Abstract
Western diets reduced in fiber promote dysbiosis and exacerbate colitis, with short-chain fatty acids (SCFAs) from fiber fermentation known to regulate glucagon-like peptide 1 (GLP-1) secretion. Whether GLP-1 dysregulation directly links diet-induced dysbiosis to colitis severity, and if this pathway can be therapeutically targeted independently of dietary fiber, remains unclear. Here, we show that dextran sulfate sodium (DSS)-induced colitis severity correlates with compensatory GLP-1 increases, while receptor blockade worsens damage, confirming GLP-1's protective role during colitis. Fiber deficiency impaired L cell function and GLP-1 release, increasing colitis susceptibility. GLP-1 receptor agonist reversed these effects, restoring barrier integrity and accelerating recovery. We engineered a probiotic, releasing a microbial peptide, that locally elevates GLP-1, which normalized gut parameters in fiber-deprived mice and alleviated colitis via GLP-1-dependent mechanisms, including improved metabolism, antimicrobial defenses , and barrier restoration. Our findings mechanistically connect fiber deficiency to colitis through GLP-1 and demonstrate that probiotic-mediated GLP-1 modulation can bypass dietary fiber requirements to maintain gut homeostasis.