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Chronic constipation: focus on microbiome-targeted therapies with prebiotics, probiotics, and synbiotics

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1. Title Title of document Chronic constipation: focus on microbiome-targeted therapies with prebiotics, probiotics, and synbiotics
2. Creator Author's name, affiliation, country Margarita Y. Serkova; North-Western State Medical University named after I.I. Mechnikov; Россия
2. Creator Author's name, affiliation, country Elena B. Avalueva; North-Western State Medical University named after I.I. Mechnikov; Россия
2. Creator Author's name, affiliation, country Stanislav I. Sitkin; North-Western State Medical University named after I.I. Mechnikov; Almazov National Medical Research Centre; Institute of Experimental Medicine; Россия
3. Subject Discipline(s)
3. Subject Keyword(s) chronic constipation; gut microbiota; synbiotic; Bifidobacterium lactis HN019; inulin
4. Description Abstract

Chronic constipation is a global medical, social, and economic problem due to its negative impact on patients’ quality of life and increased risk of colorectal cancer, cardiovascular and cerebrovascular disorders.

The gut microbiota plays an important role in the pathophysiology of constipation through its interplay with the immune system, enteral and central nervous system, representing a promising therapeutic target. Gut dysbiosis in patients with constipation is characterized by reduced relative numbers of bacteria producing lactate (Lactobacillaceae, Bifidobacteriaceae) and butyrate (Lachnospiraceae, Oscillospiraceae), as well as with increased numbers of those producing hydrogen sulfide (Desulfovibrionaceae) and methanogenic archaea (Methanobacteriaceae). The leading pathogenetic mechanism related to intestinal dysbiosis in chronic constipation, can be microbial metabolic abnormalities (metabolic dysbiosis) characterized by altered production of short-chain fatty acid, methane, hydrogen sulfide, tryptophan metabolites and by abnormal bile acid biotransformation. It has been proven that dysbiotic abnormalities of the intestinal microbiome play a role in the pathophysiology of constipation, which allows for the use of prebiotics, probiotics, and synbiotics for effective microbiome-modulating therapy in patients with chronic constipation. The proven role of dysbiotic abnormalities of the intestinal microbiome in the pathophysiology of chronic constipation determines the effectiveness of microbiome-modulating therapy (prebiotics, probiotics, synbiotics) in patients with this syndrome.

Inulin is the most studied preboitic; it is a soluble food fiber that markedly contributes to the regulation of intestinal microbiota, stimulates the growth of beneficial bacteria, and production of anti-inflammatory metabolites. Inulin normalized the intestinal function in patients with chronic constipation increasing the stool frequency, softening the stool, and reducing the intestinal transit time. In addition, inulin modulates the immune response and impacts the absorption of minerals, appetite, and satiety.

Treatment with probiotics is also associated with reduced intestinal transit time, compared to controls. According to a systematic review and meta-analysis of 30 randomized controlled trials, only Bifidobacterium lactis strains (but not other probiotics) significantly increase stool frequencies in chronic constipation in adults. Clinical studies have shown that the targeted probiotic Bifidobacterium lactis HN019 can significantly increase the stool frequencies in patients with low (≤ 3 per week) stool frequency up to 4.7–5.0 per week, reduce the intestinal transit time and the rate of functional gastroenterological symptoms in adults with constipation. Beyond its clinical effects, Bifidobacterium lactis HN019 leads to beneficial changes in intestinal microbiota, significantly increasing the bifidobacteria and decreasing the enterobacteria numbers.

The results of trials confirm the importance of synbiotic correction of dysbiotic microbiota in all patients with constipation to increase stool frequencies and improve fecal consistency, as well as to prevent the chronic disorders associated with constipation. Synbiotics, such as a combination of Bifidobacterium lactis HN019 and inulin, with the properties of both complementary and synergic synbiotic, may have the greatest microbiome-modulating and functional potential to significantly improve clinical outcomes in patients with chronic constipation compared to probiotics or prebiotics used alone.

5. Publisher Organizing agency, location Moscow Regional Research and Clinical Institute (MONIKI)
6. Contributor Sponsor(s)
7. Date (DD-MM-YYYY) 16.11.2024
8. Type Status & genre Peer-reviewed Article
8. Type Type Review Article
9. Format File format PDF (Rus),
10. Identifier Uniform Resource Identifier https://almclinmed.ru/jour/article/view/17315
10. Identifier Digital Object Identifier (DOI) 10.18786/2072-0505-2024-52-026
11. Source Title; vol., no. (year) Almanac of Clinical Medicine; Vol 52, No 5 (2024)
12. Language English=en ru
13. Relation Supp. Files Potential mechanisms of action and beneficial effects of a synbiotic containing the probiotic Bifidobacterium lactis HN019 and chicory inulin. А, fermentation of chicory inulin by gut microbiota with SCFA production. Inulin fermentation in the colon both by indigenous bifidobacteria and by the probiotic Bifidobacterium lactis HN019 strain is associated first of all with a decrease of intraluminal pH, acetate and lactate production and an increase in bifidobacteria counts (the bifidogenic effect), lactobacilli and butyrate-producing bacteria (Anaerostipes, Faecalibacterium, Anaerobutyricum). The latter use acetate and lactate for butyrate production during cross-feeding. Some commensal bacteria also produce propionate during inulin fermentation. Butyrate, acetate, and propionate are the main SCFA with anti-inflammatory, immunomodulating, and metabolic effects; they regulate energy homeostasis in colonocytes (butyrate) and facilitate the secretion of intestinal peptide hormones GLP-1 and PYY, thereby improving glucose metabolism and decreasing insulin resistance. Inulin also reduces the numbers of potential pathobionts (Bacteroides, Bilophila, Desulfovibrio), related to the proinflammatory immune response and metabolic endotoxemia, promoting a decrease in H2S production and LPS levels. Bifidobacterium lactis HN019 produces lactate and acetate, contributing to cross-feeding; it also stimulates gut motility by facilitating serotonin biosynthesis by enterochromaffin cells and fatty acid metabolism by commensals. B, immunomodulating effects of inulin and Bifidobacterium lactis HN019. Inulin regulates the differentiation and proliferation of immune cells (including Treg), reducing gut inflammation; it also augments tight junction protein expression, induces the secretion of sIgA and MUC2 by plasma and goblet cells, and promotes the secretion of IL-22 by γδ T cells and ILC3, thus supporting the intestinal barrier homeostasis. Bifidobacterium lactis HN019 suppresses pathogen colonization, including by enhancing AMP secretion; it reduces macrophage production of TNF-α and IL-6 cytokines associated with chronic inflammation and metabolic disorders; increases the activity of NK cells involved in innate immunity and enhances the phagocytic activity of polymorphonuclear leukocytes. AMP, antimicrobial peptides; ATP, adenosine triphosphate; DC, dendritic cell; EC, enterochromaffin cell; GLP-1, glucagon-like peptide 1; H2S, hydrogen sulfide; IL-6, interleukin 6; IL-22, interleukin 22; ILC3, innate lymphoid cell 3; LPS, lipopolysaccharide; MUC2, mucin 2; PYY, peptide YY; SCFA, short-chain fatty acids; sIgA, secretory immunoglobulin A; TNF-α, tumor necrosis factor α; Treg, regulatory T cell; 5-НТ, serotonin 5-hydroxytryptamine. Created with BioRender.com (381KB)
14. Coverage Geo-spatial location, chronological period, research sample (gender, age, etc.)
15. Rights Copyright and permissions Copyright (c) 2024 Serkova M.Y., Avalueva E.B., Sitkin S.I.
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