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
<b>Background/Objectives</b>: 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 stud...
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2025-06-01
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| author | Wenran Dong Ying Wang Huajinzi Li Huilin Ma Yingxi Gong Gan Luo Xiaoyan Gao |
| author_facet | Wenran Dong Ying Wang Huajinzi Li Huilin Ma Yingxi Gong Gan Luo Xiaoyan Gao |
| author_sort | Wenran Dong |
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| description | <b>Background/Objectives</b>: 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. <b>Methods</b>: 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. <b>Results</b>: 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. <b>Conclusions</b>: 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. |
| format | Article |
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| institution | DOAJ |
| issn | 2218-1989 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
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| series | Metabolites |
| spelling | doaj-art-624eef7dbf774441829b0a24ff6aabc72025-08-20T02:47:17ZengMDPI AGMetabolites2218-19892025-06-0115743310.3390/metabo15070433Integration of Pseudotargeted Metabolomics and Microbiomics Reveals That Hugan Tablets Ameliorate NASH with Liver Fibrosis in Mice by Modulating Bile Acid Metabolism via the Gut MicrobiomeWenran Dong0Ying Wang1Huajinzi Li2Huilin Ma3Yingxi Gong4Gan Luo5Xiaoyan Gao6School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, ChinaSchool of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, ChinaSchool of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, ChinaSchool of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, ChinaSchool of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, ChinaSchool of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, ChinaSchool of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China<b>Background/Objectives</b>: 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. <b>Methods</b>: 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. <b>Results</b>: 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. <b>Conclusions</b>: 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.https://www.mdpi.com/2218-1989/15/7/433Hugan tabletsnonalcoholic steatohepatitishepatic fibrosismetabolomicsgut microbiomebile acids |
| spellingShingle | Wenran Dong Ying Wang Huajinzi Li Huilin Ma Yingxi Gong Gan Luo Xiaoyan Gao 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 Metabolites Hugan tablets nonalcoholic steatohepatitis hepatic fibrosis metabolomics gut microbiome bile acids |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Hugan tablets nonalcoholic steatohepatitis hepatic fibrosis metabolomics gut microbiome bile acids |
| url | https://www.mdpi.com/2218-1989/15/7/433 |
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