title: Genetic and environmental control of host-gut microbiota interactions.
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.
authors.affiliation: Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA;
authors.forename: Elin
authors.initials: E
authors.lastname: Org
authors.affiliation: Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA;
authors.forename: Brian W
authors.initials: BW
authors.lastname: Parks
authors.affiliation: Bioinformatics IDP, University of California, Los Angeles, California 90095, USA;
authors.forename: Jong Wha J
authors.initials: JW
authors.lastname: Joo
authors.affiliation: Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA;
authors.forename: Benjamin
authors.initials: B
authors.lastname: Emert
authors.affiliation: Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA;
authors.forename: William
authors.initials: W
authors.lastname: Schwartzman
authors.affiliation: Department of Computer Science, University of California, Los Angeles, California 90095, USA;
authors.forename: Eun Yong
authors.initials: EY
authors.lastname: Kang
authors.affiliation: Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA;
authors.forename: Margarete
authors.initials: M
authors.lastname: Mehrabian
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA;
authors.forename: Calvin
authors.initials: C
authors.lastname: Pan
authors.affiliation: Departments of Pediatrics and Computer Science and Engineering, University of California, San Diego, California 92093, USA;
authors.forename: Rob
authors.initials: R
authors.lastname: Knight
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, California 90095, USA;
authors.forename: Robert
authors.initials: R
authors.lastname: Gunsalus
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California 90095, USA;
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Drake
authors.affiliation: 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;
authors.forename: Eleazar
authors.initials: E
authors.lastname: Eskin
authors.affiliation: 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.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
mesh_terms: D000818:Animals; D004032:Diet; D059305:Diet, High-Fat; D004777:Environment; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000235:genetics*; D055106:Genome-Wide Association Study; D040941:Heredity; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009765:Obesity / Q000382:microbiology; D012336:RNA, Ribosomal, 16S; D013395:Sucrose / Q000378:metabolism
chemical_list: D012336:RNA, Ribosomal, 16S; D013395:Sucrose