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Western Diet Changes Gut Microbiota and Ameliorates Liver Injury in a Mouse Model with Human-Like Bile Acid Composition.

ABSTRACT: Western-style high-fat/high-sucrose diet (HFHSD) changes gut microbiota and bile acid (BA) profiles. Because gut microbiota and BAs could influence each other, the mechanism of changes in both by HFHSD is complicated and remains unclear. We first aimed to clarify the roles of BAs in the HFHSD-induced change of gut microbiota. Then, we studied the effects of the changed gut microbiota on BA composition and liver function. Male wild-type (WT) and human-like Cyp2a12/Cyp2c70 double knockout (DKO) mice derived from C57BL/6J were fed with normal chow or HFHSD for 4 weeks. Gut microbiomes were analyzed by fecal 16S ribosomal RNA gene sequencing, and BA composition was determined by liquid chromatography-tandem mass spectrometry. The DKO mice exhibited significantly reduced fecal BA concentration, lacked muricholic acids, and increased proportions of chenodeoxycholic and lithocholic acids. Despite the marked difference in the fecal BA composition, the profiles of gut microbiota in the two mouse models were quite similar. An HFHSD resulted in a significant increase in the BA pool and fecal BA excretion in WT mice but not in DKO mice. However, microbial composition in the two mouse models was drastically but similarly changed by the HFHSD. In addition, the HFHSD-induced change of gut microbiota inhibited BA deconjugation and 7α-dehydroxylation in both types of mice, which improved chronic liver injury observed in DKO mice. Conclusion: The HFHSD itself causes the change of gut microbiota due to HFHSD, and the altered composition or concentration of BAs by HFHSD is not the primary factor. On the contrary, the gut microbiota formed by HFHSD affects BA composition and ameliorates liver injury in the mouse model with human-like hydrophobic BA composition.

SUBMITTER: Iwamoto J

PROVIDER: S-EPMC8631099 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundFibrotic liver injury is a progressive scarring event, which may permanently affect liver function and progress into devastating end-stage liver diseases due to the absence of effective therapies. Si-Wu-Tang (SWT), a traditional Chinese medicine formula used in clinic to treat gynecological disorders for centuries, has been investigated in recent preliminary findings for its role in alleviating chronic liver diseases. Here we aim to elucidate the therapeutic effects and possible mechanisms of SWT against fibrotic liver injury.MethodsUHPLC-MS/MS was performed to investigate the chemical characterization of SWT. After intragastrically administered with carbon tetrachloride (CCl4) every 3 days for 1-week, C57BL/6 mice were orally administered with SWT (5.2, 10.4 and 20.8 g/kg) once daily for 3 weeks along with CCl4 challenge. Liver function was determined by the measurement of serum biomarkers, hematoxylin and eosin (H&E) and Masson's trichrome staining. Intestinal inflammatory infiltration and the disruption of intestinal barrier were examined by H&E and E-cadherin immunohistochemical staining. The microbial composition of intestinal content was determined by 16S rRNA sequencing. Serum bile acids (BAs) profiling was analyzed by LC-MS/MS. Simultaneously, the expression of genes of interest was determined by qPCR and western blot.ResultsSWT exhibited remarkable therapeutic effects on CCl4-induced liver fibrosis, as indicated by improved collagen accumulation in livers, intestinal barrier injury and hepatic and intestinal inflammatory response. Results of 16S rRNA sequencing revealed that SWT treatment strikingly restructured intestinal microbiota in fibrotic mice by increasing the relative abundances of Bacteroides and Lachnoclostridium and decreasing the relative abundances of Alistipes and Rikenellaceae. UHPLC-MS/MS data suggested that SWT altered the composition of BAs in circulation as evidenced by increased unconjugated BAs like cholic acid and chenodeoxycholic acid but decreased conjugated BAs including taurocholic acid and taurodeoxycholic acid, compared to that in CCl4 mice. Notably, SWT efficiently improved the imbalance of BA homeostasis in livers caused by CCl4 via activating farnesoid X receptor (FXR)-fibroblast growth factor 15 enterohepatic and FXR-small heterodimer partner hepatic pathways.ConclusionSWT decreased inflammatory response, reconstructed gut microbiota-mediated BA homeostasis as well as activated FXR pathways, which eventually protected against CCl4-induced fibrotic liver injury.

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Western Diet Changes Gut Microbiota and Ameliorates Liver Injury in a Mouse Model with Human-Like Bile Acid Composition.

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