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.

doi:10.1101/2021.11.29.470403

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bioRxiv · 10.1101/2021.11.29.470403

Systems genetics uncovers microbe-lipid-host connections in the murine gut

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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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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.. 2021-11-29. Systems genetics uncovers microbe-lipid-host connections in the murine gut. https://doi.org/10.1101/2021.11.29.470403

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