The Emerging Short Chain Fatty Acid Enriched Metabotype in Irritable Bowel Syndrome and Its Potential Clinical Relevance

BACKGROUND: Metabolomic analysis in irritable bowel syndrome (IBS) has identified metabotypes enriched in faecal short-chain fatty acids (SCFAs), but it remains unclear whether this reflects rapid colonic transit or if these metabolites actively contribute to pathophysiology. AIMS: We aimed to determine whether an SCFA metabotype could be identified within a cohort of patients with moderate-severe IBS-D and assess whether this metabotype associated with greater clinical severity, alterations in gut transit time and specific microbiome features. METHODS: This was a post hoc cross-sectional exploratory analysis of baseline data from the multicentre, randomised, placebo-controlled trial of ondansetron in IBS-D (TRITON: ISRCTN17508514). Faecal volatile organic compounds were profiled by GC-MS. The microbiome was characterised by whole-genome shotgun metagenomic sequencing. Unsupervised hierarchical clustering was used to identify an SCFA-enriched metabotype and non-negative matrix factorisation (NMF) enabled the derivation of complementary metabosignatures by assessing continuous gradients in metabolite composition. RESULTS: A SCFA-enriched metabotype was identified in 20/63 participants (31.7%). This metabotype was associated with more severe abdominal pain, urgency, increased stool frequency and faster whole-gut transit. NMF identified three metabosignatures: S3 was typified by a high proportion of SCFAs and captured the SCFA-enriched metabotype, while S1 and S2 corresponded to the non-SCFA ("Other") metabotype. SCFA relative abundance positively correlated with symptom severity and inversely correlated with transit time. The Other metabotype and S1/S2 signatures were enriched in taxa linked to slower transit, whereas S3 showed no overlapping taxa with the SCFA metabotype. CONCLUSION: A faecal metabotype enriched in SCFAs associated with an IBS-D phenotype characterised by pain, urgency, rapid transit and higher stool frequency.