TY - JOUR

T1 - Gut microbial metabolites as key mediators in inflammatory bowel disease

AU - Sall, Tatiana

AU - Litvinova, Ekaterina

AU - Arzhanova, Elena

AU - Sitkin, Stanislav

AU - Vakhitov, Timur

PY - 2026

Y1 - 2026

N2 - BACKGROUND Inflammatory bowel disease (IBD) is characterized by inflammation of the intestinal mucosa, increased intestinal permeability, and impaired immune regulation, all of which are accompanied and aggravated by gut microbial dysbiosis. Disturbed microbial composition contributes to the pathogenesis of IBD by altering the production of microbial metabolites, which may either alleviate or exacerbate IBD progression. The main feature of metabolic dysbiosis in IBD is impaired microbial synthesis of biologically active compounds characteristic of eubiosis, including short-chain fatty acids. The use of a combination of these metabolites in IBD patients appears promising due to its potential synergistic effects on host health and microbiota composition. AIM To evaluate the effect of bacterial metabolites composition (butyric, propionic, valeric acids) on in vitro and in vivo IBD models. METHODS We used Caco-2 cells exposed to lipopolysaccharides and Mucin-2 knockout mice as in vitro and in vivo IBD models. Caco-2 cells were exposed to lipopolysaccharides with metabolites for 24 hours. Muc2-/- mice were given metabolites via oral gavage daily for 1 week. C57BL/6 mice were used as healthy controls. Immune cells were analyzed by flow cytometry; intestinal barrier integrity by fluorescein isothiocyanate-dextran transport; cytokine expression by real-time quantitative polymerase chain reaction; cytokine content by ELISA; and the mouse metabolome and microbiome composition by gas chromatography-mass spectrometry and 16S rRNA metagenomic sequencing. RESULTS Butyric acid decreased Caco-2 cell monolayer integrity and intestinal permeability in Muc2-/- mice; propionic and valeric acids decreased gene expression and the concentration of pro-inflammatory cytokines in Caco-2 cells and in the Muc2-/- mouse intestine; and the combination of these metabolites increased cell viability and possessed anti-inflammatory and intestinal barrier-strengthening properties. Metabolites and their combination increased the number of regulatory T cells and anti-inflammatory M2 peritoneal macrophages. Metabolite treatment increased gut microbiota biodiversity and Bacillota abundance in Muc2-/- mice, while reducing the abundance of Thermodesulfobacteriota and Pseudomonadota, and decreased the levels of lactate, long-chain fatty acids, and 2-hydroxybutyric acid, which are markers of metabolic dysbiosis in a disturbed microbiota and dysregulated metabolism in inflamed host cells. We revealed 2-hydroxybutyric acid’s biological activity toward IBD progression: It increased intestinal permeability, inflammation, and the number of pro-inflammatory M1 macrophages; decreased cell viability and the number of regulatory T cells. CONCLUSION We have shown that certain bacterial metabolites may promote IBD development, while others may have a therapeutic effect, especially when used in combination.

AB - BACKGROUND Inflammatory bowel disease (IBD) is characterized by inflammation of the intestinal mucosa, increased intestinal permeability, and impaired immune regulation, all of which are accompanied and aggravated by gut microbial dysbiosis. Disturbed microbial composition contributes to the pathogenesis of IBD by altering the production of microbial metabolites, which may either alleviate or exacerbate IBD progression. The main feature of metabolic dysbiosis in IBD is impaired microbial synthesis of biologically active compounds characteristic of eubiosis, including short-chain fatty acids. The use of a combination of these metabolites in IBD patients appears promising due to its potential synergistic effects on host health and microbiota composition. AIM To evaluate the effect of bacterial metabolites composition (butyric, propionic, valeric acids) on in vitro and in vivo IBD models. METHODS We used Caco-2 cells exposed to lipopolysaccharides and Mucin-2 knockout mice as in vitro and in vivo IBD models. Caco-2 cells were exposed to lipopolysaccharides with metabolites for 24 hours. Muc2-/- mice were given metabolites via oral gavage daily for 1 week. C57BL/6 mice were used as healthy controls. Immune cells were analyzed by flow cytometry; intestinal barrier integrity by fluorescein isothiocyanate-dextran transport; cytokine expression by real-time quantitative polymerase chain reaction; cytokine content by ELISA; and the mouse metabolome and microbiome composition by gas chromatography-mass spectrometry and 16S rRNA metagenomic sequencing. RESULTS Butyric acid decreased Caco-2 cell monolayer integrity and intestinal permeability in Muc2-/- mice; propionic and valeric acids decreased gene expression and the concentration of pro-inflammatory cytokines in Caco-2 cells and in the Muc2-/- mouse intestine; and the combination of these metabolites increased cell viability and possessed anti-inflammatory and intestinal barrier-strengthening properties. Metabolites and their combination increased the number of regulatory T cells and anti-inflammatory M2 peritoneal macrophages. Metabolite treatment increased gut microbiota biodiversity and Bacillota abundance in Muc2-/- mice, while reducing the abundance of Thermodesulfobacteriota and Pseudomonadota, and decreased the levels of lactate, long-chain fatty acids, and 2-hydroxybutyric acid, which are markers of metabolic dysbiosis in a disturbed microbiota and dysregulated metabolism in inflamed host cells. We revealed 2-hydroxybutyric acid’s biological activity toward IBD progression: It increased intestinal permeability, inflammation, and the number of pro-inflammatory M1 macrophages; decreased cell viability and the number of regulatory T cells. CONCLUSION We have shown that certain bacterial metabolites may promote IBD development, while others may have a therapeutic effect, especially when used in combination.

KW - 2-Hydroxybutyrate

KW - Butyrate

KW - Dysbiosis

KW - Gut microbial metabolites

KW - Inflammatory bowel disease

KW - Metabiotic concept

KW - Microbe-host cross-talk

KW - Propionate

KW - Synergistic regulatory activity

KW - Valerate

UR - https://www.scopus.com/pages/publications/105049830804

UR - https://www.mendeley.com/catalogue/33049353-b27d-3bf2-b033-1d591baa0ed6/

U2 - 10.3748/wjg.121041

DO - 10.3748/wjg.121041

M3 - Article

VL - 32

JO - World Journal of Gastroenterology

JF - World Journal of Gastroenterology

SN - 2219-2840

IS - 39

ER -