P-316 Gut Microbiota–derived Butyrate Contributes to the Detrimental Effects of Prebiotic Fibers During Inflammatory Bowel Disease

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Abstract

Background:

Natural dietary fiber serves as a substrate for gut microbiota fermentation generating short-chain fatty acids (SCFA), which are thought to offer protection against inflammatory bowel disease (IBD). However, certain fibers are known to cause moderate to severe intestinal side effects in IBD patients. We hypothesize that soluble fiber (inulin and pectin) which are more accessible for microbiota fermentation may offer more pronounced gut protective effects than insoluble fiber (cellulose).

Methods:

Chronic colitis was induced in dietary cellulose, inulin or pectin-fed C57BL/6 mice by administering 3 weekly injections of interleukin-10 receptor neutralizing antibody (α-IL-10R mAb). Mice were euthanized 2 weeks after the last injection and colitis development was examined by fecal occult blood, serological (serum cytokines), biochemical (colonic myeloperoxidase [MPO] activity), histological ((1) mucosal thickening, (2) immune cell infiltrates in colonic lamina propria, 4-epithelial hyperplasia, and (3) colonic crypt damage), and immunological parameters (colonic expression of pro- and anti-inflammatory genes).

Results:

WT mice receiving dietary cellulose along with α-IL-10R mAb exhibited robust colitis—as characterized by splenomegaly, colomegaly, elevated colonic MPO activity, pro-inflammatory cytokines (keratinocyte-derived chemokine [Kc], interleukin [Il]-1β and inducible nitric oxide synthase [iNos]), systemic and fecal lipocalin 2 levels (an inflammatory marker), and colon histology score—when compared to control mice. Similar results were observed in toll-like receptor 5 knockout (Tlr5KO) mice which are prone to develop microbiota-dependent spontaneous colitis. Surprisingly, prebiotic fiber inulin failed to protect against α-IL-10R neutralization-induced chronic colitis in both WT and Tlr5KO mice. Interestingly, pectin ameliorates colitis development, supporting the notion that not all dietary fibers are created equal in modulating host gut inflammation. To determine why pectin and not inulin ameliorated the α-IL-10R neutralization-induced colitis, we analyzed the cecal SCFA (known to have pronounced effects on intestinal health) using gas chromatography-mass spectrometry (GC-MS). This analysis revealed that the butyrate level was specifically augmented in both healthy and colitic inulin-fed mice. To identify whether the elevated butyrate level worsened IBD in mice, we pretreated them with metronidazole which specifically deplete the butyrate producers in the gut, before inducing the colitis. Metronidazole treatment specifically reduced the butyrogenic bacteria Lachnospiraceae, Ruminococcaceae, and Clostridium cluster XIVa, and butyryl CoA:acetate CoA-transferase—an enzyme responsible for butyrate production—without affecting the total gut bacterial load. Most importantly, upon metronidazole treatment, the cecal butyrate level was virtually undetectable and mice were protected from colitis.

Conclusions:

Altogether, this observation suggests that butyrate contributes to dietary fiber-induced side effects in IBD patients, however, extensive studies are required to establish the causative role of butyrate in the worsening of IBD, specifically in prebiotic fiber-fed mice. Moreover, the detailed mechanistic study on how pectin dampens gut inflammation may yield development of novel dietary therapeutics to treat human IBD.

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