Clostridium Scindens Protects Against Vancomycin-Induced Cholestasis and Liver Fibrosis by Activating Intestinal...

Area of Science:

• Hepatology
• Microbiology
• Gastroenterology

Background:

• Primary sclerosing cholangitis (PSC) involves abnormal bile acid metabolism and gut microbiota, lacking effective treatments.
• Vancomycin, an antibiotic, shows potential but its mechanism in PSC progression is unclear.

Purpose of the Study:

• To elucidate the mechanism of vancomycin's impact on PSC progression.
• To investigate the role of gut microbiota, specifically Clostridium scindens, in modulating vancomycin's effects on cholestatic liver injury.

Main Methods:

• Vancomycin treatment in mice to assess hepatic collagen deposition and bile acid levels.
• Analysis of gut microbiota composition, focusing on Clostridia XIVa and Clostridium scindens.
• Intervention with Clostridium scindens gavage, engineered E. coli Nissle 1917 (EcN-BaiE), fexaramine (Fex), or FGF19 to evaluate effects on liver injury and fibrosis.

Main Results:

• Vancomycin treatment increased liver injury and fibrosis by inhibiting the intestinal FXR-FGF15/19 axis and elevating bile acids, associated with reduced Clostridia XIVa.
• Clostridium scindens administration alleviated vancomycin-induced bile acid accumulation and liver fibrosis through FXR-FGF15/19 activation.
• Engineered EcN-BaiE and FXR-FGF15/19 pathway activators (Fex, FGF19) reversed vancomycin-induced liver damage.

Conclusions:

• Long-term oral vancomycin exacerbates cholestatic liver injury in a PSC mouse model.
• Clostridium scindens mitigates vancomycin-induced liver injury by restoring bile acid homeostasis via the FXR-FGF15/19 pathway.
• Clostridium scindens represents a potential therapeutic strategy for PSC patients, highlighting the need to monitor bile acid levels during vancomycin treatment.