Host response to cholestyramine can be mediated by the gut microbiota

Background: The gut microbiota has been implicated as a major factor contributing to metabolic diseases and the response to drugs used for the treatment of such diseases. In this study, we tested the effect of cholestyramine, a bile acid sequestrant that reduces blood cholesterol, on the murine gut microbiota and metabolism. We also explored the hypothesis that some effects of this drug on systemic metabolism can be attributed to alterations in the gut microbiota. Methods: We used a Western diet (WD) for 8 weeks to induce metabolic disease in mice, then treated some mice with cholestyramine added to WD. Metabolic phenotyping, gene expression in liver and ileum, and microbiota 16S rRNA genes were analyzed. Then, transkingdom network analysis was used to find candidate microbes for the cholestyramine effect. Results: We observed that cholestyramine decreased glucose and epididymal fat levels and detected dysregulation of genes known to be regulated by cholestyramine in the liver and ileum. Analysis of gut microbiota showed increased alpha diversity in cholestyramine-treated mice, with fourteen taxa showing restoration of relative abundance to levels resembling those in mice fed a control diet. Using transkingdom network analysis, we inferred two amplicon sequence variants (ASVs), one from the Lachnospiraceae family (ASV49) and the other from the Muribaculaceae family (ASV1), as potential regulators of cholestyramine effects. ASV49 was also negatively linked with glucose levels, further indicating its beneficial role. Conclusion: Our results indicate that the gut microbiota has a role in the beneficial effects of cholestyramine and suggest specific microbes as targets of future investigations.