Dysregulation of gut microbiota-mediated bile acid (BA) metabolism plays an important role in the pathogenesis of hepatic steatosis and nonalcoholic fatty liver disease (NAFLD). Our previous studies found that bisphenol A (BPA) exposure induced hepatic steatosis and gut microbiota dysbiosis. However, whether the gut microbiota-dependent BA metabolism alterations were involved in BPA-induced hepatic steatosis remains unclear. Therefore, we explored the gut microbiota-related metabolic mechanisms of hepatic steatosis induced by BPA. Male CD-1 mice were exposed to low-dose BPA (50 μg/kg/day) for 6 months. Fecal microbiota transplantation (FMT) and broad-spectrum antibiotic cocktail (ABX) treatment were further adopted to test the role of gut microbiota in the adverse effects of BPA. We found that BPA induced hepatic steatosis in mice. Additionally, 16S rRNA gene sequencing showed that BPA reduced the relative abundance of Bacteroides, Parabacteroides and Akkermansia, which are associated with BA metabolism. Metabolomic analyses demonstrated that BPA significantly altered the ratio of conjugated to unconjugated BAs and increased the total level of taurine-α/β-muricholic acid while decreasing the level of chenodeoxycholic acid, thus inhibiting the activation of special receptors, including farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5), in the ileum and liver. The inhibition of FXR reduced short heterodimer partner and subsequently induced cholesterol 7α-hydroxylase and sterol regulatory element-binding protein-1c expression, which is related to hepatic BA synthesis and lipogenesis, eventually leading to liver cholestasis and steatosis. Furthermore, we found that mice that received FMT from BPA-exposed mice developed hepatic steatosis, and the influences of BPA on hepatic steatosis and FXR/TGR5 signaling could be eliminated by ABX treatment, confirming the role of gut microbiota in BPA effects. Collectively, our study illustrates that suppressed microbiota-BA-FXR/TGR signaling pathways may be a potential mechanism for hepatic steatosis induced by BPA, providing a new target for the prevention of BPA-induced NAFLD.

肠道微生物介导的胆汁酸（BA）代谢失调在肝脂肪变性和非酒精性脂肪肝（NAFLD）的发病机制中发挥着重要作用。我们之前的研究发现，双酚 A (BPA) 暴露会导致肝脏脂肪变性和肠道微生物群失调。然而，肠道微生物群依赖性 BA 代谢改变是否与 BPA 诱导的肝脂肪变性有关仍不清楚。因此，我们探讨了BPA诱导的肝脂肪变性的肠道菌群相关代谢机制。雄性 CD-1 小鼠暴露于低剂量 BPA（50 μg/kg/天）6 个月。进一步采用粪便微生物群移植（FMT）和广谱抗生素鸡尾酒（ABX）治疗来测试肠道微生物群在BPA不良反应中的作用。我们发现 BPA 会诱导小鼠肝脂肪变性。此外，拟杆菌属、副拟杆菌属和阿克曼氏菌属，这与 BA 代谢有关。代谢组学分析表明，BPA 显着改变了缀合与非缀合 BA 的比例，增加了牛磺酸-α/β-鼠胆酸的总水平，同时降低了鹅去氧胆酸的水平，从而抑制了特殊受体的激活，包括法呢醇 X 受体 (FXR) ）和武田 G 蛋白偶联受体 5 (TGR5)，位于回肠和肝脏。FXR的抑制减少了短异二聚体伴侣，随后诱导胆固醇7α-羟化酶和甾醇调节元件结合蛋白-1c的表达，这与肝脏BA合成和脂肪生成有关，最终导致肝脏胆汁淤积和脂肪变性。此外，我们发现接受 BPA 暴露小鼠 FMT 的小鼠出现了肝脂肪变性，ABX 治疗可以消除 BPA 对肝脂肪变性和 FXR/TGR5 信号传导的影响，证实了肠道微生物群在 BPA 效应中的作用。总的来说，我们的研究表明，受抑制的微生物群-BA-FXR/TGR信号通路可能是BPA诱导的肝脂肪变性的潜在机制，为预防BPA诱导的NAFLD提供了新的靶点。