Role of serotonin in gastrointestinal dysmotility associated with diabetes and COVID-19

Abstract

Serotonin (5-hydroxytryptamine [5-HT]) plays a critical role in modulating gastrointestinal (GI) motility. Up to 95% of the total 5-HT in the body is synthesized from enterochromaffin cells in the GI tract. However, mechanistic pathways connecting abnormal serotonergic signaling to GI symptoms in the context of diabetes and/or coronavirus disease 2019 (COVID-19) remain elusive.In the first study, we demonstrated that enhancing 5-HT2B receptor (HTR2B) signaling in interstitial cells of Cajal via a specific agonist (BW723C86) substantially improved colonic motility in diabetic mice with constipation. In the second study, we observed a positive correlation between elevated plasma 5-HT levels and diarrheal symptoms in patients with COVID-19. Additionally, elevated plasma 5-HT levels were positively correlated with worsening symptoms in patients with COVID-19. In the third study, we summarized the expected pathophysiological mechanisms (impaired barrier function, gut inflammation, altered 5-HT metabolism, and gut microbiota dysbiosis) underlying the GI symptoms in COVID-19 patients. Taken together, we propose that enhancing HTR2B signaling in diabetes and reducing the 5-HT levels in COVID-19 patients might be beneficial in treating GI manifestations in these conditions.