Fluoride induces hepatointestinal damage and vitamin B2 mitigation by regulating IL-17A and Bifidobacterium in ileum.

INTRODUCTION: 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. OBJECTIVES: To explore the mechanisms by which fluoride-induced intestinal-hepatic damage and vitamin B2 alleviation. METHODS: Fluoride and/or vitamin B2-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. RESULTS: 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 B2 supplementation attenuated fluoride-induced enterohepatic circulation dysfunction through IL-17A and ileal microbiome, Bifidobacterium supplementation also reversed fluoride-induced hepatointestinal injury. CONCLUSION: 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 B2, which will be useful in the therapy of fluorosis and other hepatoenterological diseases.

Biotransformation of Rutin in In Vitro Porcine Ileal and Colonic Fermentation Models.

Quercetin, a polyphenol antioxidant, is widely distributed in food in the form of glycoside rutin, which is not readily absorbed in the gastrointestinal tract. The microbiota of the colon is known to biotransform rutin, generating quercetin aglycones that can be absorbed. We investigated the role of the ileal and colonic microbiota in rutin biotransformation using established in vitro fermentation models. Overall, a higher rate of rutin biotransformation was observed during colonic fermentation compared with ileal fermentation. The colonic microbiome showed higher potential for rutin conversion to quercetin through an increased abundance of α-rhamnosidase- and ß-glucosidase-encoding genes compared to the ileal microbiome. Nonetheless, rutin metabolism occurred rapidly during ileal fermentation (∼20% rutin disappearance after 1 h). The appearance of quercetin varied depending on the ileal inoculum and correlated with an increased abundance of Firmicutes, suggesting that quercetin absorption could be improved via modulation of the ileal microbiota.