Yanan Zhang, Shuyu Tu, Xian Shao, Jinxin Meng, Zhuobiao Zhang, Wei Wei, Xuping Jing, Zhewen Qin, Jianan Wu, Weilv Xu, Bofei Dong, Jinsong Gao, Aijuan Qu, Shuxian Chen, Li Zhang, Gong Peng, Bo Shan, Hui Shi, Shu Jeffrey Zhu
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.