Abstract

The gut microbiota plays a crucial role in maintaining intestinal stem cell (ISC) homeostasis and epithelial barrier integrity. Here, we report that Blautia coccoides ( B. coccoides ) is significantly reduced in inflammatory bowel disease (IBD) patients and dextran sulfate sodium (DSS)-induced colitis mice. Through an integrated approach combining RNA sequencing, metabolomic profiling, and ISC lineage tracing across multiple mucosal injury models, we demonstrate that B. coccoides colonization enhances β-hydroxybutyrate (BHB) production in intestinal epithelial cells (IECs), which activates HOPX⁺ reserve ISCs and promotes regeneration of the LGR5⁺ ISC pool, thereby accelerating epithelial repair. We further show that B. coccoides -derived indole-3-lactic acid (ILA), a tryptophan (Trp) metabolite, is converted into indole-3-propionic acid (IPA) by commensal bacteria such as P. russellii or C. sporogenes , stimulating IEC BHB synthesis. Using an engineered Escherichia coli strain expressing BC-derived phenyllactate dehydrogenase ( fldH ), we establish that both dietary Trp and bacterial fldH activity are essential for ILA/IPA generation and subsequent mucosal healing. Our findings reveal a microbiota-metabolite-ISC regulatory axis critical for epithelial regeneration and propose novel metabolite-based therapeutic strategies for IBD and other intestinal disorders associated with barrier dysfunction.