Disruption of gut bacteria-derived hydrogen sulfide signaling mediates antibacterial-induced acute anorexia.

Abstract

Numerous commonly used antibacterial agents frequently induce acute anorexia as a clinical side effect, yet the underlying mechanism remains poorly understood. Here, we investigated the role of gut bacteria-derived hydrogen sulfide (H₂S) signaling in the regulation of feeding behavior and its involvement in antibiotic-associated anorexia. Using methylene blue colorimetric and fluorescent probe-based detection, we found that 24-h fasting elevated H₂S levels in rat feces and serum, which robustly stimulated feeding behavior. 16S rRNA sequencing revealed that fasting reshaped the gut microbiota and enriched certain H₂S-producing bacterial taxa. Through fecal microbiota transplantation and pharmacological manipulations, our findings suggest a contribution of microbiota-derived H₂S to fasting-induced feeding behavior. Mechanistically, fasting-induced H₂S promoted feeding by activating AMP-activated protein kinase (AMPK) in the hypothalamic arcuate nucleus, a key center for feeding regulation, via an S-sulfhydration-dependent mechanism, which in turn enhanced the activity of neuropeptide Y-positive neurons. Furthermore, we showed that impaired gut bacterial H₂S signaling contributed to metronidazole-induced acute anorexia, a common adverse clinical effect. Given that H₂S-producing taxa, especially Desulfovibrio, are sensitive to a broad range of antibacterial agents, our findings suggest an important role for gut bacterial H₂S signaling in gut-brain communication and appetite control, and point to a microbiota-host feedback mechanism underlying antibacterial-induced acute anorexia.