Serotonin receptor 4 agonism prevents high fat diet induced reduction in GLP-1 in mice.

Hormone-producing enteroendocrine cells (EECs) are present throughout the gastrointestinal tract and respond to various nutrient and gut microbiota produced metabolites stimuli. Two important EEC subtypes, Glucagon like peptide-1 (GLP-1) producing L-cells and serotonin (5-HT) producing enterochromaffin (EC) cells interact via paracrine signaling and exhibit bidirectional regulation of expression and secretion of produced hormones. Accordingly, in vitro studies suggest potential to modulate 5-HT secretion by GLP-1 receptor agonism, and L-cell differentiation via serotonin receptor 4 agonism. However, the importance of this cellular signaling on host metabolism is poorly understood. In this study, we found that two weeks of high fat diet (HFD) feeding reduced RNA expression of gut hormones, including proglucagon (Gcg) gene encoding GLP-1 and Tryptophan hydroxylase1 (Tph1) gene encoding rate limiting enzyme in 5-HT synthesis, specifically in the colon and reduced plasma GLP-1 levels. Levels of propionate and butyrate were also reduced following HFD. However, supplementation of sodium propionate did not improve HFD induced reduction in GLP-1. In contrast, chemical induction of serotonin receptor 4 promoted GLP-1 levels, colonic Gcg RNA expression accompanied by improvement in glucose tolerance in HFD-fed mouse. Thus, this study suggests a novel mechanism to improve glucose tolerance via serotonin receptor 4 stimulation in the HFD induced obese mouse model.

Microbial metabolite p-cresol inhibits gut hormone expression and regulates small intestinal transit in mice.

p-cresol is a metabolite produced by microbial metabolism of aromatic amino acid tyrosine. p-cresol and its conjugated forms, p-cresyl sulfate and p-cresyl glucuronide, are uremic toxins that correlate positively with chronic kidney disease and diabetes pathogenesis. However, how p-cresol affects gut hormones is unclear. Here, we expose immortalized GLUTag cells to increasing concentrations of p-cresol and found that p-cresol inhibited Gcg expression and reduced glucagon-like peptide-1 (GLP-1) secretion in vitro. In mice, administration of p-cresol in the drinking water for 2 weeks reduced the transcript levels of Gcg and other gut hormones in the colon; however, it did not affect either fasting or glucose-induced plasma GLP-1 levels. Furthermore, it did not affect glucose tolerance but promoted faster small intestinal transit in mice. Overall, our data suggest that microbial metabolite p-cresol suppresses transcript levels of gut hormones and regulates small intestinal transit in mice.

Microbial regulation of enteroendocrine cells.

There has been an enormous interest to investigate impact of gut microbiota on host physiology over the past decade. To further understand its role at organismal level, it is important to delineate host-microbiota interaction at tissue and cell level. Diet, antibiotics, disease, or surgery produce shifts in composition of the gut microbiota that further alter levels of microbial-derived metabolites. Enteroendocrine cells (EECs) are specialized hormone-producing cells in the gut epithelium that sense changes in the intestinal milieu through chemosensing G protein-coupled receptors. Accordingly, microbial metabolites interact with the EECs to stimulate or suppress hormone secretion, which act through endocrine and paracrine signaling to regulate local intestinal and diverse physiological functions and impact overall host metabolism. The remarkable success of glucagon-like peptide-1-based drugs for treatment of type 2 diabetes and obesity highlights the relevance to investigate microbial regulation of EECs to tackle metabolic diseases through novel microbiota-based therapies.