Gut microbial H2S promotes metabolic dysfunction in mice via hepatic PPARα suppression

This study investigates the role of gut microbiota-derived hydrogen sulfide (H2S) in obesity and glucose metabolism disorders. By integrating human gut metagenomic data, intervention experiments in mouse models, and in vitro cellular assays, we identified a signature of microbial sulfur metabolism in human cohorts and provided experimental evidence for its causal role and underlying metabolic mechanisms in mice. In clinical cohorts with obesity and glucose metabolism disorders, we observed a notable enrichment of genes involved in sulfur transport and H2S production. In mouse models, administration of H2S-producing Desulfovibrio desulfuricans, engineered Escherichia coli expressing phsABC, and the H2S donor NaHS consistently induced body weight gain and impaired glucose tolerance. Transcriptome analysis and cellular experiments indicated that H2S was associated with downregulation of the PPAR signaling pathway and lipid metabolism pathways in the liver, which may contribute to the abnormal accumulation of lipids and glycogen. Furthermore, rescue experiments using a PPAR agonist and an H2S adsorbent partially reversed these metabolic abnormalities. Collectively, our work provides experimental evidence in mouse models demonstrating that gut microbial H2S promotes metabolic dysfunction through hepatic PPARα suppression, providing potential targets for microbiome-based therapeutic interventions.