, but later colonization and rapid growth of these MOs occurs. Bifidumbacterium bifidum is the first to be found in breastfed newborns, entering the sterile intestine with breast milk; later, other bacteria (L. casei, L. fermentum, L. salivares, L. brevis) begin to populate the newborn’s intestines as a result of its contact with the environment environment. Unlike obligate, the composition of facultative intestinal microflora changes depending on the action of certain environmental factors. This facultative microflora is represented by opportunistic MOs: staphylococci, streptococci, clostridia, Proteus, yeast-like fungi, etc. The composition of the microflora of different gastrointestinal biotopes and the content of various MOs in the feces of healthy adults are shown in Tables 1 and 2.

Violation of eubiosis is designated by the term “dysbiosis” or “dysbacteriosis” (the latter was first introduced by A. Nissle in 1916). In the CIS countries, the term “intestinal dysbiosis” is widely used in the literature; such a diagnosis is established based on the results of a study of the microflora of the colon. In foreign literature, the term “bacterial overgrowth syndrome” (SIBO) is used to refer to disturbances in the composition of intestinal microflora, which includes changes in the quantitative and species composition of microorganisms characteristic of a particular biotope. The main difference between the concepts of “SIBO” and “intestinal dysbiosis” lies not so much in terminological nuances, but in the content that goes into them. With SIBO, we are talking about a change not in the “microbial landscape” of the large intestine, but in the composition of the microflora of the small intestine. The causes of SIBO include decreased gastric secretion, dysfunction or resection of the ileocecal valve, disorders of intestinal digestion and absorption, impaired immunity, intestinal obstruction, consequences of surgical interventions (adductor loop syndrome, enteroenteric anastomoses, structural disorders of the intestinal wall).

Thus, the gastrointestinal tract is unevenly colonized by bacteria. The highest density of microbial contamination in the large intestine is about 400 different species. The total biomass of colon microbial cells is approximately 1.5 kg, which corresponds to 1011-1012 CFU/g contents (about 1/3 of the dry weight of feces). It is the large intestine, due to such a high contamination, that bears the greatest functional load compared to other biotopes. The main (resident) flora of the colon is represented by bifidobacteria, bacteroides and lactobacilli, which make up up to 90% of the entire colon microbiota. These representatives belong to anaerobic MO. Resident microflora also includes fecal enterococcus and propionic acid bacteria, but their share in the total pool of microbial populations is insignificant. The accompanying (facultative) microflora is represented mainly by aerobic microorganisms: Escherichia, eubacteria, fusobacteria, various cocci - a total of about 10%. Less than 1% accounts for numerous representatives of residual microflora, including aerobes and anaerobes. In general, 90% of the intestinal microflora are anaerobic bacteria, the anaerobic/aerobic ratio is 10:1. Thus, the main representatives of the intestinal microflora are aerobic lactobacilli (L. acidophilus, L. plantarum, L. casei, L. fermentum, L. salivares, L. cellobiosus) and anaerobic bifidobacteria (B. bifidum, B. infantis, B. longum , B. adolescentis).

The main functions of intestinal microflora normally include:

Colonization resistance of the macroorganism (intermicrobial antagonism, inhibition of growth and development of pathogenic microorganisms, prevention of the spread of putrefactive bacteria from the lower parts of the large intestine to the upper, maintaining an acidic pH, protecting the ecosystem of the mucous membranes from pathogenic microorganisms);

Detoxification (inactivation of enterokinase and alkaline phosphatase, prevention of the synthesis of toxic amines, ammonia, phenol, sulfur, sulfur dioxide, cresol);

Enzymatic function (hydrolysis of metabolic products of proteins, lipids and carbohydrates);

Digestive function (increased physiological activity of the glands of the alimentary canal, increased enzyme activity, participation in the conjugation and recycling of bile acids, metabolism of fatty acids and bilirubin, monosaccharides and electrolytes);

Synthesis of amino acids (arginine, tryptophan, tyrosine, cysteine, lysine, etc.), vitamins (B, K, E, PP, H), volatile (short-chain) fatty acids, antioxidants (vitamin E, glutathione), bioamines (histamine, serotonin , piperidine, γ-aminobutyric acid), hormonally active substances (norepinephrine, steroids);

Antianemic function (improved absorption and assimilation of iron);

Antirachitic function (improving the absorption of calcium and calciferols);

Anti-atherosclerotic function (regulation of lipid levels, cholesterol);

Antimutagenic and anticarcinogenic activity (hydrolysis of carcinogens from the metabolic products of proteins, lipids, carbohydrates, deconjugation of bile and hydroxylation of fatty acids, inactivation of histamine, xenobiotics, procarcinogenic substances, etc.);

Immune function (induction of the synthesis of immunoglobulins, lysozyme, interferon, stimulation of the local immune system, regulation of nonspecific and specific cellular and humoral immunity).

Intestinal microflora can be normal only in the physiological state of the macroorganism. However, the quantitative and qualitative composition of normal microflora, as well as its functions, can be easily disrupted, which leads to the development of dysbiosis, which is currently understood as quantitative and/or qualitative changes in the intestinal microbiocenosis, as well as the appearance of microorganisms in places not typical for their habitat. According to modern epidemiological studies, 90% of the world's population suffers from intestinal dysbiosis to one degree or another. This is due to poor nutrition, stress, decreased immunological reactivity of the body, environmental and physicochemical factors of the external environment, unjustified and uncontrolled use of medications that affect the microflora of the body. It has been established that after suffering an acute intestinal infection in the absence of adequate therapy, dysbiotic changes in the intestines persist for at least 2-3 years. Intestinal dysbiosis is especially common in children of the 1st year of life (70-80%) and newborns (80-100%). In children over 1 year of age, dysbiosis is detected in 60-70% of cases, in healthy children over 3 years of age - in 30-50%.

The following can be distinguished main factors in the development of dysbiosis:

A. Exogenous:

Industrial poisons;

Violation of sanitary and hygienic standards in everyday life and at work;

Ionizing radiation;

Climatic and geographical factors;

Surgical interventions on the gastrointestinal tract.

B. Endogenous:

Immune disorders;

Stressful conditions;

Non-infectious diseases of the gastrointestinal tract (pathology of the intestine and gallbladder, gastric ulcer, etc.);

Infectious diseases;

Diabetes;

Rheumatic diseases;

Starvation;

Poor nutrition;

Elderly and senile age;

Irrational use of medications.

In children, factors for the development of dysbiosis can also be:

Anatomical disorders;

Food allergies;

Errors in nutrition;

Antibacterial therapy (including rational).

Clinical manifestations of dysbiosis are varied and are largely determined by the degree of disruption of the normal intestinal biocenosis. In some patients, any manifestations of dysbacteriosis may be completely absent, but most often there are the following characteristic complaints:

Unstable stool (constipation, diarrhea, or their alternation);

Bloating and rumbling in the stomach;

Pain in the lower abdomen, decreasing after the passage of gas;

Nausea, belching, bitterness in the mouth.

In addition, as a result of long-term dysbacteriosis, a number of pathological conditions arise secondarily, namely:

Asthenoneurotic syndrome (caused by hypovitaminosis and intoxication);

Anemia;

Hypoproteinemia;

Osteomalacia;

Reducing body weight;

Hypovitaminosis (mainly for fat-soluble vitamins).

In young children with the development of dysbacteriosis, regurgitation, vomiting, a decrease in the rate of increase in body weight, anxiety, and sleep disturbances are observed. The stool may be copious, liquid or mushy, foamy, greenish, with a sour or putrid odor. Abdominal pain is paroxysmal in nature, appears 2-3 hours after eating and is accompanied by bloating and the urge to defecate. Clinically, there are four degrees of severity of disturbances in the “microbial landscape” of the intestine:

1st degree– compensated (latent) dysbacteriosis, characterized by a change in the quantitative composition of aerobic microorganisms with a normal ratio of bifidobacteria and lactobacilli. There are no clinical signs.

2nd degree– subcompensated (localized) dysbacteriosis, manifested along with a decrease in the qualitative and quantitative composition of Escherichia, a moderate decrease in the content of bifidobacteria with a simultaneous increase in the number of opportunistic MOs. At the same time, a moderately pronounced inflammatory process (enteritis, colitis) occurs in the intestines.

3rd degree– widespread dysbacteriosis, characterized by significant changes in the qualitative and quantitative composition of normal microflora. Clinically manifested by intestinal dysfunction of varying severity.

4th degree– generalized (decompensated) dysbiosis, in which, along with a significant increase in the content of E. coli, there is an almost complete absence of bifidobacteria and a sharp decrease in the level of lactic acid bacteria. Clinically manifested by severe intestinal dysfunction, bacteremia, septic complications, dystrophic changes in internal organs.

There are general and specific methods for assessing microbial ecology and colonization resistance: histochemical, morphological, molecular genetic methods for studying MO, combined methods for studying biomaterial, stress tests, etc. (Table 3). However, these methods, available to large research institutions, cannot be used to their full extent in widespread laboratory practice. In this regard, the most common method for diagnosing the state of microbiocenosis (in particular, dysbacteriosis) in most cases remains routine bacteriological analysis of feces, as well as polymerase chain reaction, gas chromatography-mass spectrometry and the study of microbial metabolites.

Possible clinical consequences of dysbiosis include:

Digestive disorders (diarrhea or constipation, flatulence, abdominal pain, regurgitation, vomiting);

Pathology of the digestive canal;

Allergic dermatoses (pseudoallergy);

Secondary immunodeficiency conditions;

Worsening of the course of immune-dependent pathology (bronchial asthma, chronic obstructive pulmonary diseases, etc.).

At present, it is quite obvious that, by its nature, intestinal dysbiosis is a secondary phenomenon that reflects the functional state of the gastrointestinal tract and biliary system in the process of interaction with the environment and in connection with other problems of the human body. Therefore, it cannot be considered as an independent disease.

However, dysbiosis can lead to the development of infectious and inflammatory lesions in various parts of the intestine, as well as maintain or aggravate pathological changes in the gastrointestinal tract. At the same time, the term “dysbacteriosis” refers purely to microbiological concepts, and cannot be used as a clinical diagnosis. Intestinal dysbiosis almost never occurs in isolation, so to correct it it is necessary to identify and eliminate the factors that provoke its development. Without this, probiotic therapy will be ineffective or even pointless. So, A.I. Parfenov et al., in order to correct dysbiotic intestinal disorders, recommend reducing excess colonization of the small intestine, restoring normal microflora and intestinal motility, and improving intestinal digestion.

All of the above clinical manifestations of intestinal dysbiosis, as well as the serious consequences that this condition can lead to, dictate the urgent need to eliminate it. Currently, the following possible ways to correct dysbiosis are identified::

Treatment of gastrointestinal pathology;

Elimination of risk factors for the development of dysbacteriosis;

Prescription of bacteriotherapy (probiotics);

The use of immunocorrectors;

Use of oral bacterial vaccines;

Diet food;

Enterosorption.

The most important among the methods of correcting dysbiosis, according to most experts, is the use of probiotic preparations. Probiotics (eubiotics) are freeze-dried live weakened strains of normal intestinal microflora, which, after ingestion, populate it. Bacteria activated in the intestines produce acetic and lactic acids, creating an acidic environment that inhibits putrefactive and gas-forming microorganisms (clostridia, proteus, bacteroides), and also synthesize antibacterial substances that inhibit the division of various opportunistic bacteria and pathogens of intestinal infections (salmonella, shigella and etc.). In this case, probiotics are prescribed not as replacement therapy, but as a means of providing conditions for the restoration of normal microflora. Probiotics are used both for the treatment and prevention of dysbiosis, especially in children. Suppression of rotting and fermentation processes by probiotics eliminates flatulence and normalizes the processes of digestion and absorption in the intestines. Restoring normal microflora helps stimulate the body’s immune system, increases its resistance to infectious agents, and makes it possible to realize many other positive effects that normal microflora has on the body. Table 4 shows a comparative description of probiotics registered in Ukraine.

As can be seen from the data presented in Table 4, the active principle of bifido-containing drugs is live bifidobacteria, which have antagonistic activity against a wide range of pathogenic and opportunistic pathogens. Their main therapeutic purpose is to ensure rapid normalization of the intestinal microflora and urogenital tract. Therefore, bifido-containing drugs are used to normalize the microbiocenosis of the gastrointestinal tract, increase the body’s nonspecific resistance, stimulate the functional activity of the digestive system, and for the prevention of nosocomial infections in maternity hospitals and hospitals. These drugs are prescribed to children and adults for the treatment of acute intestinal infections (shigellosis, salmonellosis, staphylococcal enterocolitis, rotavirus infection, food toxic infection), as well as gastrointestinal diseases (peptic ulcers of the stomach and duodenum, pancreatitis, cholecystitis, chronic diseases of the liver and biliary tract), allergic diseases, pneumonia, bronchitis, accompanied by dysbacteriosis. These drugs are also prescribed for inflammatory diseases of the urogenital tract, in surgical patients with diseases of the intestines, liver, pancreas (in the pre- and postoperative period) in order to correct intestinal microbiocenosis. This group of drugs is recommended during a course of antibacterial therapy, the use of glucocorticosteroids, non-steroidal anti-inflammatory drugs, radiation therapy, chemotherapy (in the treatment of patients with cancer pathology).

The active ingredient of lactose-containing preparations is live lactobacilli, which have a wide range of antagonistic activity due to the production of organic acids, lysozyme, hydrogen peroxide and various antibiotic substances. Lactobacilli synthesize various enzymes and vitamins that take part in digestion and have an immunomodulatory effect. It is advisable to prescribe these drugs to children and adults in the treatment of acute intestinal infections, chronic gastrointestinal diseases with severe dysbiotic phenomena, especially in case of lactoflora deficiency or if it is necessary to use these drugs in combination with antibiotics. Experience in recent years has shown that the use of lactose-containing drugs is highly effective in the treatment of patients with rotavirus gastroenteritis and other intestinal infections for which antibacterial therapy is unsuccessful.

The therapeutic effects of coli-containing drugs are due to the antagonistic activity of Escherichia coli against pathogenic and opportunistic pathogens, including Shigella, Salmonella, Proteus, etc. These drugs are used in the treatment of prolonged and chronic dysentery, after-treatment of convalescents after acute intestinal infections, chronic colitis and enterocolitis of various etiologies , with intestinal dysbiosis occurring against the background of E. coli deficiency. However, taking into account the immunomodulatory and adjuvant effects of E. coli lipopolysaccharide, one should be careful when prescribing coli-containing drugs to patients with ulcerative colitis in the acute stage, in which stimulation of local gastrointestinal immunity is undesirable.

In view of the numerous positive effects of lacto- and bifido-containing microorganisms, for the correction of intestinal dysbiosis and its prevention, it is most advisable to use complex preparations containing several main components of normal flora. Linex is one of the most balanced probiotics, which includes live lyophilized bacteria from various parts of the intestine: Lactobacillus acidophilus, Bifidumbakterium infantis v. liberorum, Streptococcus faecium. These bacteria are representatives of the normal intestinal microflora, are resistant to antibiotics and other chemotherapeutic agents, and do not transfer this resistance to pathogenic strains of MO. Once in the intestine, the components of Linex perform all the functions of normal intestinal microflora: they reduce the pH of the intestinal contents, create unfavorable conditions for the reproduction and vital activity of pathogenic microorganisms, participate in the synthesis of vitamins B, PP, K, E, C, folic acid, create favorable conditions for absorption of iron, calcium, zinc, cobalt, B vitamins. In addition, lactic acid bacteria in Linex colonize the small intestine and carry out enzymatic breakdown of proteins, fats, complex carbohydrates, incl. with lactase deficiency in children. Proteins and carbohydrates that are not absorbed in the small intestine undergo deeper breakdown in the large intestine by anaerobes, in particular bifidobacteria, which are part of Linex. Bifidobacteria produce the enzyme phosphoprotein phosphatase, necessary for the metabolism of milk casein in infants, stabilize the membranes of intestinal epithelial cells, participate in the resorption of monosaccharides and regulate electrolyte balance in the intestine. Linex components are also involved in the metabolism of fatty acids and have hypocholesterolemic and antitoxic effects. In addition to the main probiotic effect, the combination of microorganisms that make up Linex also provides its pronounced bactericidal and antidiarrheal properties. Taking into account all of the above, it can be argued that Linex meets all modern requirements for probiotics: it is of natural origin, creates an acidic environment in different biotopes of the gastrointestinal tract, thereby preventing the proliferation of putrefactive and pathogenic flora, normalizes intestinal motility, populates it with normal symbionts, is safe, has a clinically proven effect and is convenient to use. In recent years, significant positive experience has been accumulated in clinical practice with the use of Linex in children and adults.

To prevent and treat dysbiosis, along with medicinal forms of probiotics, functional food products and dietary supplements are also used. These are special forms of probiotics, which are food products that contain live probiotic strains of microorganisms, intended for daily consumption and having a regulating effect on the physiological functions and biochemical reactions of the human body. Such dietary supplements include the Biofamily product line, which contains components of normal intestinal microflora, individually balanced for different age groups.

Probiotics are used mainly as prophylactics and concomitant therapy, but in the future, according to R. Walker and M. Buckley, it is possible to expand the indications for their use, which will include:

Biological therapy using antibiotic-sensitive bacteria to replace resistant microorganisms;

Prevention of translocation of pathogenic bacteria from the skin and mucous membranes into the internal environment of the macroorganism;

Promoting faster weight gain;

Eradication of certain types of bacteria from the body (for example, Helicobacter pylori);

Restoring the composition of microflora after treatment with antibiotics;

Changing the composition of the intestinal microflora in accordance with the characteristics of the diet;

Improving oxalate metabolism to reduce the incidence of kidney and bladder stones;

Destruction of potentially hazardous chemicals;

Suppression of pathogenic tumors (S. aureus and Clostridium difficile) in hospital patients;

Prevention of bladder infections.

In conclusion, it is worth emphasizing that intestinal dysbiosis must be promptly diagnosed and treated, and even better, it must be prevented with the help of probiotic preparations and/or products. Doctors and patients today have a sufficient choice of means to preserve and maintain the balance of the normal microflora of the body. The general task is their rational and targeted use, taking into account the individual characteristics of the microbiocenosis of a particular macroorganism.

Probiotics versus antibiotics?

Experts say that in the 21st century, microbiological methods will come to the fore in the fight against human ailments, as well as their prevention. Therefore, the new concept of “Probiotics and functional nutrition”, developed at the end of the last century, according to the scientific world, is as significant an achievement of the 20th century as human space flight or the creation of computers.

Svetlana RUKHLIA

Functional nutrition is something that helps improve the functioning of all our organs and systems. Probiotics are living organisms that, when used in adequate quantities, have a health-improving effect on humans.

Poor nutrition and environmental disasters, uncontrolled use of antibiotics in medicine and agriculture, the use of preservatives, chlorination of water, stress and... the list goes on for a long time - lead to the occurrence of dysbacteriosis. According to Academician of the Russian Academy of Medical Sciences V. Pokrovsky, 90% of the Russian population suffers from this disease. Modification of the microflora reduces the body's defenses, causes digestive and metabolic disorders, and these, in turn, bring many serious ailments to a person, including diabetes and bronchial asthma.

According to the vice-president of the St. Petersburg branch of the Union of Pediatricians of Russia and the chief specialist in child nutrition of the Health Committee, Professor Elena Bulatova, “for normal life, the human body requires normal microflora, the basis of which is probiotic microorganisms, primarily bifidobacteria and lactobacilli. It has been scientifically proven that the use of probiotics is the most effective way to correct dysbiosis. Recently, a lot of scientific research has been carried out in the world on this topic, and their results suggest that the “era of probiotics” is approaching, which should replace the “era of antibiotics”.

In the treatment of dysbiosis, sorbed probiotics, which are drugs of the latest (fourth) generation, are most effective. However, treatment, like diagnosis, should remain the prerogative of doctors, but the prevention of microflora disorders can (and should!) be done independently. Fortunately, today there are many functional food products that contain probiotics on city shelves. But it is important to understand that these products are not intended for a single massive course of “obtaining useful substances,” but for systematic daily use. From which it follows that their inclusion in the diet should become as natural a necessity as, say, brushing your teeth.

By the way, according to doctors, for a full life/survival, bacteria need an acidic environment - accordingly, our body receives them in minimal quantities from sweet kefir and cottage cheese. However, to the delight of those with a sweet tooth, a product purchased in sour form can be sweetened independently, and if, without delaying the matter, it is consumed immediately, there will be no threat to the life and quality of bacteria.

Determine the meaning of words
and you will rid the world of half of its errors.
Descartes

The aphorism included in the epigraph of this article perfectly reflects the state of the problem of dysbiosis, since many questions still remain. Doctors often use the terms “dysbacteriosis”, “dysbiosis”, “intestinal microecology”, “intestinal microbiocenosis” as synonyms, which, in a strictly scientific sense, are not equivalent. The fundamental question is not even in the terms used, but in understanding the essence of the problem and its general biological significance. Its solution will allow more reasonable and targeted therapy aimed at correcting microbiocenosis.

General ideas about normal microbiocenosis of the gastrointestinal tract

The gastrointestinal tract is one of the most complex microecological environments of the human body, in which, on the total area of the mucous membrane, which is about 400 m2, there is an exceptionally high and diverse (over 500 species) density of microbial contamination, in which the interaction between the protective systems of the macroorganism is very finely balanced and microbial associations. Bacteria are believed to account for 35 to 50% of the volume of the human colon, and their total biomass in the gastrointestinal tract approaches 1.5 kg.

However, bacteria are unevenly distributed in the gastrointestinal tract. If in the stomach the microbial colonization density is low and is only about 103-104 CFU/ml, and in the ileum - 107-108 CFU/ml, then already in the area of the ileocecal valve in the colon the bacterial density gradient reaches 1011-1012 CFU/ml. Despite such a wide variety of bacterial species living in the gastrointestinal tract, most can only be identified molecular genetically.

Among commensal bacteria cultured from the gastrointestinal tract, more than 99.9% are obligate anaerobes, of which the dominant representatives are: Bacteroides, Bifidobacterium, Eubacterium, Lactobacillus, Clostridium, Fusobacterium, Peptococcus, Peptostreptococcus, Escherichia And Veillonella. The composition of detected bacteria in different parts of the gastrointestinal tract is very variable. Depending on the frequency and consistency of detection of bacteria, all microflora is divided into three groups ( ).

The individuality and stability of the gastrointestinal tract microbiocenosis under physiological conditions in humans is one of the characteristic features. The mechanisms for maintaining the stability of qualitative and quantitative parameters of indigenous microflora, despite the permanent supply of exogenous microorganisms with water and food, have not yet been fully elucidated. Among the leading factors ensuring such stability, natural defense systems are traditionally considered, which also provide nonspecific anti-infective resistance ( ).

Although the structural and functional significance of these systems in ensuring the stability of microbiocenosis has not been studied to the same extent, available clinical observations clearly indicate that disturbances in their functional activity are naturally accompanied by changes in the composition of the flora. The influence of normal acidity of gastric juice is especially great, ensuring minimal entry of exogenous microorganisms into the small intestine.

In addition, the development of the concept of a microbial community (microbiota) implies the presence of regulatory influences between microorganisms, allowing them to coordinately participate in processes occurring in certain biotopes (in particular, in the gastrointestinal tract). One of the key mechanisms of intercellular interaction between bacteria is the quorum sensing mechanism, first described in 1999, but in fact completely unstudied in the indigenous microflora of the gastrointestinal tract.

Clinical aspects of gastrointestinal microbiocenosis disorders

Modern research indicates that the obligate microflora of the gastrointestinal tract is directly involved in many vital processes of the macroorganism within the digestive tract itself, and also provides numerous and varied systemic regulatory functions, due to which the indigenous microflora (normal microbiocenosis) of the intestine is often considered as an integral part of the macroorganism or as extracorporeal organ ( ).

Disturbance of the gastrointestinal microbiocenosis, characterized by a decrease in the qualitative and quantitative indicators of obligate and facultative microflora, can also have a negative impact on human health. In addition to the “loss” of physiological functions associated with a decrease in the density of the presence of indigenous microflora, the development of dysbiosis can be associated with: a) translocation of bacteria and the development of endogenous infectious processes (up to purulent-septic conditions); b) with a decrease in the body’s resistance; c) with the development of allergic and immunopathological conditions; d) the formation of pathogenic bacterial clones, due to the abundance of plasmid and chromosomal genes in the intestinal lumen.

Principles of correction of dysbiotic gastrointestinal disorders

The problem of studying the microbiocenosis of the gastrointestinal tract comes down to attempts to correct it with the help of microbiological preparations. These attempts were made at the dawn of the study of this problem (L. G. Peretz), and are continuing with increasing intensity now. To date, extensive experience has been accumulated in the use of probiotics. They are usually used as prophylactic drugs and for the correction of dysbiotic disorders. However, there are many articles that describe their therapeutic effect in a number of pathological conditions.

Since the development of dysbiosis is not characterized by a banal deficiency of representatives of obligate and/or facultative microflora, but is an indicator indicating a violation of the microecosystem, simply prescribing probiotics to correct microbiocenosis is clearly not enough. The main goal of the doctor should not be to “seed” the intestinal mucosa of patients with normal microflora, but to restore the microbiocenosis of the gastrointestinal tract and the density of colonization of indigenous microflora. Achieving this goal is possible:

thanks to diet therapy;
elimination of the action of exo- and endogenous factors that caused and maintained disruption of microbiocenosis (chronic inflammatory processes of various localizations, lifestyle and nutrition, cancer, etc.);
limiting colonization of the gastrointestinal mucosa by opportunistic microflora (selective decontamination);
absorption and removal of toxic substances from the lumen of the gastrointestinal tract;
restoration of the functional activity of the gastrointestinal tract (acidity of gastric juice, motor-evacuation activity of the intestine; optimization of the function of the hepatobiliary system, etc.);
prescribing biological products (pro-, pre- and synbiotics) that create and maintain optimal conditions that contribute to the restoration of microbiocenosis and provide replacement functions.

Prebiotics are chemical components (microbial and non-microbial origin) that can selectively stimulate the growth and/or metabolic activity of one or more groups of bacteria that are part of the normal indigenous microflora. Combined preparations that include bacterial preparations and growth stimulants are referred to as synbiotics.

According to modern concepts, strains used as probiotics must meet the following criteria: a) be safe for humans; b) be resistant to the action of acidic stomach contents, bile and pancreatic enzymes; c) have pronounced adhesive properties against epithelial cells of the gastrointestinal mucosa; d) exhibit antimicrobial activity; e) inhibit the adhesion of pathogenic bacteria; f) be resistant to antibiotics; g) maintain stability during storage of the drug.

Most often, various types of lacto- and bifidobacteria are used as probiotics ( ).

Preference given to drugs containing lactic acid bacteria Lactobacillus spp.. And Bifidobacterium spp., due to the fact that they are resistant to the action of gastric juice, bile and pancreatic enzymes, easily adhere and colonize the intestinal mucosa.

In order to increase the clinical effectiveness of probiotics, preference is currently given to the development and use of complex preparations, which include several strains of bifidobacteria and lactobacilli, vitamin complexes, and pectins, which is believed to increase their adhesiveness and colonization of the intestinal mucosa. Capsule forms also have certain advantages both in the stability of the drug and in maintaining the activity of the strain when passing through the acid barrier of the stomach.

Such drugs include Linex, Bificol, Acilact, Acipol, Bifistim, etc. The duration of treatment with probiotics usually ranges from 2 weeks to 1-2 months. It is advisable to combine the intake of probiotics with the use of alkaline solutions (table mineral waters).

The clinical effectiveness of probiotics is associated with the colonization of the intestinal mucosa and the replacement restoration of the functions of normal indigenous intestinal microflora ( ), which ensures the creation of a microecological environment conducive to the restoration of indigenous microflora. Although the bacterial strains used in the production of probiotics are selected from the microflora of the human gastrointestinal tract, they still do not have long-term colonization resistance and are eliminated from the intestines within 3-7 weeks.

In recent years, the drug Enterol, which contains the yeast Saccharomyces boulardii, has become widespread as a probiotic. These yeasts are not part of the normal indigenous microflora of the gastrointestinal tract, but have pronounced antagonistic properties against a wide range of pathogenic and opportunistic bacteria, remain viable during transit through the gastrointestinal tract, and are absolutely resistant to the action of any antibacterial drugs (sensitive only to antifungal drugs). The spectrum of their enzymatic activity, according to modern research, ensures their participation in the processes of digestion and metabolism. Saccharomyces boulardii are classified as self-eliminating strains, since their elimination occurs within 3-4 days after stopping the drug. The usual course of treatment with Enterol is 7-10 days.

In restoring intestinal microbiocenosis, increasing attention is paid to a relatively new class of drugs - prebiotics, the most important requirement for which is the selectivity of action only on indigenous microflora without increasing the growth and reproduction of toxin-producing clostridia, toxigenic strains of Escherichia coli and proteolytic bacteroids. The use of these drugs is possible only if bifidobacteria and lactobacilli dominate in the indigenous intestinal microflora.

The most commonly used prebiotics are Hilak forte and various dietary fiber preparations (corn flakes, cereals, bread).

Hilak forte contains substrates of metabolic products of indigenous intestinal microflora, which promote the regeneration of epithelial cells of the intestinal mucosa and the rapid restoration of normal flora. The drug is usually prescribed 40-60 drops 3 times a day in a small amount of liquid (except milk). The dosage and duration of taking the drug are determined individually.

The clinical effectiveness of combined preparations of probiotics and prebiotics (synbiotics) remains poorly studied due to insufficient experience.

Safety considerations for using probiotics

Long-term experience with the clinical use of probiotics has contributed to the dissemination and strengthening of the opinion of their safety. However, clinical observational data published in the medical press (especially in recent years) indicate the need for a more in-depth analysis of the safety issues of using probiotics.

It is currently believed that oral ingestion of live bacteria could theoretically be responsible for four types of side effects: a) the development of infectious processes caused by the strains included in the probiotics; b) development of metabolic disorders; c) excessive immunostimulation of the intestinal lymphatic system; d) the formation of new clones of bacterial strains due to the transfer of genes responsible for the expression of pathogenicity factors.

The greatest concern is the possibility of developing infectious processes. Since probiotic strains of bacteria are selected from among representatives of indigenous microflora, the risk of developing infectious processes is assessed as very low, but possible. This thesis is supported by a number of clinical observations and review articles that describe cases of the development of asymptomatic bacteremia, severe sepsis, endocarditis, pneumonia and abscesses caused by lacto-, bifido- or other bacteria. The entry of bacteria into the bloodstream is possible due to their translocation through the intestinal mucosa. Most common risk factors associated with bacteremia Lactobacillus, are pathological processes of the gastrointestinal tract, causing a decrease in protective barrier functions that increase the permeability of the intestinal mucous membranes (tumors of the gastrointestinal tract, trauma, surgery) and immunosuppressive conditions.

Many authors note that bacteremia Lactobacillus very difficult to diagnose because this type of bacteria is difficult to culture and identify, and in cases where growth is obtained, it is often regarded as contamination. Most often infectious processes were caused by Lactobacillus rhamnosus, Lactobacillus fermentum And Lactobacillus casei.

Enterococcus faecium And E. faecalis can also cause the development of infectious processes. In addition, there are already indications of the emergence of vancomycin-resistant strains of enterococci.

The widespread use of preparations containing yeast also causes some concern - Saccharomyces boulardii, which is associated with diagnosed fungemia. Most researchers note that the development of fungemia is due to exposure to Saccharomyces boulardii on vascular catheters.

So, dysbiotic disorders of the gastrointestinal tract are an urgent problem of practical healthcare, requiring in-depth theoretical, experimental and clinical research. Despite the fact that the use of probiotics is an important part of the correction of microbiocenosis, it should not be an end in itself.

For questions regarding literature, please contact the editor.

V. A. Malov, Doctor of Medical Sciences, Professor
N. M. Gyulazyan, Candidate of Medical Sciences
MMA im. I. M. Sechenova, Moscow

Intestinal microflora is a collection of non-pathogenic microorganisms that live in the intestines of a healthy person. Human organisms and bacteria coexist in conditions of mutually beneficial cooperation - symbiosis. Flora in the intestines appears in infancy and persists throughout a person’s life.

Representatives of the intestinal flora

Microorganisms in the human intestine

	Normal	Opportunistic	Pathogenic
Name of bacteria	Propionibacteria; Peptostreptococci; Bacteroides; Escherichia;	Proteas; Enterobacter; Citrobacter; Acinetobacter; Pseudomonas; Serrations; Fusobacteria; Yeasts and yeast-like fungi.	Shigella; Salmonella; Yersinia; Vibrio cholerae.

Disturbance of intestinal microflora

Changing the composition of the intestinal microflora can lead to serious consequences.

It can be associated both with the penetration of pathogenic microorganisms that are not normally found in the digestive system, and with a decrease in the content of normal microflora -.

Causes

Symptoms

The symptoms of dysbacteriosis depend on the severity of the disorders and the presence of concomitant diseases.

. The patient experiences flatulence, belching, and may experience diarrhea or constipation. Patients constantly feel an unpleasant taste in their mouth.
. Many patients note the appearance of food allergies to foods that were previously tolerated normally. This manifestation is most typical for children. Allergies can be expressed by both skin symptoms (itching, hives, swelling) and intestinal signs. These include sharp pain in the lower abdomen, nausea, vomiting, loose stools with foam.
Malabsorption. With the prolonged presence of dysbacteriosis, this leads to changes in the entire metabolism - the occurrence of energy deficiency and hypovitaminosis. The condition is usually accompanied by anemia, calcium deficiency and other ionic disorders.
Intoxication. It is characterized by weakness, headache, and a slight increase in temperature.

How to check intestinal microflora?

To assess the state of the intestinal microflora, the patient undergoes. To do this, either a scraping or an aspirate from the intestine is taken. The resulting material is sent for bacteriological examination. In the laboratory, bacteria are inoculated onto nutrient media. By growing colonies of microorganisms, one can judge the state of the intestinal flora. This test is an accurate way to diagnose its disorders.

The presence of dysbacteriosis can be indirectly indicated by research methods that are aimed at detecting changes in the composition of feces. These include biochemical examination of stool. Such diagnostics makes it possible to detect characteristic chemical changes that indicate the presence of certain microorganisms in the intestines.

Prevention and treatment of microflora disorders

Nutrition

First of all, it involves preparing a balanced diet. It must include fermented milk products containing. Food should contain enough natural vitamins. If there is a risk of seasonal hypovitaminosis, it is recommended to additionally use multivitamin complexes.

Destruction of pathogenic bacteria

To eliminate pathogens from the intestines, special antibacterial drugs with selective action are used. They do not affect the state of normal microflora, but at the same time destroy harmful bacteria. This group includes non-absorbable antibiotics (for example, nifuroxazide) and (rifaximin).

Restoration of normal microflora

Medicines from several groups are used:

include live cultures of microorganisms that are normally found in the human intestine.
Medicines from the group include all the necessary substances so that “useful” bacteria can quickly multiply.
Both those and other components are part of the combined products -.

Immunity restoration

Normalization of local immunity helps maintain a constant composition of the intestinal flora. For this purpose, the patient is prescribed drugs with an immunomodulatory effect - echinacea-based products, nucleic acids.