Department of Endocrinology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
mBio. 2024 Feb 14;15(2):e0294323. doi: 10.1128/mbio.02943-23. Epub 2024 Jan 16.
Long-term/high-dose glucocorticoid (GC) use results in glycolipid metabolism disorder, which severely limits its clinical application. The role of the gut microbiota and its metabolites in GC-induced glycolipid metabolism disorder remains unclear. Our previous human study found that obvious gut microbiota dysbiosis characterized by an increasing abundance of and a decreased abundance of and were observed in patients with endogenous hypercortisolism. In this study, we established a mouse model of GC-induced glycolipid metabolism disorder (Dex group) and found that the relative abundances of and were increased, while the abundances of , , and were decreased significantly in the Dex group. Compared with the control group, serum total short-chain fatty acids (SCFAs), acetic acid, propionic acid, and GLP-1 levels were all decreased in the Dex group. The mRNA expression of the GPR41 receptor and Pcsk1 in the colon was significantly decreased in the Dex group. Furthermore, GC-induced glycolipid metabolism disorder could be alleviated by depletion of the gut microbiota or fecal bacteria transplantation with control bacteria. The abundances of and the serum GLP-1 levels were significantly increased, while the abundances of and were significantly decreased after fecal bacteria transplantation with control bacteria. Our work indicates that gut microbiota dysbiosis and decreased levels of serum acetic acid and propionic acid may participate in GC-induced glycolipid metabolism disorder. These findings may provide novel insights into the prevention and treatment of GC-induced metabolic disorders.IMPORTANCEThe role of the gut microbiota in glucocorticoid (GC)-induced glycolipid metabolism disorder remains unclear. In our study, gut microbiota dysbiosis characterized by an increased abundance of / and a decreased abundance of Lachnospiraceae_NK4A136_group was observed in mice with GC-induced glycolipid metabolism disorder. Some bacteria were shared in our previous study in patients with endogenous hypercortisolism and the mouse model used in the study. Furthermore, the depletion of the gut microbiota and fecal bacteria transplantation with control bacteria could alleviate GC-induced glycolipid metabolism disorder. Plasma acetic acid, propionic acid, and GLP-1 and the mRNA expression of the GPR41 receptor and Pcsk1 in the colon were decreased significantly in mice with GC-induced glycolipid metabolism disorder, which indicated that the gut microbiota/SCFA/GPR41/GLP-1 axis may participate in GC-induced glycolipid metabolism disorder. Our findings indicate that the gut microbiota may serve as a novel therapeutic target for GC-related metabolic disorders.
长期/大剂量使用糖皮质激素（GC）会导致糖脂代谢紊乱，严重限制了其临床应用。肠道微生物群及其代谢物在 GC 诱导的糖脂代谢紊乱中的作用尚不清楚。我们之前的人类研究发现，内源性皮质醇增多症患者存在明显的肠道微生物群失调，表现为 丰度增加， 和 丰度减少。在这项研究中，我们建立了 GC 诱导的糖脂代谢紊乱小鼠模型（Dex 组），发现 Dex 组 的相对丰度增加， 、 、 的丰度显著降低。与对照组相比，Dex 组血清总短链脂肪酸（SCFAs）、乙酸、丙酸和 GLP-1 水平均降低。Dex 组结肠 GPR41 受体和 Pcsk1 的 mRNA 表达明显降低。此外，通过耗尽肠道微生物群或用对照细菌进行粪便细菌移植可以缓解 GC 诱导的糖脂代谢紊乱。用对照细菌进行粪便细菌移植后， 的丰度和血清 GLP-1 水平显著增加，而 的丰度和 显著降低。我们的工作表明，肠道微生物群失调和血清乙酸、丙酸水平降低可能参与 GC 诱导的糖脂代谢紊乱。这些发现可能为 GC 诱导的代谢紊乱的预防和治疗提供新的思路。
重要性：肠道微生物群在糖皮质激素（GC）诱导的糖脂代谢紊乱中的作用尚不清楚。在我们的研究中，GC 诱导的糖脂代谢紊乱小鼠模型中观察到以 增加和 Lachnospiraceae_NK4A136_group 减少为特征的肠道微生物群失调。我们之前在内源性皮质醇增多症患者和研究中使用的小鼠模型中观察到一些共同的细菌。此外，耗尽肠道微生物群或用对照细菌进行粪便细菌移植可以缓解 GC 诱导的糖脂代谢紊乱。GC 诱导的糖脂代谢紊乱小鼠模型中，血浆乙酸、丙酸、GLP-1 及结肠 GPR41 受体和 Pcsk1 的 mRNA 表达明显降低，表明肠道微生物群/短链脂肪酸/GPR41/GLP-1 轴可能参与 GC 诱导的糖脂代谢紊乱。我们的研究结果表明，肠道微生物群可能成为 GC 相关代谢紊乱的新治疗靶点。
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