Genetic and environmental control of host-gut microbiota interactions
- Elin Org1,
- Brian W. Parks1,
- Jong Wha J. Joo2,
- Benjamin Emert1,
- William Schwartzman1,
- Eun Yong Kang3,
- Margarete Mehrabian1,
- Calvin Pan4,
- Rob Knight5,
- Robert Gunsalus6,
- Thomas A. Drake7,
- Eleazar Eskin3,4 and
- Aldons J. Lusis1,4,8
- 1Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA;
- 2Bioinformatics IDP, University of California, Los Angeles, California 90095, USA;
- 3Department of Computer Science, University of California, Los Angeles, California 90095, USA;
- 4Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA;
- 5Departments of Pediatrics and Computer Science and Engineering, University of California, San Diego, California 92093, USA;
- 6Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, California 90095, USA;
- 7Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California 90095, USA;
- 8Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, California 90095, USA
- Corresponding author: jlusis{at}mednet.ucla.edu
Abstract
Genetics provides a potentially powerful approach to dissect host-gut microbiota interactions. Toward this end, we profiled gut microbiota using 16s rRNA gene sequencing in a panel of 110 diverse inbred strains of mice. This panel has previously been studied for a wide range of metabolic traits and can be used for high-resolution association mapping. Using a SNP-based approach with a linear mixed model, we estimated the heritability of microbiota composition. We conclude that, in a controlled environment, the genetic background accounts for a substantial fraction of abundance of most common microbiota. The mice were previously studied for response to a high-fat, high-sucrose diet, and we hypothesized that the dietary response was determined in part by gut microbiota composition. We tested this using a cross-fostering strategy in which a strain showing a modest response, SWR, was seeded with microbiota from a strain showing a strong response, A×B19. Consistent with a role of microbiota in dietary response, the cross-fostered SWR pups exhibited a significantly increased response in weight gain. To examine specific microbiota contributing to the response, we identified various genera whose abundance correlated with dietary response. Among these, we chose Akkermansia muciniphila, a common anaerobe previously associated with metabolic effects. When administered to strain A×B19 by gavage, the dietary response was significantly blunted for obesity, plasma lipids, and insulin resistance. In an effort to further understand host-microbiota interactions, we mapped loci controlling microbiota composition and prioritized candidate genes. Our publicly available data provide a resource for future studies.
Footnotes
-
[Supplemental material is available for this article.]
-
Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.194118.115.
-
Freely available online through the Genome Research Open Access option.
- Received May 8, 2015.
- Accepted August 7, 2015.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
