Poster Session II - A218 BUTYRATE’S ROLE IN MODULATING TIGHT JUNCTIONS, GPR41/43 RECEPTORS, AND IMMUNOGLOBULIN RESPONSES IN EXPERIMENTAL COLITIS

TL;DR

This study explores how butyrate, a gut microbiota metabolite, affects intestinal barriers and immune responses in a mouse model of colitis.

Contribution

The study provides new insights into butyrate's role in modulating tight junctions and local immune responses in experimental colitis.

Findings

Butyrate increased ZO-1 expression, suggesting improved epithelial barrier function.

Butyrate reduced colonic TNF-a and IL-17 levels in colitic mice.

Butyrate had limited effects on systemic immunoglobulin isotypes but decreased IgG1 in colon washes of colitic mice.

Abstract

Inflammatory bowel disease (IBD) involves impaired mucosal barrier function, cytokines, and dysregulated B-cell responses. Emerging evidence suggests that the gut microbiota and its metabolites, including short-chain fatty acids (SCFA) like butyrate, modulate intestinal inflammation. However, the specific role of butyrate via its epithelial receptors in regulating mucosal permeability and B-cell activity remains unclear. We hypothesize that butyrate influences epithelial barrier integrity and B-cell function during colonic inflammation.

To determine how butyrate modulates epithelial tight junctions, GPR41/43 receptor activation, and mucosal immune responses, including lumen immunoglobulin release, in experimental colitis.

C57BL/6 mice (n = 8/group) received 150 mM sodium butyrate in drinking water for 30 days before inducing colitis with 5% dextran sulfate sodium (DSS) for 5 days. Disease activity index (DAI), colon length, and macroscopic scores were recorded to evaluate colitis severity. Immunofluorescence staining was performed on mid-colon segments to assess epithelial Zonula Occludens-1 (ZO-1) and butyrate receptors GPR41 and GPR43 expression. Serum and colon wash samples were analyzed for immunoglobulin isotypes (IgA, IgG1, IgM IgG2b) using ELISA, in addition to colonic and serum TGF-b, and colonic TNF-a and IL-17.

DSS-induced colitis significantly increased DAI and macroscopic damage and reduced colon length compared to controls. Butyrate-treated colitic mice demonstrated a higher DAI on day 5 than colitic mice, without improvement in colon length or macroscopic pathology. Butyrate significantly increased ZO-1 immunofluorescence in both control and colitic mice. In parallel, expression of butyrate receptors GPR41 and GPR43 was elevated in both colitic and non-colitic butyrate-treated mice, with the highest levels observed in colitic group. Systemically, colitis significantly decreased serum IgG2b. In both colitic and non-colitic mice, butyrate treatment did not alter serum immunoglobulin isotypes. In colon washes, colitis significantly increased serum IgA, and butyrate treatment significantly decreased IgG1 a level in colitic mice. Serum and colonic levels of TGF-b were not modified in colitic and non-colitic mice, regardless of the treatment. However, in colitis, butyrate treatment decreased significantly colonic TNF-a and IL-17.

Together, these findings suggest that butyrate enhances epithelial barrier function by upregulating ZO-1, but has limited effects on systemic immunoglobulin responses, while modulating local IgG1 and pro-inflammatory cytokines in colitis. Our results support a model in which butyrate provides protective effects on mucosal immunity. These insights could inform the development of microbiota and SCFA-based therapeutic strategies for IBD.

NSERC