Investigation of abdominal pain management in diarrhea-predominant irritable bowel syndrome via short-chain fatty acids/GLP-1 axis

Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common functional bowel disorder characterized by abdominal pain, bloating, abdominal distention and diarrhea. Abdominal pain is the dominant symptom found in patients with IBS-D, where conventional medications used for alleviating abdominal pain do not effectively reduce abdominal pain in IBS-D patients due to visceral hypersensitivity. Therefore, the development of novel therapies for managing abdominal pain in IBS-D is of great importance. Glucagon-like peptide-1 (GLP1) is a hormone produced by intestinal enteroendocrine L-cells. A recent clinical study showed a GLP-1 agonist ROSE-010 effectively alleviates abdominal pain in IBS patients. Despite the exogenous GLP-1 therapies provide a novel strategy for the relief of abdominal pain, our current understanding for the pathogenesis of visceral hypersensitivity in IBS-D are still limited.

Gut-microbial metabolites are involved in the pathogenesis/treatment of IBS-D including diarrheal symptoms and abdominal pain symptoms and our group has done a series of research work to understand the correlation and causative roles of gut microbiota and gut-microbial metabolites on the pathogenesis of IBS-D (Microbiome, 2018, Journal of Clinical Investigation, 2020, The ISME Journal, 2020 and Cell Host & Microbe, 2022, under revision). Recent evidence suggests gut-microbial metabolites short-chain fatty acids (SCFA) including acetate, propionate and butyrate can stimulate endogenous GLP-1 secretion, suggesting SCFA potentially alleviate visceral hypersensitivity in IBS-D patients and be associated with the severity of abdominal pain. However, the changes of SCFA in IBS remain controversial and whether SCFA is beneficial for the management of abdominal pain in IBS is unclear. In our preliminary studies, we demonstrated that fecal SCFA levels were significantly reduced in a subset of IBS-D patients, accompanied with reduced serum GLP-1 levels. We also showed that fecal SCFA levels and serum GLP-1 levels were inversely associated with the severity of abdominal pain index in IBS-D patients, suggesting the SCFA/GLP-1 signaling axis is impaired in a subset of IBS-D patients. Moreover, we revealed fecal microbiota transplant (FMT) from IBS-D patients with SCFA-enriched gut microbiota resulted in lower visceral hypersensitivity in mice when compared with mice colonized with SCFA-reduced gut microbiota from IBS-D patients. Consistently, we showed fecal SCFA levels and serum GLP-1 levels were higher in mice from the SCFA-enriched gut microbiota-FMT group.

Therefore, we hypothesize that modulation of endogenous SCFA/GLP-1 axis via gut microbiota alleviate the abdominal pain symptoms in IBS-D. To test our hypothesis, we will (1) investigate the regulatory role of SCFA/GLP-1 signaling axis for visceral hypersensitivity in mouse models of IBS-D. (2) characterize microbial abundances and genomic variants of SCFA-producers in IBS-D patients. (3) investigate the effects of IBS-D-associated SCFAproducers and their underlying mechanisms in abdominal pain. This study will not only for the first time reveal the molecular mechanism underlying the regulation of visceral sensitivity by gut microbiota, but also provide novel therapeutic options to relieve abdominal pain in IBS-D patients.