Investigating the role of hydrogen sulfide in the regulation of glucagon-like peptide-2 secretion and gut physiology

Abstract

Hydrogen sulfide (H2S) is an endogenously produced gasotransmitter which regulates a variety of physiological processes including hormone regulation. In individuals with Crohn’s disease or colitis, H2S is elevated. Whether H2S plays a role in gut disease development or protection is not clear. Glucagon-Like Peptide-2 (GLP-2) is a gut health-promoting peptide hormone produced in the enteroendocrine L-cells (EECs) located primarily in the distal gastrointestinal (GI) tract. In the gut, GLP-2 increases cell proliferation, enhances barrier function, and decreases inflammation. In this study, it is hypothesized that local H2S produced in the distal GI tract and in EECs can regulate GLP-2 secretion and downstream gut physiology. GLP-2 secretion and gut physiology was examined in mice lacking the H2S producing enzyme cystathionine gamma-lyase (CSE). Additionally, H2S production and GLP-2 secretion was examined from mouse enteroendocrine L-cells (GLUTag). CSE knockout (KO) mice had significantly reduced intestinal H2S production and claudin-7 expression. In cells, H2S was also produced directly from EECs which could be partially blocked by CSE inhibitors. When EECs were treated with H2S donors (NaHS and GYY 4137), the effect on GLP-2 secretion was variable with a slight suppression with high dose NaHS and no effect with GYY 4137. Finally, when cells were treated with CSE inhibitor, GLP-2 secretion was significantly reduced. Our work indicates that the EEC L-cell can produce the gasotransmitter H2S. Adding additional H2S has a variable effect while inhibiting endogenous production suppresses GLP-2 secretion. These findings suggest that GLP- 2 may play a role in the interplay between H2S and gastric health, which could provide support for the potential use of H2S drugs in the treatment of GI diseases.