Integration of Pseudotargeted Metabolomics and Microbiomics Reveals That Hugan Tablets Ameliorate NASH with Liver Fibrosis in Mice by Modulating Bile Acid Metabolism via the Gut Microbiome

TL;DR

This study shows that Hugan tablets reduce liver fibrosis in mice with NASH by changing gut bacteria and bile acid metabolism.

Contribution

The novel integration of pseudotargeted metabolomics and microbiomics reveals how Hugan tablets work against NASH via gut microbiome modulation.

Findings

Hugan tablets alleviate NASH-related liver fibrosis in mice.

The gut microbiome is essential for the anti-fibrotic effects of Hugan tablets.

Hugan tablets regulate bile acid metabolism through microbial enzyme interactions.

Abstract

Background/Objectives: Non-alcoholic steatohepatitis (NASH) carries a high risk of developing hepatic fibrosis. Hugan tablets (HGTs), a traditional Chinese medicine, have exhibited potent anti-hepatic fibrosis effects, though the underlying mechanisms remain unclarified. This study aims to assess the efficacy of HGTs against NASH-related liver fibrosis in mice and investigate the underlying mechanisms via the integration of pseudotargeted metabolomics and microbiomics. Methods: C57BL/6 mice were fed a choline-deficient, ethionine-supplemented (CDE) diet and treated with HGTs. The therapeutic effects of HGTs in CDE mice were assessed. The underlying mechanism of HGTs was investigated by the integration of microbiomics, a pseudo-sterile model, untargeted followed by pseudotargeted metabolomics, and molecular docking. Results: HGTs alleviated NASH-related hepatic fibrosis in CDE mice and restored the composition of the gut microbiota. The depletion of the gut microbiota eliminated the anti-hepatic fibrosis effect of HGTs. HGTs increased intestinal 7-ketolithocholic acid and tauroursodeoxycholic acid via 7α/β-hydroxysteroid dehydrogenase (7α/βHSDH), while reducing deoxycholic acid (DCA) and taurodeoxycholic acid through inhibition of bile acid 7α-dehydratase (BaiE), leading to lower hepatic DCA. Six intestinal components of HGTs interacted with 7αHSDH, 7βHSDH, and BaiE, which are expressed in the bacterial genera altered by HGTs. Conclusions: HGTs alleviate NASH fibrosis by reshaping the gut microbiome, acting on microbial BA-metabolizing enzymes, and regulating the BA metabolism in the liver and gut.

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