Microbiota and short chain fatty acid relationships underlie clinical heterogeneity and identify key microbial targets in irritable bowel syndrome (IBS)

Abstract Short chain fatty acids ( SCFA) are key microbial metabolites that modulate intestinal homeostasis and may influence irritable bowel syndrome (IBS) pathophysiology. We aimed to assess microbial features associated with SCFA and determine if features varied across IBS subtypes and endophenotypes. We analyzed stool microbial metagenomes, stool SCFA, and measurable IBS traits (stool bile acids, colonic transit, stool form) in 41 patients with IBS (IBS with constipation IBS-C IBS with diarrhea IBS-D) and 17 healthy controls. We used partial canonical correspondence analyses (pCCA), conditioned on transit, to quantify microbe-SCFA associations across groups. We further compared gut microbiome-encoded potential for substrate utilization across groups and within a subset of participants selected by their stool characteristics as well as stool microbiomes of patients with and without clinical bile acid malabsorption (BAM). Microbe-SCFA associations differed across groups and revealed key taxa including Dorea sp. CAG:317 and Bifidobacterium pseudocatenulatum in IBS-D and Akkermansia muciniphila and Prevotella copri in IBS-C that that could underlie subtype-specific microbially-mediated mechanisms. The greatest number of microbe-SCFA associations were observed in IBS-D. Several SCFA-producing species demonstrated inverse correlations with SCFA. Fewer bacterial taxa were associated with acetate to butyrate ratios in IBS compared to health. In participants selected by stool form, we demonstrated differential abundances of microbial genes/pathways for SCFA metabolism and degradation of carbohydrates and mucin across groups. SCFA-producing taxa were reduced in IBS-D patients with BAM. Keystone taxa responsible for SCFA production differ by IBS subtype and traits. IBS microbiomes appear exhibit reduced functional redundancy. Differences in substrate preferences are also linked to bowel functions. Focusing on taxa that drive SCFA profiles and stool form may be a rational strategy for identifying relevant microbial targets in IBS.