Sun Yewen, Qu Yuchen, Yang Zhuan, Lv Bo, Wang Guanjun, Fan Kai, Wang Yuyuan, Pan Jie, Du Ziyan, Yu Yunli
Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, China.
College of Pharmaceutical Science, Soochow University, Suzhou, China.
Front Pharmacol. 2025 Apr 4;16:1569856. doi: 10.3389/fphar.2025.1569856. eCollection 2025.
Moxifloxacin (MFLX) frequently induces dysglycemia when used in the treatment of infectious diseases, particularly in patients with diabetes. However, the mechanism through which MFLX affects host glucose metabolism remains unclear. This study aimed to investigate the possible mechanism underlying MFLX-induced hyperglycemia.
In this study, we investigated the short-term (3 days) and long-term (14 days) effects of MFLX on glucose metabolism in normal and type 2 diabetic GK rats. After oral administration of 40 mg/kg of MFLX, blood glucose, insulin, GLP-1, and fibroblast growth factor 15 (FGF15) levels in the blood of rats, as well as bile acids in both blood and feces, and gut microbiota, were examined. Liver and ileum tissues were promptly harvested for detecting the expression of hepatic 7α-hydroxylase (CYP7A1) and intestinal Takeda G-protein-coupled receptor 5 (TGR5) and farnesoid X receptor (FXR). In addition, we explored the effect of secondary bile acids (SBAs) on GLP-1 secretion in NCI-H716 cells, and observed the direct effect of MFLX on the expression of CYP7A1 in HepG2 cells and TGR5, FXR in NCI-H716 cells.
It was demonstrated that MFLX induced hyperglycemia in diabetic rats, with a more pronounced reduction in serum insulin, GLP-1, and FGF15 levels than observed in normal rats. Gut microbiota associated with SBAs metabolism were significantly reduced, leading to decreased intestinal deoxycholic acid (DCA) and lithocholic acid (LCA). studies revealed that DCA and LCA (25 μM, 50 μM, and 100 μM) promoted GLP-1 secretion in a concentration-dependent manner in NCI-H716 cells. Meanwhile, we observed that the expression of intestinal TGR5 and FXR significantly downregulated, whereas CYP7A1 expression in liver was increased in GK rats after MFLX treatment. MFLX itself (0.1 μM, 1 μM, and 10 μM) did not directly altered TGR5 or FXR expressions in NCI-H716 cells, nor did it alter CYP7A1 expression in HepG2 cells, which indicated that the impact of MFLX on glucose metabolism was primarily induced by changes in bile acids metabolism resulting from alterations in the gut microbiota.
Our studies showed MFLX more likely to cause hyperglycemia when used in diabetic states and highlighted the critical role of gut microbiota-SBAs-TGR5/FXR pathway in MFLX-induced hyperglycemia.
莫西沙星（MFLX）在用于治疗感染性疾病时经常诱发血糖异常，尤其是糖尿病患者。然而，MFLX影响宿主葡萄糖代谢的机制尚不清楚。本研究旨在探讨MFLX诱导高血糖的潜在机制。
在本研究中，我们研究了MFLX对正常和2型糖尿病GK大鼠葡萄糖代谢的短期（3天）和长期（14天）影响。口服40mg/kg的MFLX后，检测大鼠血液中的血糖、胰岛素、胰高血糖素样肽-1（GLP-1）和成纤维细胞生长因子15（FGF15）水平，以及血液和粪便中的胆汁酸和肠道微生物群。迅速采集肝脏和回肠组织，检测肝脏7α-羟化酶（CYP7A1）、肠道武田G蛋白偶联受体5（TGR5）和法尼醇X受体（FXR）的表达。此外，我们探讨了次级胆汁酸（SBAs）对NCI-H716细胞中GLP-1分泌的影响，并观察了MFLX对HepG2细胞中CYP7A1表达以及NCI-H716细胞中TGR5、FXR表达的直接影响。
结果表明，MFLX可诱导糖尿病大鼠出现高血糖，与正常大鼠相比，血清胰岛素、GLP-1和FGF15水平降低更为明显。与SBAs代谢相关的肠道微生物群显著减少，导致肠道脱氧胆酸（DCA）和石胆酸（LCA）减少。研究表明，DCA和LCA（25μM、50μM和100μM）在NCI-H716细胞中以浓度依赖性方式促进GLP-1分泌。同时，我们观察到，MFLX处理后的GK大鼠肠道TGR5和FXR的表达显著下调，而肝脏中CYP7A1的表达增加。MFLX本身（0.1μM、1μM和10μM）不会直接改变NCI-H716细胞中TGR5或FXR的表达，也不会改变HepG2细胞中CYP7A1的表达，这表明MFLX对葡萄糖代谢的影响主要是由肠道微生物群改变导致的胆汁酸代谢变化引起的。
我们的研究表明，MFLX在糖尿病状态下更易导致高血糖，并强调了肠道微生物群-SBAs-TGR5/FXR途径在MFLX诱导的高血糖中的关键作用。
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