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Aim. The practical guidelines are intended for primary care physicians, general practitioners, paediatricians, gastroenterologists and general internists to advance the treatment and prevention of gastroenterological diseases in adults and children in therapies with probiotics, prebiotics, synbiotics and their enriched functional foods.Key points. Probiotics are live microorganisms that sustain health of the host when supplied in adequate amounts. Prebiotics include human-indigestible but accessible to gut microbiota substances expediting specific changes in the composition and/or activity of gastrointestinal microbiota that favour the host health. The mechanism of probiotic action comprises the quorum resistance maintenance, nutrient substrate metabolism and end metabolite recycling, macroorganism-sustaining substrate production, as well as the mediation of local and adaptive immune responses.The Russian Federation regulates market differently for biologically active food additives (BAFA), medicinal products (drugs) and functional food products (FFP). We overview the probiotic strains regulated in Russia as BAFAs, drugs and FFPs and provide recommendations on the use of these strains in treatment and prevention of gastroenterological diseases in children and adults.Conclusion. The clinical efficacy of probiotics, prebiotics, synbiotics and fortified functional foods depends on the prebiotic and strain properties and is verified in appropriate comparative clinical trials. Not all probiotics registered in Russia as BAFAs, drugs and FFPs have a strain identity, which provides no warranty of the clinical effect expected. The FFP legislation demands improved regulation mechanisms and control for therapeutic efficacy.

Aim. Current clinical recommendations are intended to supply gastroenterologists, physicians and general practitioners with modern methods for the diagnosis and treatment of constipation.Key points. Constipation is defined as primary (functional) and secondary form, the latter comprising a manifestation of another illness. The causes of constipation are diagnosed with colonoscopy, especially in patients aged over 50 having “anxiety symptoms” and hereditary colorectal oncological predisposition. Indications may also include the bowel transit time estimation with radiopaque markers, balloon expulsion test, anorectal manometry, defecography and electromyography. Therapy for constipation should be comprehensive and concern lifestyle, diet recommendations and use of medications (psyllium, macrogol, lactulose, lactitol, contact laxatives, prucalopride). Patients with a less effective conservative therapy and largely reduced quality of life should be considered for surgical intervention.Conclusion. An effective therapy for constipation requires a correct diagnosis of its causes.

Aim. To provide practical recommendations on the use of probiotics for the treatment and prevention of gastroenterological diseases in adults.General provisions. Probiotics are living microorganisms that benefit the health of the host when administered in adequate amounts. The main functions of probiotics include the support for colonisation resistance, the metabolism of food substrates and utilisation of end metabolites, the production of substrates necessary for the macro-organism, as well as the regulation of local and adaptive immune responses. Probiotics can be registered in the Russian Federation as biologically active food additives (BAFA) or as pharmaceutical products (drugs) in accordance with the microbiological standards and legislative requirements of the Russian Federation. The probiotics registered in the Russian Federation as BAFA for adults include bacteria of the Lactobacillus, Bifidobacterium, Enterococcus, Pediococcus, Lactococcus, Streptococcus, Bacillus, and Escherichia genera, and fungi of the Saccharomyces genus; probiotics registered as drugs — bacteria of Lactobid, Lactobacid, Escherichia and Enterococcus genera and fungi of the Saccharomyces genus. Some probiotics registered in the Russian Federation include probiotic strains that have proved to be effective for the prevention and treatment of antibiotic-associated diarrhea, the prevention of C. difficile-associated disease, the eradication of H. pylori infection, as well as for the treatment of irritable bowel syndrome and functional constipation.Conclusions. The clinical efficacy of probiotics depends on the probiotic strains included in their composition and is confirmed by a comparative analysis of the results of appropriate clinical studies. Not all probiotics registered in the Russian Federation as BAFA or drugs contain bacterial or fungal strains; as a result, the expected clinical effect may not be achieved.

Aim. To provide a definition and classification of nutraceutical products and to show their significane in modern integrative medicine.Background. Nutraceuticals are foodstuffs and their components, which have a positive effect on human health, including preventive maintenance and treatment of diseases. Nutraceuticals include healthy and functional foods, as well as biologically active food additives (BAFA). Healthy foods are nutritional foodstuffs without any artificial modification. These include organic, whole, and natural foods. Alongside a high nutritional value, functional food products have a positive effect on the human body due to functional food ingredients. BAFAs are food additives that contains one or several food ingredients (vitamins, mineral substances, plant components, amino acids and others). Specialists express conflicting viewpoints concerning nutraceuticals. Some nutraceuticals, such as probiotics, have confirmed their effectiveness in clinical trials, while the beneficial properties of others require further elucidation.Conclusions. The application of nutraceuticals, as well as their combined use with pharmaceuticals, in accordance with recommendations by scientific professional associations formulated on the basis of valid research studies can lead to an improvement in the quality of the life and longevity of the population. This position forms a basis for the development of integrative medicine — a contemporary approach to the treatment of diseases.

Aim. To review data on the efficiency and safety of using Ustekinumab in patients with Crohn’s disease.Key findings. Ustekinumab is a fully human monoclonal antibody of the IgG1k class to the p40 subunit of IL-12 and IL-23. The drug interrupts the cascade of humoral and cellular reactions leading to transmural inflammation of the intestinal wall by blocking the interaction of the p40 subunit with the IL-12Rβ1 chain on the surface of T-lymphocytes and NK cells. A number of placebo-controlled studies have demonstrated the effectiveness of Ustekinumab in the induction and the maintenance of remission in those patients with Crohn’s disease who showed no response to conventional therapy (glucocorticosteroids and immunosuppressants) and therapy with TNF-α antagonists. In addition, the efficiency of Ustekinumab in maintaining a clinical response and clinical remission over two years of therapy has been shown. The drug has a favourable safety profile and a low immunogenicity.Conclusion. The reviewed studies show Ustekinumab to be an effective and safe drug for the induction and the maintenance of clinical remission in patients with Crohn’s disease.

Today, a number of studies conclusively show that certain bacterial strains, mainly from the genera Lactobacillus and Bifidobacterium, influence the functioning of the central nervous system, leading to changes in beahvior, nociception and the cognitive abilities of humans and animals. Such strains serve as the basis for developing probiotics with a curative potential for the central nervous system - psychobioitcs. However, the question of how to find such strains and which criteria to use for their selection remains unanswered. Some compounds produced by bacteria, such as gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter of the central nervous system, are potential mediators between bacterial cells and the host. Previously, we established that some species of Lactobacillus and Bifidobacterium are capable of producing GABA. We presumed that GABA-producing Lactobacillus and Bifidobacterium strains are great candidates to use as psychobiotics. Therefore, we selected the strains Lactobacillus plantarum 90sk and Bifidobacterium adolescentis 150 as efficient GABA producers. The goal of this work was to assess the probiotic properties of the selected strains as well as their antidepressive effects in mice. We established that the ingestion of the probiotic composition based on the selected strains by BALB/c mice for 2 weeks reduced depressive-like behavior in the forced swimming test; the effect was similar to that of fluoxetine.

Probiotic bacteria are widely accepted as therapeutic agents against inflammatory bowel diseases for their immunostimulating effects. In the last decade, more evidence has emerged supporting the positive effects of probiotics on the course of neurodegenerative and psychiatric diseases. This brief review summarizes the data from clinical studies of probiotics possessing antidepressant properties and focuses on the potential genes and proteins underlying these mechanisms. Data from small-sample placebo-controlled pilot studies indicate that certain strains of bacteria can significantly reduce the symptoms of depression, especially in depressed patients. Despite the disparity between studies attempting to pinpoint the bacterial putative genes and proteins accounting for these mechanisms, they ultimately show that bacteria are a potential source of metabiotics—microbial metabolites or structural components. Since the constituents of cells—namely, secreted proteins, peptides and cell wall components—are most likely to be entangled in the gut–brain axis, they can serve as starting point in the search for probiotics with concrete properties.

Aim. To assess the effect of rifaximin and a multi-strain probiotic on the intestinal microbiome and the indicators of cardiovascular risk in patients with coronary heart disease (CHD).Materials and methods.A study conducted during the 2016–2019 period included 120 people over 50 years old divided into 3 groups. Group 1 comprised patients with coronary heart disease receiving standard treatment. Group 2 comprised patients with coronary heart disease receiving additionally a probiotic (Bifidobacterium bifidum no less than 1x109 CFU; Bifidobacterium longum no less than 1x109 CFU; Bifidobacterium infantis no less than 1x109 CFU; Lactobacillus rhamnosus no less than 1x109 CFU) within 28 days. Group 3 comprised CHD patients receiving rifaximin for 7 days followed by addition of the multi-strain probiotic under test for 21 days. Group 4 consisted of healthy individuals, comparable in age and sex with the examined CHD patients. In group 4, blood and stool tests were performed once to provide a comparison with group 1. TMAO concentration was determined using liquid chromatography–mass spectrometry. To study the composition of fecal microflora, 16S sequencing was used followed by a graphical representation of the results. The results were analysed using the IBM SPSS 22.0 statistical data processing software.Results.An additional administration of the probiotic (Bifidobacterium bifidum no less than 1x109 CFU; Bifidobacterium longum no less than 1x109 CFU; Bifidobacterium infantis no less than 1x109 CFU; Lactobacillus rhamnosus no less than 1x109 CFU) is found to have no effect on the lipid profile and the platelet aggregation rate. Rifaximin therapy reduced the amount of total cholesterol, low density lipoproteins (LDL), very low density (VLDL) lipoproteins and triglycerides (p 0.05) downward trend in all groups. The composition of the fecal microbiota, at the end of administration of the probiotic, showed an increase in the proportion of bacteria of the Streptococcaceae, Lactobacillaceae, Enterobacteriaceae families and a decrease in the Ruminococcaceae family (p>0.05). After rifaximin therapy, a decrease in the proportion of bacteria of the Clostridiaceae (p 0.05) family and a decrease in the Clostridium and Escherichia/Shigella (p > 0.05) genera was observed. The use of the probiotic after a course of treatment with rifaximin did not have a significant effect on the composition of the microflora. In general, the high variability of fecal microbiota between different patients (significantly superior to intergroup differences) does not allow us to draw unambiguous conclusions.Conclusions. The use of a multi-strain probiotic as an additional therapy in patients with coronary heart disease within 28 days did not have a significant effect on lipid metabolism, TMAO level and the composition of fecal microflora. The consecutive use of rifaximin and the probiotic had a beneficial effect on such factors as lipid metabolism (decrease in the level of total cholesterol, LDL, VLDL, triglycerides), but did not affect the concentration of TMAO and the composition of the intestinal microflora in patients with coronary heart disease.

The aims of this work were to identify in vivo manifestations of antioxidant activity of Lactobacillus strains isolated from healthy human biotopes and to show the possibility of protective action of the selected strain on the model of oxidative stress induced by paraquat in the model of early Parkinson’s disease (PD) in mice. We studied the protective effects of 14 Lactobacillus strains belonging to five species on the lifespan of the soil nematode Caenorhabditis elegans experiencing oxidative stress induced by paraquat. The Lactobacillus strains used in this study were selected previously based on their ability to reduce oxidative stress in vitro. One of the strains that showed promising results on C. elegans was tested in a mouse model of PD in which C57/BL6 mice were injected regularly with paraquat. We assessed the state of their internal organs, the preservation of dopaminergic neurons in the substantia nigra as well as their motor coordination. The positive impact of Lactobacillus fermentum U-21 strain supplementation on paraquat treated animals was observed. L. fermentum U-21 strain reduced the toxicity of paraquat in C. elegans model: the lifespan of the soil nematode C. elegans was extended by 25%. L. fermentum U-21 protected the mice against anatomical and behavioral changes typical of PD: there were no changes in the coordination of movement and the preservation of dopaminergic neurons in the brain. Life span of the nematode C. elegans pre-grown on a lawn of E. coli OP50 + Lactobacillus under oxidative stress conditions; the concentration of the oxidizing agent paraquat in the S medium was 50 mmol l−1.

The human gastrointestinal microbiota (HGM) is known for its rich diversity of bacterial species and strains. Yet many studies stop at characterizing the HGM at the family level. This is mainly due to lack of adequate methods for a high-resolution profiling of the HGM. One way to characterize the strain diversity of the HGM is to look for strain-specific functional markers. Here, we propose using type II toxin-antitoxin systems (TAS). To identify TAS systems in the HGM, we previously developed the software TAGMA. This software was designed to detect the TAS systems, MazEF and RelBE, in lactobacilli and bifidobacteria. In this study, we updated the gene catalog created previously and used it to test our software anew on 1346 strains of bacteria, which belonged to 489 species and 49 genera. We also sequenced the genomes of 20 fecal samples and analyzed the results with TAGMA. Although some differences were detected at the strain level, the results showed no particular difference in the bacterial species between our method and other classic analysis software. These results support the use of the updated catalog of genes encoding type II TAS as a useful tool for computer-assisted species and strain characterization of the HGM.

We report that the results of our study indicate that Lactobacillus brevis 47 f strain isolated from the faeces of a healthy individual prevents the manifestations of experimental mucositis induced by treatment of Balb/c mice with the anticancer drug 5-fluorouracil (5 FU, 100 mg/kg i.p. &times, 3 days). The presence of damage to the intestine and the colon was determined by a morphometric analysis of specimens including the height of villi, the amount of goblet cells and infiltrating mononuclear cells, and the expression of the proliferative Ki-67 antigen. Changes in the lipid peroxidation in the blood and the intestine were determined by severalfold increase of the concentration of malonic dialdehyde. Oral administration of L.brevis 47 f strain prior to 5 FU decreased the drug-induced morphological and biochemical changes to their respective physiological levels, the ability of intestinal epitheliocytes to express Ki-67 was partially restored. These effects of L.brevis 47 f strain were more pronounced or similar to those of the reference compound Rebamipid, a quinoline derivative known to protect the gut from drug-induced toxicity. Thus, the new lactobacilli strain attenuates the severity of 5 FU-induced enteropathy.

Toxin–antitoxin systems are genetic modules usually consisting of two genes encoding a stable toxin and labile antidote (antitoxin). These systems are localized on plasmids, phages, and chromosomes and are widespread in bacteria and archaea. The review summarizes recent data regarding the classifications of toxin–antitoxin systems, their mechanisms of action and toxin targets, as well as their functional significance for bacterial cells and possibility of use.

Gamma-amino butyric acid (GABA) is an active biogenic substance synthesized in plants, fungi, vertebrate animals and bacteria. Lactic acid bacteria are considered the main producers of GABA among bacteria. GABA-producing lactobacilli are isolated from food products such as cheese, yogurt, sourdough, etc. and are the source of bioactive properties assigned to those foods. The ability of human-derived lactobacilli and bifidobacteria to synthesize GABA remains poorly characterized. In this paper, we screened our collection of 135 human-derived Lactobacillus and Bifidobacterium strains for their ability to produce GABA from its precursor monosodium glutamate. Fifty eight strains were able to produce GABA. The most efficient GABA-producers were Bifidobacterium strains (up to 6 g/L). Time profiles of cell growth and GABA production as well as the influence of pyridoxal phosphate on GABA production were studied for L. plantarum 90sk, L. brevis 15f, B. adolescentis 150 and B. angulatum GT102. DNA of these strains was sequenced; the gadB and gadC genes were identified. The presence of these genes was analyzed in 14 metagenomes of healthy individuals. The genes were found in the following genera of bacteria: Bacteroidetes (Bacteroides, Parabacteroides, Alistipes, Odoribacter, Prevotella), Proteobacterium (Esherichia), Firmicutes (Enterococcus), Actinobacteria (Bifidobacterium). These data indicate that gad genes as well as the ability to produce GABA are widely distributed among lactobacilli and bifidobacteria (mainly in L. plantarum, L. brevis, B. adolescentis, B. angulatum, B. dentium) and other gut-derived bacterial species. Perhaps, GABA is involved in the interaction of gut microbiota with the macroorganism and the ability to synthesize GABA may be an important feature in the selection of bacterial strains – psychobiotics.

Background All living organisms experience physiological changes regulated by endogenous circadian rhythms. The main factor controlling the circadian clock is the duration of daylight. The aim of this research was to identify the impact of various lighting conditions on physiological parameters and gut microbiota composition in rats. 3 groups of outbred rats were subjected to normal light-dark cycles, darkness and constant lighting. Results After 1 and 3 months we studied urinary catecholamine levels in rats; indicators of lipid peroxidation and antioxidant activity in the blood; protein levels of BMAL1, CLOCK and THRA in the hypothalamus; composition and functional activity of the gut microbiota. Subjecting the rats to conditions promoting desynchronosis for 3 months caused disruptions in homeostasis. Conclusions Changing the lighting conditions led to changes in almost all the physiological parameters that we studied. Catecholamines can be regarded as a synchronization super system of split-level circadian oscillators. We established a correlation between hypothalamic levels of Bmal1 and urinary catecholamine concentrations. The magnitude of changes in the GM taxonomic composition was different for LL/LD and DD/LD but the direction of these changes was similar. As for the predicted functional properties of the GM which characterize its metabolic activity, they didn’t change as dramatically as the taxonomic composition. All differences may be viewed as a compensatory reaction to new environmental conditions and the organism has adapted to those conditions. Electronic supplementary material The online version of this article (10.1186/s12866-019-1535-2) contains supplementary material, which is available to authorized users.

The purpose of the first multidisciplinary Consensus: to comprehensively analyze the pathophysiological, clinical, and pharmacotherapeutic aspects of the syndrome of increased epithelial permeability (SPEP) as one of the basic mechanisms of the development of human pathology. The Consensus presents the structure of the three main levels of cytoprotection: preepithelial, epithelial and subepithelial, and the structure of intercellular tight contacts in epithelial tissues and endothelium is considered in detail. The clinical sections of the Consensus are devoted to the role of SPEP in diseases of the digestive system, cardio-cardio-vascular and other visceral systems. A separate section summarizes the materials illustrating the significant role of SPEP in mental disorders and diseases of the nervous system. A separate chapter of the Consensus is devoted to cytoprotective therapy in SPEP. Cytoprotective effects of such proton pump inhibitor as rabeprazole, bismuth preparations and probiotics have been shown. Special attention is paid to the clinical and pharmacological specialties of the cytoprotector of rebamipide. Clinical the effectiveness of re-bamipide shown as in functional, so in organic lesions of the digestive system. Its anti-cancer preventive effects are of practical importance.

Oxidative stress cause serious damages in human organism resulting in multiple diseases. Antioxidant therapy includes diet, the use of chemical agents or commensal bacteria such as lactobacilli. This study aims to evaluate the antioxidant (AO) activity of cell-free culture supernatants of lactobacilli, isolated from different parts of the human body. A test system based on Escherichia coli MG1655 strains carrying plasmids encoding luminescent biosensors pSoxS-lux and pKatG-lux inducible by superoxide anion and hydrogen peroxide, respectively, was used to analyze cell-free culture supernatants of lactobacilli. Bioluminescent detection systems are suitable for quick screening of AO activity of lactobacilli. The majority of strains (51 out of 81) belonging to six different species demonstrated various levels of antioxidant activity. This activity was confirmed using the trolox equivalent method. The genome of one of the strains showing high AO activity was sequenced, and the genes putatively involved in AO capacity were determined. Potencies of standard AO and CFS from the most active Lactobacillus strains. Percentages of decrease in the detected luminescence (IAO%) in the presence of AO or CFS are presented. L. br.-L. brevis, L. pl. -L. plantarum, L. rh.-L. rhamnosus.

Recent research has indicated that in addition to the unique genotype each individual may also have a unique microbiota composition. Difference in microbiota composition may emerge from both its species and strain constituents. It is important to know the precise composition especially for the gut microbiota (GM), since it can contribute to the health assessment, personalized treatment, and disease prevention for individuals and groups (cohorts). The existing methods for species and strain composition in microbiota are not always precise and usually not so easy to use. Probiotic bacteria of the genus Bifidobacterium and Lactobacillus make an essential component of human GM. Previously we have shown that in certain Bifidobacterium and Lactobacillus species the RelBE and MazEF superfamily of toxin-antitoxin (TA) systems may be used as functional biomarkers to differentiate these groups of bacteria at the species and strain levels. We have composed a database of TA genes of these superfamily specific for all lactobacilli and bifidobacteria species with complete genome sequence and confirmed that in all Lactobacillus and Bifidobacterium species TA gene composition is species and strain specific. To analyze composition of species and strains of two bacteria genera, Bifidobacterium and Lactobacillus, in human GM we developed TAGMA (toxin antitoxin genes for metagenomes analyses) software based on polymorphism in TA genes. TAGMA was tested on gut metagenomic samples. The results of our analysis have shown that TAGMA can be used to characterize species and strains of Lactobacillus and Bifidobacterium in metagenomes.

The diversity of Lb. rhamnosus and Lb. fermentum strains isolated from feces, saliva, and the vaginal cavity of 18-22-year-old healthy women residing in central regions of the Russian Federation has been characterized. The results obtained using multilocus sequence typing were identical to those obtained with the analysis of genetic and genomic polymorphism in TA systems. Different as well as identical Lb. rhamnosus and Lb. fermentum sequence types (ST) were isolated from various parts of the body of the same person. Identical ST were also isolated from different women, suggesting that such strains belong to a common pool of strains circulating among the population members. Our results demonstrate that TAs are suitable for characterizing intra-specific diversity of Lb. rhamnosus and Lb. fermentum strains. The advantage of using polymorphisms in TA systems for genotyping is based on the weak number of genes used, and consequently, less time is required for the analysis.