A microbiota-IPA axis facilitates intestinal stem cell-mediated regeneration in colitis through a Hopx-associated program

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.