Study on the molecular mechanisms of rifaximin in the treatment of non‑alcoholic steatohepatitis based on the <em>Helicobacter</em>‑DCA‑Fxr‑Hnf1&alpha; signalling pathway

Wan,Yi-Peng; Li,Shuang; Li,Dan; Huang,Xiao-Mei; Wu,Jian-Hua; Jian,Jie

doi:10.3892/mmr.2024.13407

Study on the molecular mechanisms of rifaximin in the treatment of non‑alcoholic steatohepatitis based on the Helicobacter‑DCA‑Fxr‑Hnf1α signalling pathway

Authors:
- Yi-Peng Wan
- Shuang Li
- Dan Li
- Xiao-Mei Huang
- Jian-Hua Wu
- Jie Jian
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Affiliations: Department of Gastroenterology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Teaching, Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China
Published online on: November 28, 2024 https://doi.org/10.3892/mmr.2024.13407
Article Number: 42
Copyright: © Wan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Non‑alcoholic steatohepatitis (NASH), the more progressive form of non‑alcoholic fatty liver disease, has become a major cause of cirrhosis and liver cancer. The aim of the present study was to investigate the anti‑NASH effect of the nonabsorbable antibiotic rifaximin and its specific molecular mechanisms. A methionine‑choline deficient (MCD) diet was used to induce NASH formation in mice. The mice with NASH were treated with rifaximin to observe its effects on liver fat deposition, hepatocyte inflammation and liver fibrosis. Furthermore, the intestinal microbiota of mice with NASH was analysed by 16S rRNA sequencing and terminal ileal bile acid levels were assessed using liquid chromatography‑electrospray ionization‑tandem mass spectrometry analysis. Furthermore, the correlation between the intestinal microflora and bile acid levels in the terminal ileum was investigated, and the effects of rifaximin on the intestinal Helicobacter‑deoxycholic acid (DCA)‑farnesoid X receptor (Fxr)‑hepatocyte nuclear factor 1α (Hnf1α) signalling pathway were examined. Moreover, analyses of mice after intestinal decontamination with broad‑spectrum antibiotics and of hepatocyte‑specific Hnf1α knockout (Hnf1α^H‑KO) mice were used to elucidate the molecular mechanisms by which rifaximin improves NASH. Notably, treatment with rifaximin markedly ameliorated liver steatosis, hepatocyte inflammation and liver fibrosis in mice with MCD diet‑induced NASH. Rifaximin modulated the gut microbiota, especially Helicobacter hepaticus, in mice with NASH. In addition, rifaximin inhibited the intestinal Helicobacter‑DCA‑Fxr‑Hnf1α signalling pathway in mice with NASH. By contrast, rifaximin did not exert an anti‑NASH effect on decontamination‑treated mice or Hnf1α^H‑KO mice. Taken together, these results indicated that rifaximin can ameliorate NASH in mice by modulating the Helicobacter‑DCA‑Fxr‑Hnf1α signalling pathway, providing a theoretical basis for the clinical treatment of patients with NASH with rifaximin.

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