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

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