Systems genetic discovery of host-microbiome interactions reveals mechanisms of microbial involvement in disease

Abstract

The role of the microbiome in health and disease involves complex networks of host genetics, genomics, microbes and environment. Identifying the mechanisms of these interactions has remained challenging. Systems genetics in the laboratory mouse enables data-driven discovery of network components and mechanisms of host-microbial interactions underlying multiple disease phenotypes. To examine the interplay among the whole host genome, transcriptome and microbiome, we mapped quantitative trait loci and correlated the abundance of cecal mRNA, luminal microflora, physiology and behavior in incipient strains of the highly diverse Collaborative Cross mouse population. The relationships that are extracted can be tested experimentally to ascribe causality among host and microbe in behavior and physiology, providing insight into disease. Application of this strategy in the Collaborative Cross population revealed experimentally validated mechanisms of microbial involvement in models of autism, inflammatory bowel disease and sleep disorder.\n\neTOC BlurbHost genetic diversity provides a variable selection environment and physiological context for microbiota and their interaction with host physiology. Using a highly diverse mouse population Bubier et al. identified a variety of host, microbe and potentially disease interactions.\n\nHighlights* 18 significant species-specific QTL regulating microbial abundance were identified\n* Cis and trans eQTL for 1,600 cecal transcripts were mapped in the Collaborative Cross\n* Sleep phenotypes were highly correlated with the abundance of B.P. Odoribacter\n* Elimination of sleep-associated microbes restored normal sleep patterns in mice.