Systems genetics uncovers associations among host amylase locus, gut microbiome, and metabolic traits in mice.

Background: Population studies have revealed associations between host genetic and gut microbiome in humans and mice. However, the molecular bases for how host genetic variation impacts the gut microbial community and bacterial metabolic niches remain largely unknown.

Results: We leveraged 90 inbred hyperlipidemic mouse strains from the hybrid mouse diversity panel (HMDP), previously studied for a variety of cardio-metabolic traits. Metagenomic analysis of cecal DNA followed by genome-wide association analysis identified genomic loci that were associated with microbial enterotypes in the gut. Among these, we detected a genetic locus surrounding multiple amylase genes that were associated with abundances of Firmicutes (Lachnospiraceae family) and Bacteroidetes (Muribaculaceae family) taxa encoding distinct starch and sugar degrading capabilities. The genetic variants at the amylase gene locus were associated with distinct gut microbial communities (enterotypes) with different predicted metabolic capacities for carbohydrate degradation. Mendelian randomization analysis revealed host phenotypes, including liver fibrosis and plasma HDL-cholesterol levels, that were associated with gut microbiome enterotypes.

Conclusions: This work reveals novel relationships among host genetic variation, gut microbial enterotypes, and host metabolic traits and supports the notion that variation of host amylase may represent a key determinant of gut microbiome in mice. Video Abstract.