Diet-induced Gut Microbiome and Colon Transcriptome Changes in C57BL/6J, C57BL/6N and HCA2-/- Mice

Abstract

Genetic variation drives phenotypic and gut microbiome diversity, while also regulating metabolism and immune responses. C57BL/6J and C57BL/6NCrl inbred mice strains have different metabolic phenotypes in response to diet-induced obesity (DIO), but the mechanism(s) behind this remains unclear. We found significant variation in diet-related hepatic steatosis, strain-dependent gut microbiota composition and time-determined colonic immune system activation between these two mice strains in response to an HFD challenge. Gut microbiome profiling demonstrated that B6N mice and B6J mice harbor different microbial communities after chow or high-fat diet feeding for 1, 6 or 12 weeks. Compared to B6N mice, B6J mice exhibited enrichment of inflammatory bowel disease-regulated microbiota, and depletion of protection taxa. These changes in microbial composition were associated with colon atrophy and goblet cell depletion in B6J mice. On analysis of the intestinal transcriptome of both strains, we found there were four pathways closely-related to colon dysfunction or disease development induced in B6J mice, including B cell function, primary immunodeficiency, inflammatory bowel disease and NF-κB pathway. Overall, this study demonstrates that genetic factors in B6J and B6N mice strongly shape intestinal flora, resulting in protection from diet-induced colonic inflammation or induction of liver steatosis in C57BL/6NCrl mice. Dietary interventions can impact gut microbiome composition, intestinal and systemic immune system function, and the pathophysiology of inflammatory disorders. Increasing body of evidence indicates that fermentable fiber protectives the intestine when exposed to various dietary challenges. However, the potential mechanism(s) responsible for this beneficial effect is unclear. In this study, we demonstrated that low fiber-induced colon atrophy is associated with alteration in gut microbiome composition and inhibition of meiotic cell cycle and nuclear division in WT mice. Surprisingly, in HCA2-/- mice, lack of dietary fiber did not result in the same degree of colon atrophy that was observed in WT mice. This effect on colon atrophy was associated with an HCA2 deficiency-induced immune activation and depletion of pathogenic gut microbiota. However, diets lacking fiber still induced inflammation in HCA2-/- mice, further supporting the important role of fermentable fiber in maintaining colon health.