The role of intestinal hydrogen sulfide on GLP-1 secretion and downstream metabolism

Abstract

Metabolic hormones released from the gastrointestinal tract are core regulators for digestion, satiety, gut motility, and glucose homeostasis. Advancements in the management of type 2 diabetes and obesity have recently included the use of incretin hormone-based therapies, such as glucagon-like peptide-1 (GLP-1) analogs. GLP-1 can enhance glucose-dependent insulin secretion and stimulate satiety after a meal. The release of this incretin is stimulated by the entry of nutrients in the lumen or circulation. In addition, microbial metabolites have recently emerged as a new group of potent stimulators of GLP-1 secretion. Hydrogen sulfide (H2S), produced from sulfate-reducing bacteria (SRB) of the distal ileum and colon, are localized in the same niche as GLP-1 secreting L-cells. The physiological role of endogenous H2S is well established in many biological systems, however it is not well understood how or if H2S can affect the enteroendocrine system. Therefore, we hypothesized that microbial H2S from the distal GI tract can potentially alter GLP-1 secretion and downstream metabolism, and further investigated the potential mechanisms involved in the process. In murine colonic L-cells (GLUTag), we demonstrated that H2S donors (NaHS and GYY4137) significantly enhanced GLP-1 secretion and that the process was regulated through the p38 MAPK signaling pathway. In male C57BL/6 mice, a 4-week chondroitin sulfate prebiotic diet successfully elevated SRB and colonic H2S levels, enhanced the GLP-1 response, and reduced food intake. Together, this study demonstrated a direct role for H2S in the stimulation of GLP-1 and a potential role for sulfur prebiotics to increase the H2S producing SRB as a means to enhance GLP-1 and improve metabolism