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

Publisher: D. A. Spandidos Country of Publication: Greece NLM ID: 101475259 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1791-3004 (Electronic) Linking ISSN: 17912997 NLM ISO Abbreviation: Mol Med Rep Subsets: MEDLINE

Original Publication: Athens, Greece : D. A. Spandidos

Non-alcoholic Fatty Liver Disease*/drug therapy ; Non-alcoholic Fatty Liver Disease*/metabolism ; Non-alcoholic Fatty Liver Disease*/pathology ; Rifaximin*/pharmacology ; Rifaximin*/therapeutic use ; Signal Transduction*/drug effects ; Gastrointestinal Microbiome*/drug effects ; Hepatocyte Nuclear Factor 1-alpha*/metabolism ; Hepatocyte Nuclear Factor 1-alpha*/genetics; Animals ; Mice ; Male ; Helicobacter/drug effects ; Bile Acids and Salts/metabolism ; Disease Models, Animal ; Mice, Inbred C57BL ; Mice, Knockout ; Liver Cirrhosis/drug therapy ; Liver Cirrhosis/metabolism ; Liver Cirrhosis/pathology ; Liver/metabolism ; Liver/drug effects ; Liver/pathology ; Receptors, Cytoplasmic and Nuclear

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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Keywords: deoxycholic acid; farnesoid X receptor; hepatocyte nuclear factor 1α; intestinal microbiota; non‑alcoholic steatohepatitis; rifaximin

L36O5T016N (Rifaximin)
0 (Hepatocyte Nuclear Factor 1-alpha)
0C5V0MRU6P (farnesoid X-activated receptor)
0 (Bile Acids and Salts)
0 (Hnf1a protein, mouse)
0 (Receptors, Cytoplasmic and Nuclear)

Date Created: 20241129 Date Completed: 20241129 Latest Revision: 20241213

20241213

PMC11632295

10.3892/mmr.2024.13407

39611479