Microbiota-derived IPA protects against colitis by regulating intestinal HMGCS2-mediated ketogenesis to facilitate mucosal healing

The gut microbiota sustains intestinal homeostasis, yet how microbial metabolites direct epithelial repair remains unclear. Here we identify indole-3-propionic acid (IPA), a tryptophan-derived bacterial metabolite, as a key regulator of mucosal healing. IPA activates PPARα in intestinal epithelial cells, enhancing transcription of the ketogenic enzyme HMGCS2 and boosting β‑hydroxybutyrate (BHB) production. BHB in turn stimulates LGR5⁺ intestinal stem cells, accelerating epithelial regeneration. Using germ-free models and the IPA‑producer Peptostreptococcus russellii, we show that dietary tryptophan and specific commensals sustain luminal IPA levels, which are critical for recovery in colitis. Restoration of IPA or BHB attenuates inflammation and barrier defects, outlining a microbiota‑metabolite‑stem cell axis that could be therapeutically targeted in inflammatory bowel disease and other barrier disorders. Here, Zhang et al. demonstrate that the microbial metabolite indole-3-propionic acid stimulates production of β-hydroxybutyrate in intestinal cells, in turn activating regenerative stem cells to promote mucosal healing in colitis.