Host response to cholestyramine can be mediated by the gut microbiota

Abstract: The gut microbiome has been implicated as a major factor contributing to metabolic diseases as well as being contributors to the response to drugs used for the treatment of such diseases. In this study, using a diet-induced obesity mouse model, we tested the effect of cholestyramine, a bile acid sequestrant, on the murine gut microbiome and mammalian metabolism. We also explored the hypothesis that some beneficial effects of this drug on systemic metabolism can be attributed to alterations in gut microbiota. First, we demonstrated that cholestyramine can decrease glucose and epidydimal fat levels. Next, while investigating gut microbiota we found increased alpha diversity of the gut microbiome of cholestyramine-treated mice, with fourteen taxa showing restoration of abundance to levels resembling those in mice fed with a control diet. Analyzing expression of genes known to be regulated by cholestyramine (including Cyp7a1), we confirmed the expected effect of this drug in the liver and ileum. Finally, using a transkingdom network analysis we inferred Acetatifactor muris and Muribaculum intestinale as potential mediators/modifiers of cholestyramine effects on the mammalian host. In addition, A. muris correlated positively with glucagon (Gcg) expression in the ileum and negatively correlated with small heterodimer partner (Shp) expression in the liver. Interestingly, A. muris also correlated negatively with glucose levels, further indicating the potential probiotic role for A. muris. In conclusion, our results indicate the gut microbiome has a role in the beneficial effects of cholestyramine and suggest specific microbes as targets of future investigations. Contact information and principal investigators: Andriy Morgun: [e-mail] Natalia Shulzhenko: [e-mail] Summary: Administration of cholestyramine in C57Bl/6 WT mice on a Western diet alters the gut microbiome composition and helps restore phenotypic parameters commonly observed in individuals with Type 2 Diabetes (e.g. hyperglycemia). The intestinal microbiota was analyzed in 30 mice total, split evenly amount two experiments. In each experiment there were three groups; 1) Normal diet fed mice (n = 5), 2) Western diet fed mice (n = 5), and 3) Western diet fed mice supplemented with cholestyramine (n = 5). Contact: Project contact: Nolan Newman ([e-mail]); Principle investigators: Andriy Morgun ([e-mail]) and Natalia Shulzhenko ([e-mail]). This submission was powered by METAGENOTE (https://metagenote.niaid.nih.gov).