School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China.
School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China.
J Ethnopharmacol. 2025 Jan 30;337(Pt 1):118804. doi: 10.1016/j.jep.2024.118804. Epub 2024 Sep 11.
Current treatment options for cholestatic liver diseases are limited, and addressing impaired intestinal barrier has emerged as a promising therapeutic approach. Si-Ni-San (SNS) is a Traditional Chinese Medicine (TCM) formula commonly utilized in the management of chronic liver diseases. Our previous studies have indicated that SNS effectively enhanced intestinal barrier function through the modulation of gut microbiota.
This study aims to verify the therapeutic effects of SNS on cholestatic liver injury, focusing on elucidating the underlying mechanism involving the gut-liver axis.
The 16s RNA gene sequencing, non-targeted metabolomics were used to investigate the effects of SNS on the gut microbiota dysbiosis. Fecal microbiota transplantation (FMT) was conducted to identify potential beneficial probiotics underlying the therapeutic effects of SNS.
Our results demonstrated that SNS significantly ameliorated cholestatic liver injury induced by partial bile duct ligation (pBDL). Additionally, SNS effectively suppressed cholestasis-induced inflammation and barrier dysfunction in both the small intestine and colon. While SNS did not impact the intestinal FXR-FGF15-hepatic CYP7A1 axis, it notably improved gut microbiota dysbiosis and modulated the profile of microbial metabolites, including beneficial secondary bile acids and tryptophan derivatives. Furthermore, gut microbiota depletion experiments and FMT confirmed that the therapeutic benefits of SNS in cholestatic liver disease are dependent on gut microbiota modulation, particularly through the promotion of the growth of potential probiotic P. goldsteinii. Moreover, a synergistic improvement in cholestatic liver injury was observed with the co-administration of P. goldsteinii and SNS.
Our study underscores that SNS effectively alleviates cholestatic liver injury by addressing gut microbiota dysbiosis and enhancing intestinal barrier function, supporting its rational clinical utilization. Furthermore, we highlight P. goldsteinii as a promising probiotic candidate for the management of cholestatic liver diseases.
目前针对胆汁淤积性肝病的治疗选择有限，而改善肠道屏障功能已成为一种有前途的治疗方法。四逆散（SNS）是一种常用于治疗慢性肝病的中药（TCM）配方。我们之前的研究表明，SNS 通过调节肠道微生物群有效地增强了肠道屏障功能。
本研究旨在验证 SNS 对胆汁淤积性肝损伤的治疗作用，重点阐明涉及肠-肝轴的潜在机制。
使用 16s RNA 基因测序和非靶向代谢组学研究 SNS 对肠道微生物失调的影响。进行粪便微生物群移植（FMT）以鉴定 SNS 治疗作用背后的潜在有益益生菌。
我们的结果表明，SNS 显著改善了部分胆管结扎（pBDL）诱导的胆汁淤积性肝损伤。此外，SNS 有效地抑制了胆汁淤积引起的小肠和结肠的炎症和屏障功能障碍。虽然 SNS 不影响肠道 FXR-FGF15-肝 CYP7A1 轴，但它显著改善了肠道微生物失调，并调节了微生物代谢产物的特征，包括有益的次级胆汁酸和色氨酸衍生物。此外，肠道微生物群耗竭实验和 FMT 证实，SNS 在胆汁淤积性肝病中的治疗益处依赖于肠道微生物群的调节，特别是通过促进潜在益生菌 P. goldsteinii 的生长。此外，与 SNS 联合使用 P. goldsteinii 可协同改善胆汁淤积性肝损伤。
我们的研究强调，SNS 通过解决肠道微生物失调和增强肠道屏障功能有效缓解胆汁淤积性肝损伤，支持其合理的临床应用。此外，我们强调 P. goldsteinii 是管理胆汁淤积性肝病的有前途的益生菌候选物。
