Exenatide improves hypogonadism and attenuates inflammation in diabetic mice by modulating gut microbiota

• Published in: International immunopharmacology 2023-07, Vol.120, p.110339-110339, Article 110339
• Main Authors: Chen, Yuping, Shu, Anmei, Jiang, Ming, Jiang, Jinjin, Du, Qiu, Chen, Tianbao, Shaw, Chris, Chai, Wengang, Chao, TianQi, Li, Xiangzhe, Wu, Qin, Gao, Cuixiang
• Format: Article
• Language: English
• Subjects: Animals; Diabetes mellitus; Diabetes Mellitus, Experimental - drug therapy; Exenatide; Exenatide - pharmacology; Exenatide - therapeutic use; Gastrointestinal Microbiome; Gut microbiota; Hypogonadism; Hypogonadism - drug therapy; Inflammation; Interleukin-6; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2023.110339

[Display omitted] •Diabetes can lead to male hypogonadism and gut microbiota dysbiosis.•Exenatide showed protective effects on diabetes-induced male hypogonadism.•The protective effects of Exenatide were associated with reduced inflammation of the colon and testis after improvement of gut microbiota dysbiosis. With the rising incidence of diabetes and its onset at a younger age, the impact on the male reproductive system has gradually gained attention. Exenatide is a glucagon-like peptide-1 receptor agonist effective in the treatment of diabetes. However, its role in diabetes-induced reproductive complications has rarely been reported. The study aimed to investigate the mechanism by which exenatide improved diabetic hypogonadism by regulating gut microbiota (GM) mediated inflammation. C57BL/6J mice were equally divided into normal control (NC), diabetic model control (DM) and exenatide-treated (Exe) groups. Testicular, pancreatic, colonic, and fecal samples were collected to assess microbiota, morphologic damage, and inflammation. Exenatide significantly reduced the fasting blood glucose (FBG) level in diabetic mice, increased the testosterone level, ameliorated the pathological morphological damage of islet, colon, and testes, and reduced the expression of pro-inflammatory factors, tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6 in colon and testis. Furthermore, exenatide significantly reduced the abundance of some pathogenic bacteria, such as Streptococcaceae and Erysipelotrichaceae, and increased that of beneficial bacteria Akkermansia. Probiotics, such as Lactobacillus were negatively correlated with TNF-α, nuclear factor-kappa-B (NF-κB), IL-6, and FBG. Conditional pathogenic bacteria such as Escherichia/Shigella Streptococcus were positively correlated with TNF-α, NF-κB, IL-6, and FBG. The fecal bacteria transplantation experiment revealed that the abundance of pathogenic bacteria, Peptostreptococcaceae, significantly decreased from Exe group mice to pseudo-sterile diabetic mice, and the pathological damage to testes was also alleviated. These data suggested the protective effects of exenatide on male reproductive damage induced by diabetes by regulating GM.