Systems genetics uncovers microbe-lipid-host connections in the murine gut
Zhang, Q.; Linke, V.; Overmyer, K. A.; Traeger, L. L.; Kasahara, K.; Miller, I. J.; Manson, D. E.; Polaske, T. J.; Kerby, R. L.; Kemis, J. H.; Trujillo, E. A.; Reddy, T. R.; Russell, J. D.; Schueler, K. L.; Stapleton, D. S.; Rabaglia, M. E.; Seldin, M.; Gatti, D. M.; Keele, G. R.; Pham, D. T.; Gerdt, J. P.; Vivas, E. I.; Lusis, A. J.; Keller, M. P.; Churchill, G. A.; Blackwell, H. E.; Broman, K. W.; Attie, A. D.; Coon, J. J.; Rey, F. E.
Show abstract
The molecular bases of how host genetic variation impact gut microbiome remain largely unknown. Here, we used a genetically diverse mouse population and systems genetics strategies to identify interactions between molecular phenotypes, including microbial functions, intestinal transcripts and cecal lipids that influence microbe-host dynamics. Quantitative trait loci (QTL) analysis identified genomic regions associated with variations in bacterial taxa, bacterial functions, including motility, sporulation and lipopolysaccharide production, and levels of bacterial- and host-derived lipids. We found overlapping QTL for the abundance of Akkermansia muciniphila and cecal levels of ornithine lipids (OL). Follow-up studies revealed that A. muciniphila is a major source of these lipids in the gut, provided evidence that OL have immunomodulatory effects and identified intestinal transcripts co-regulated with these traits. Collectively, these results suggest that OL are key players in A. muciniphila-host interactions and support the role of host genetics as a determinant of responses to gut microbes.
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