High-Temperature-and-Humidity Reduces Plasma Insulin and Gut Hormones through FXR Activation Accompanied by a Metabolic Compensatory Gut Microbiota

Abstract Environmental high-temperature-and-humidity (HTH) causes discomfort and is associated with a series of diseases; however, the underlying mechanism linking HTH and these diseases remains unclear. In this study, we demonstrated that HTH remarkably impaired the secretion of insulin, GLP-1, and ghrelin rapidly and persistently in mice. We then performed a longitudinal analysis of alterations to the gut microbiota following HTH exposure. There was no distinct alteration in the gut microbiota associated with the impaired secretion of insulin and gut hormones. The causal mediation analysis also excluded the predominant role of gut bacteria in insulin and gut hormone levels. In contrast, fecal microbiota transplant experiments confirmed that the gut microbiota decreased the plasma levels of glucose and triglyceride, likely through augmented thermogenesis. This implied that the gut microbiota compensated for the metabolic effect of insufficient insulin on glucose and lipid synthesis in HTH-treated mice. Furthermore, we revealed a profound alteration in bile acids (BAs) with characteristics of decreased tauro-conjugation rapidly following HTH exposure, and a reduced bile acid pool emerged gradually. Using proteomic analysis, we showed that multiple farnesoid X receptor (FXR)-targeted proteins, including BA transporters SLC10A2, FABP6, and OSTα/OSTβ, were enriched in the ileum 8 weeks after HTH exposure, thus implying an augmented reabsorption of bile acids in response to the reduced BAs pool. Considering the critical role of FXR in GLP-1 suppression as well as in controlling BA homeostasis, lipoprotein and glucose metabolism, hepatic regeneration, intestinal bacterial growth, and the response to hepatotoxins, our results revealed a link between environmental HTH, bile acids, gut microbiota, and energy metabolism. This study sheds new light on the pathogenesis of several ambient HTH-associated diseases.