High Humidity Environment Increases FBG by Impairing the Intestinal Barrier

Yao Wang^1,2,3,4Kai Zhuang^1,2,4*Qiuxia Yi⁵Yalan Wu^1,2,4Lynn Luo^1,2,4Yulin Ouyang⁶Liang Li³Chun Li⁴Huanhuan LUO^1,2,4*

• ¹State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, China
• ²Chinese Medicine Guangdong Laboratory, hengqin, China
• ³Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Chinese Medicine, Zhongshan, China
• ⁴College of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
• ⁵The Affiliated Hospital of Liaoning University of Traditional Chinese Medicine,, Shenyang, China
• ⁶School of Pharmaceutics, Guangzhou University of Chinese Medicineou, guangzhou, China

Climate and environmental changes pose significant threats to human metabolism. However, the effects of specific environmental factors on metabolic diseases remain poorly understood. In this study, we investigated the impact of a high humidity environment (HH) on fasting blood glucose (FBG), intestinal barrier integrity, and gut microbiota composition using both clinical samples and a controlled male mouse model. Clinical samples collected during HH exposure revealed elevated FBG, increased glucagon (GC) levels, impairment of the intestinal barrier, and decreased serum gamma-aminobutyric acid (GABA) concentrations. Gut microbiota profiling through 16S rDNA sequencing indicated an increased abundance of genus Alistipes, Parabacteroides, and Akkermansia under HH conditions. Further mechanistic studies, fecal microbiota transplantation (FMT) and Mendelian randomization (MR) analysis, suggested that HH-induced changes in gut microbiota may mediate FBG elevation. Western blotting and immunofluorescence staining confirmed intestinal barrier disruption. Metabolomic analysis demonstrated reduced GABA levels in serum, which correlated with barrier impairment and activation of the MDP-NOD2 signaling pathway in pancreatic β-cells. Moreover, we observed downregulation of GAD67 expression in pancreatic β-cells, resulting in decreased GABA synthesis. This reduction contributed to increased GC secretion from islet α-cells and elevated FBG levels. Notably, treatment with an antibiotic cocktail (ABX) effectively reversed these alterations. In conclusion, our findings demonstrate that a high humidity environment disrupts gut microbiota homeostasis, impairs the intestinal barrier, and reduces GABA synthesis in pancreatic β-cells, thereby promoting the development of type 2 diabetes mellitus (T2DM).