Recently, the gastrointestinal microbiome, and its metabolites, has emerged as a potential regulator of host metabolism. However, to date little is known on the precise mechanisms of how this regulation occurs. Hydrogen sulfide (H₂S) is abundantly produced in the colon by sulfate-reducing bacteria (SRB). H₂S is a bioactive gas that plays regulatory roles in many systems, including metabolic hormone regulation. This gas metabolite is produced in close proximity to the glucagonlike peptide-1 (GLP-1)–secreting cells in the gut epithelium. GLP-1 is a peptide hormone that plays pivotal roles in both glucose homeostasis and appetite regulation. We hypothesized that H₂S can directly regulate GLP-1 secretion. We demonstrated that H₂S donors (NaHS and GYY4137) directly stimulate GLP-1 secretion in murine L-cells (GLUTag) and that this occurs through p38 mitogen-activated protein kinase without affecting cell viability. We then increased SRB in mice by supplementing the diet with a prebiotic chondroitin sulfate for 4 weeks. Mice treated with chondroitin sulfate had elevated Desulfovibrio piger levels in the feces and increased colonic and fecal H₂S concentration. These animals also had enhanced GLP-1 and insulin secretion, improved oral glucose tolerance, and reduced food consumption. These results indicate that H₂S plays a stimulatory role in GLP-1 secretion and that sulfate prebiotics can enhance GLP-1 release and its downstream metabolic actions.

Diabetes and its comorbidities continue to be a major health problem worldwide. Understanding the precise mechanisms that control glucose homeostasis and their dysregulation during diabetes are a major research focus. Hydrogen sulfide (H₂S) has emerged as an important regulator of glucose homeostasis. This is achieved through its production and action in several metabolic and hormone producing organs including the pancreas, liver, and adipose. Of importance, H₂S production and signaling in these tissues are altered during both type 1 and type 2 diabetes mellitus. This review first examines how H₂S is produced both endogenously and by gastrointestinal microbes, with a particular focus on the altered production that occurs during obesity and diabetes. Next, the action of H₂S on the metabolic organs with key roles in glucose homeostasis, with a particular focus on insulin, is described. Recent work has also suggested that the effects of H₂S on glucose homeostasis goes beyond its role in insulin secretion. Several studies have demonstrated important roles for H₂S in hepatic glucose output and adipose glucose uptake. The mechanism of H₂S action on these metabolic organs is described. In the final part of this review, future directions examining the roles of H₂S in other metabolic and glucoregulatory hormone secreting tissues are proposed.

The host’s intestinal microbiota contributes to endocrine and metabolic responses, but a dysbiosis in this environment can lead to obesity and insulin resistance. Recent work has demonstrated a role for microbial metabolites in the regulation of gut hormones, including the metabolic hormone, glucagon-like peptide-1 (GLP-1). Muramyl dipeptide (MDP) is a bacterial cell wall component which has been shown to improve insulin sensitivity and glucose tolerance in diet-induced obese mice by acting through the nucleotide oligomerization domain 2 (NOD2) receptor. The purpose of this study was to understand the effects of MDP on GLP-1 secretion and glucose regulation. We hypothesized that MDP enhances glucose tolerance by inducing intestinal GLP-1 secretion through NOD2 activation. First, we observed a significant increase in GLP-1 secretion when murine and human L-cells were treated with a fatty acid MDP derivative (L18-MDP). Importantly, we demonstrated the expression of the NOD2 receptor in mouse intestine and in L-cells. In mice, two intraperitoneal injections of MDP (5 mg/kg body weight) caused a significant increase in fasting total GLP-1 in chow-fed mice, however this did not lead to an improvement in oral glucose tolerance. When mice were exposed to a high-fat diet, they eventually lost this MDP-induced GLP-1 release. Finally, we demonstrated in L-cells that hyperglycemic conditions reduce the mRNA expression of NOD2 and GLP-1. Together these findings suggest MDP may play a role in enhancing GLP-1 during normal glycemic conditions but loses its ability to do so in hyperglycemia.

Radiation therapy for abdominopelvic malignancies often results in damage to the gastrointestinal tract (GIT) and permanent changes in bowel function. An overlooked component of the pathophysiology of radiation-induced bowel injury is the role of the gut microbiome. The goal of this research was to identify the impacts of acute radiation exposure on the GIT and gut microbiome. C57BL/6 mice exposed to whole-body X-rays (0.1–3 Gy) were assessed for histological and microbiome changes 48 h post-radiation exposure. Within the ileum, a dose of 3 Gy significantly decreased crypt depth as well as the number of goblet cells, but increased overall goblet cell size. Overall, radiation altered the microbial distribution within each of the main phyla in a dose- and tissue-dependent manner. Within the Firmicutes phylum, high dose irradiation resulted in significant alterations in bacteria from the class Bacilli within the small bowels, and from the class Clostridia in the large bowels. The 3 Gy radiation also significantly increased the abundance of bacterial families from the Bacteroidetes phylum in the colon and feces. Overall, we identified various alterations in microbiome composition following acute radiation exposure, which could potentially lead to novel biomarkers for tracking patient toxicities or could be used as targets for mitigation strategies against radiation damage.

Enterotoxigenic Escherichia coli (ETEC) produces the heat-stable enterotoxin b (STb), which is responsible for secretory diarrhea in humans and animals. This toxin is secreted within the intestinal lumen of animals and humans following ETEC colonization, becoming active on enterocytes and altering fluid homeostasis. Several studies have outlined the nature of this toxin and its effects on gut health and the integrity of the intestinal epithelium. This review summarizes the mechanisms of how STb alters the gastrointestinal tract. These include the manipulation of mucosal tight junction protein integrity, the formation of enterocyte cellular pores and toxin internalization and the stimulation of programmed cell death. We conclude with insights into the potential link between STb intoxication and altered gut hormone regulation, and downstream physiology.

Summary: Introduction: The gastrointestinal (GI) microbiome has emerged as a potential regulator of metabolism. However, the precise mechanisms of how microorganisms may influence physiology remain largely unknown. Interestingly, GI microorganisms, including methanogens, are localized within the same regions as the glucagon‐like peptide‐1 (GLP‐1) secreting L cells. GLP‐1 plays key roles appetite and glucose regulation. Furthermore, both methane and GLP‐1 levels are altered in obese humans with metabolic disease. We predict that high‐fat diet‐induced obesity alters the abundance of GI methanogens and that methane may play a role in the GLP‐1 secretory response from the L cell.Methods: To demonstrate this, GLP‐1 secretion response and faecal methanogens were examined in mice given a high‐fat diet for 14 weeks. In addition, the direct effect of methane on GLP‐1 secretion was assessed in two L‐cell models (NCI‐H716 and GLUTag).Results: High‐fat diet caused a significant increase in both GLP‐1 secretion and faecal methanogen content. There was a direct correlation between GLP‐1 secretion response and faecal methanogen levels. In L cells, methane stimulated GLP‐1 secretion and enhanced intracellular cAMP content.Conclusion: These results indicate that alterations in the methanogen communities occurring in obesity may play a vital role in directly enhancing GLP‐1 secretion, and that methane can directly stimulate the secretion of GLP‐1.