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Genome Res. 2015 Oct;25(10):1558-69. doi: 10.1101/gr.194118.115. Epub 2015 Aug 10.

Genetic and environmental control of host-gut microbiota interactions.

Author information

1
Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA;
2
Bioinformatics IDP, University of California, Los Angeles, California 90095, USA;
3
Department of Computer Science, University of California, Los Angeles, California 90095, USA;
4
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA;
5
Departments of Pediatrics and Computer Science and Engineering, University of California, San Diego, California 92093, USA;
6
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, California 90095, USA;
7
Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California 90095, USA;
8
Department of Computer Science, University of California, Los Angeles, California 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA;
9
Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, California 90095, USA.

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.

PMID:
26260972
PMCID:
PMC4579341
DOI:
10.1101/gr.194118.115
[Indexed for MEDLINE]
Free PMC Article

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