Penthorum chinense Pursh. extract attenuates non-alcholic fatty liver disease by regulating gut microbiota and bile acid metabolism in mice.

Penthorum chinense Pursh. (PCP) is commonly used as a Miao ethnomedicine and health food for liver protection in China. Gansukeli (WS3-B-2526-97) is made from the extract of PCP (PCPE) for the treatment of viral hepatitis. In recent years, PCPE has been reported in the treatment of non-alcoholic fatty liver disease (NAFLD), however its potential mechanism is not fully elucidated. To investigate the ameliorating effect of PCPE on high-fat diet (HFD)-induced NAFLD mice and demonstrate whether its protective effect is gut microbiota dependent and associated with bile acid (BA) metabolism. The alleviating effect of PCPE on NAFLD was conducted on male C57BL/6J mice fed an HFD for 16 weeks, and this effect associated with gut microbiota dependent was demonstrated by pseudo-germfree mice treated with antibiotics and fecal microbiota transplantation (FMT). The composition of the gut microbiota in the cecum contents was analyzed by 16S rRNA sequencing, and the levels of BAs in liver and fecal samples were determined by UPLC/MS-MS. The results showed that administration of PCPE for 8 weeks could potently ameliorate HFD-induced NAFLD and alleviate dyslipidemia and insulin resistance. Moreover, PCPE treatment alleviated gut dysbiosis, especially reducing the relative abundance of bile salt hydrolase (BSH)-producing bacteria. Furthermore, PCPE significantly increased the levels of taurine-conjugated BAs in feces, such as tauro-β-muricholic acid (T-βMCA), tauroursodesoxycholic acid (TUDCA), and taurochenodeoxycholic acid (TCDCA), and increased hepatic chenodeoxycholic acid (CDCA). The protein and mRNA expression of farnesoid X receptor (FXR) and fibroblast growth factor 15 (FGF15) were decreased in intestine, increased taurine-conjugated BAs inhibited the intestinal signaling pathway, which was associated with increased genes expression of enzymes in the alternative BA synthesis pathway that reduced the levels of cholesterol. The increased CDCA produced via the alternative BA synthesis pathway promoted hepatic FXR activation and BA excretion. Our study is the first time to demonstrate that PCPE could ameliorate NAFLD in HFD-induced mice by regulating the gut microbiota and BA metabolism, and from a novel perspective, to clarify the mechanism of PCPE in NAFLD.

Li X ，Zhao W ，Xiao M ，Yu L ，Chen Q ，Hu X ，Zhao Y ，Xiong L ，Chen X ，Wang X ，Ba Y ，Guo Q ，Wu X ... -  《-》

Ileal Bile Acid Transporter Inhibitor Improves Hepatic Steatosis by Ameliorating Gut Microbiota Dysbiosis in NAFLD Model Mice.

Matsui M ，Fukunishi S ，Nakano T ，Ueno T ，Higuchi K ，Asai A ... -  《mBio》

Nuciferine Protects Against High-Fat Diet-Induced Hepatic Steatosis via Modulation of Gut Microbiota and Bile Acid Metabolism in Rats.

Sun J ，Fan J ，Li T ，Yan X ，Jiang Y ... -  《-》

Yellow tea polysaccharides protect against non-alcoholic fatty liver disease via regulation of gut microbiota and bile acid metabolism in mice.

Nonalcoholic fatty liver disease (NAFLD) is a major clinical and global public health issue, with no specific pharmacological treatment available. Currently, there is a lack of approved drugs for the clinical treatment of NAFLD. Large-leaf yellow tea polysaccharides (YTP) is a natural biomacromolecule with excellent prebiotic properties and significant therapeutic effects on multiple metabolic diseases. However, the specific mechanisms by which YTP regulates NAFLD remain unclear. This study aims to explore the prebiotic effects of YTP and the potential mechanisms by which it inhibits hepatic cholesterol accumulation in NAFLD mice. The effects of YTP on lipid accumulation were evaluated in NAFLD mice through obesity trait analysis and bile acids (BAs) metabolism assessment. Additionally, fecal microbiota transplantation (FMT) was performed, and high-throughput sequencing was employed to investigate the mechanisms underlying YTP's regulatory effects on gut microbiota and BA metabolism. Our study demonstrated that YTP altered the constitution of colonic BA, particularly increasing the levels of conjugated BA and non-12OH BA, which suppressed ileum FXR receptors and hepatic BA reabsorption, facilitated BA synthesis, and fecal BA excretion. The modifications were characterized by a decrease in the levels of FXR, FGF15, FGFR4, and ASBT proteins, and an increase in the levels of Cyp7a1 and Cyp27a1 proteins. YTP might affect enterohepatic circulation and by the activated the hepatic FXR-SHP pathway. Meanwhile, YTP reshaped the intestinal microbiome structure by decreasing BSH-producing genera and increasing taurine metabolism genera. The correlation analysis implied that Muribaculaceae, Pseudomonas, acterium_coprostanoligenes_group, Clostridiales, Lachnospiraceae_NK4A136_group, Delftia, Dubosiella, and Romboutsia were strongly correlated with specific BA monomers. YTP modulates bile salt hydrolase-related microbial genera to activate alternative bile acid synthesis pathways, thereby inhibiting NAFLD progression. These results suggest that YTP may serve as a potential probiotic formulation, offering a feasible dietary intervention for NAFLD.

Huang Y ，Chen H ，Chen J ，Wu Q ，Zhang W ，Li D ，Lu Y ，Chen Y ... -  《-》

Bisphenol A induced hepatic steatosis by disturbing bile acid metabolism and FXR/TGR5 signaling pathways via remodeling the gut microbiota in CD-1 mice.

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 pathways 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.

Hong T ，Zou J ，He Y ，Zhang H ，Liu H ，Mai H ，Yang J ，Cao Z ，Chen X ，Yao J ，Feng D ... -  《-》