Liang Chen, Zhuang Cuicui, Cheng Chenkai, Bai Jian, Wu Yue, Li Xiang, Yang Jie, Li Bohui, Fu Weixiang, Zhu Qianlong, Lv Jiawei, Tan Yanjia, Kumar Manthari Ram, Zhao Yangfei, Wang Jundong, Zhang Jianhai
College of Animal Science, Shanxi Agricultural University, Taigu, Shanxi 030801, PR China.
College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi 030801, PR China.
J Adv Res. 2025 Jun;72:671-684. doi: 10.1016/j.jare.2024.07.034. Epub 2024 Aug 5.
Fluorosis is a global public health disease affecting more than 50 countries and 500 million people. Excessive fluoride damages the liver and intestines, yet the mechanisms and therapeutic approaches remain unclear.
To explore the mechanisms by which fluoride-induced intestinal-hepatic damage and vitamin B alleviation.
Fluoride and/or vitamin B-treated IL-17A knockout and wild-type mouse models were established, the morphological and functional changes of liver and gut, total bile acid biosynthesis, metabolism, transport, and regulation of FXR-FGF15 signaling pathways were evaluated, the ileal microbiome was further analyzed by 16S rDNA sequence. Finally, Bifidobacterium supplementation mouse model was designed and re-examined the above indicators.
The results demonstrated that fluoride induced hepatointestinal injury and enterohepatic circulation disorder by altering the synthesis, transporters, and FXR-FGF15 pathway regulation of total bile acid. Importantly, the ileum was found to be the most sensitive and fluoride changed ileal microbiome particularly by reducing abundance of Bifidobacterium. While vitamin B supplementation attenuated fluoride-induced enterohepatic circulation dysfunction through IL-17A and ileal microbiome, Bifidobacterium supplementation also reversed fluoride-induced hepatointestinal injury.
Fluoride induces morphological and functional impairment of liver and gut tissues, as well as enterohepatic circulation disorder by altering total bile acid (TBA) synthesis, transporters, and FXR-FGF15 signaling regulation. Vitamin B2 attenuated fluoride-induced enterohepatic circulation disorder through IL-17A knockout and ileal microbiome regulation. The ileum was found to be the most sensitive to fluoride, leading to changes in ileal microbiome, particularly the reduction of Bifidobacterium. Furthermore, Bifidobacterium supplementation reversed fluoride-induced hepatointestinal injury. This study not only elucidates a novel mechanism by which fluoride causes hepatointestinal toxicity, but also provides a new physiological function of vitamin B, which will be useful in the therapy of fluorosis and other hepatoenterological diseases.
氟中毒是一种全球性公共卫生疾病，影响着50多个国家的5亿人口。过量的氟会损害肝脏和肠道，但其机制和治疗方法仍不清楚。
探讨氟诱导肠肝损伤及维生素B缓解作用的机制。
建立氟和/或维生素B处理的IL-17A基因敲除和野生型小鼠模型，评估肝脏和肠道的形态及功能变化、总胆汁酸的生物合成、代谢、转运以及FXR-FGF15信号通路的调节，通过16S rDNA序列进一步分析回肠微生物群。最后，设计补充双歧杆菌的小鼠模型并重新检测上述指标。
结果表明，氟通过改变总胆汁酸的合成、转运体以及FXR-FGF15通路调节，诱导肝肠损伤和肠肝循环紊乱。重要的是，发现回肠最为敏感，氟会改变回肠微生物群，尤其是通过降低双歧杆菌的丰度。补充维生素B可通过IL-17A和回肠微生物群减轻氟诱导的肠肝循环功能障碍，补充双歧杆菌也可逆转氟诱导的肝肠损伤。
氟通过改变总胆汁酸（TBA）合成、转运体及FXR-FGF15信号调节，诱导肝脏和肠道组织的形态及功能损伤以及肠肝循环紊乱。维生素B2通过敲除IL-17A和调节回肠微生物群减轻氟诱导的肠肝循环紊乱。发现回肠对氟最为敏感，导致回肠微生物群发生变化，尤其是双歧杆菌减少。此外，补充双歧杆菌可逆转氟诱导的肝肠损伤。本研究不仅阐明了氟导致肝肠毒性的新机制, 还揭示了维生素B的新生理功能，这将有助于治疗氟中毒及其他胃肠肝病。
