Gut metagenome in4-GBA-treated mice and WT mice with or without DSS exposure

Abstract

The role of gut microbiota‒derived metabolites in regulating the intestinal mucosal barrier remains poorly defined. Here, we identified 4-guanidinobutanoic acid (4-GBA), produced by <i>Bacteroides stercorirosoris</i>, as a critical regulator of intestinal homeostasis. Using untargeted metabolomics, organoid co-cultures, mouse models, and single-cell RNA sequencing, we demonstrated that 4-GBA enhances intestinal stem cells (ISCs) function and goblet cell differentiation. This promotes <i>Akkermansia muciniphila</i> enrichment through mucus-dependent niche expansion, establishing a microbiota‒host feedback loop. Mechanistically, 4-GBA upregulates the proton-coupled amino acid transporter SLC36A1 and activates the Hedgehog signaling pathway to drive epithelial reprogramming. Clinically, SLC36A1 expression inversely correlates with ulcerative colitis (UC) severity in human samples. Furthermore, the SLC36A1 agonist sarcosine enhances barrier homeostasis and attenuates colitis in mice, highlighting the diagnostic and therapeutic potential of this axis in UC. Our findings reveal a novel microbiome-host axis through which a microbial metabolite modulates epithelial function and microbial ecology, offering a potential therapeutic strategy targeting microbiota-epithelial crosstalk for UC management.