Heritable components of the human fecal microbiome are associated with visceral fat

Genome Biology, Sep 2016

Background Variation in the human fecal microbiota has previously been associated with body mass index (BMI). Although obesity is a global health burden, the accumulation of abdominal visceral fat is the specific cardio-metabolic disease risk factor. Here, we explore links between the fecal microbiota and abdominal adiposity using body composition as measured by dual-energy X-ray absorptiometry in a large sample of twins from the TwinsUK cohort, comparing fecal 16S rRNA diversity profiles with six adiposity measures. Results We profile six adiposity measures in 3666 twins and estimate their heritability, finding novel evidence for strong genetic effects underlying visceral fat and android/gynoid ratio. We confirm the association of lower diversity of the fecal microbiome with obesity and adiposity measures, and then compare the association between fecal microbial composition and the adiposity phenotypes in a discovery subsample of twins. We identify associations between the relative abundances of fecal microbial operational taxonomic units (OTUs) and abdominal adiposity measures. Most of these results involve visceral fat associations, with the strongest associations between visceral fat and Oscillospira members. Using BMI as a surrogate phenotype, we pursue replication in independent samples from three population-based cohorts including American Gut, Flemish Gut Flora Project and the extended TwinsUK cohort. Meta-analyses across the replication samples indicate that 8 OTUs replicate at a stringent threshold across all cohorts, while 49 OTUs achieve nominal significance in at least one replication sample. Heritability analysis of the adiposity-associated microbial OTUs prompted us to assess host genetic-microbe interactions at obesity-associated human candidate loci. We observe significant associations of adiposity-OTU abundances with host genetic variants in the FHIT, TDRG1 and ELAVL4 genes, suggesting a potential role for host genes to mediate the link between the fecal microbiome and obesity. Conclusions Our results provide novel insights into the role of the fecal microbiota in cardio-metabolic disease with clear potential for prevention and novel therapies.

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Heritable components of the human fecal microbiome are associated with visceral fat

Beaumont et al. Genome Biology Heritable components of the human fecal microbiome are associated with visceral fat Michelle Beaumont 0 4 Julia K. Goodrich 1 2 Matthew A. Jackson 0 4 Idil Yet 0 4 Emily R. Davenport 1 Sara Vieira-Silva 3 9 Justine Debelius 5 8 Tess Pallister 0 4 Massimo Mangino 0 4 Jeroen Raes 3 9 Rob Knight 5 6 7 8 Andrew G. Clark 2 Ruth E. Ley 2 10 Tim D. Spector 0 4 Jordana T. Bell 0 4 0 Department of Twin Research & Genetic Epidemiology, King's College London, St Thomas' Hospital , 3rd Floor, South Wing, Block D, London SE1 7EH , UK 1 Department of Molecular Biology and Genetics, Cornell University , Ithaca, NY 14853 , USA 2 Department of Microbiology, Cornell University , Ithaca, NY 14853 , USA 3 VIB lab for Bioinformatics and (eco-)systems biology , Leuven , Belgium 4 Department of Twin Research & Genetic Epidemiology, King's College London, St Thomas' Hospital , 3rd Floor, South Wing, Block D, London SE1 7EH , UK 5 Present address: Departments of Pediatrics and Computer Science and Engineering, University of California San Diego , La Jolla, CA 92093 , USA 6 Howard Hughes Medical Institute , Boulder, CO 80309 , USA 7 Biofrontiers Institute, University of Colorado , Boulder, CO 80309 , USA 8 Department of Chemistry and Biochemistry, University of Colorado , Boulder, CO 80309 , USA 9 Department of Microbiology and Immunology, KU Leuven - University of Leuven , Leuven , Belgium 10 Department of Microbiome Science, Max Planck Institute for Developmental Biology , Tübingen , Germany Background: Variation in the human fecal microbiota has previously been associated with body mass index (BMI). Although obesity is a global health burden, the accumulation of abdominal visceral fat is the specific cardio-metabolic disease risk factor. Here, we explore links between the fecal microbiota and abdominal adiposity using body composition as measured by dual-energy X-ray absorptiometry in a large sample of twins from the TwinsUK cohort, comparing fecal 16S rRNA diversity profiles with six adiposity measures. Results: We profile six adiposity measures in 3666 twins and estimate their heritability, finding novel evidence for strong genetic effects underlying visceral fat and android/gynoid ratio. We confirm the association of lower diversity of the fecal microbiome with obesity and adiposity measures, and then compare the association between fecal microbial composition and the adiposity phenotypes in a discovery subsample of twins. We identify associations between the relative abundances of fecal microbial operational taxonomic units (OTUs) and abdominal adiposity measures. Most of these results involve visceral fat associations, with the strongest associations between visceral fat and Oscillospira members. Using BMI as a surrogate phenotype, we pursue replication in independent samples from three population-based cohorts including American Gut, Flemish Gut Flora Project and the extended TwinsUK cohort. Meta-analyses across the replication samples indicate that 8 OTUs replicate at a stringent threshold across all cohorts, while 49 OTUs achieve nominal significance in at least one replication sample. Heritability analysis of the adiposity-associated microbial OTUs prompted us to assess host genetic-microbe interactions at obesity-associated human candidate loci. We observe significant associations of adiposity-OTU abundances with host genetic variants in the FHIT, TDRG1 and ELAVL4 genes, suggesting a potential role for host genes to mediate the link between the fecal microbiome and obesity. Conclusions: Our results provide novel insights into the role of the fecal microbiota in cardio-metabolic disease with clear potential for prevention and novel therapies. Fecal microbiome; Obesity; Visceral fat; Heritability; Genetic association; Twins - Background Obesity has rapidly become a global public health problem, with obesity-related disease now one of the leading causes of preventable death worldwide [1]. Although overall obesity poses a global health epidemic, it is the accumulation of excess abdominal fat that is a critical risk factor for cardiovascular and metabolic disease [2]. Changes in diet and a sedentary lifestyle can partly explain the rise in obesity, and family and twin studies also show a genetic influence, with obesity heritability estimates of 0.60–0.70 [3–6]. Genome-wide association studies (GWASs) have identified genetic risk factors [7–9], but genetic variants detected to date explain less than 3 % of the heritability of obesity, with a prediction ability of up to 20 %, suggesting a role for other mechanisms [10]. Recent insights show that the gut microbiota may play a crucial role in obesity and cardio-metabolic disease © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, (...truncated)


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Michelle Beaumont, Julia Goodrich, Matthew Jackson, Idil Yet, Emily Davenport, Sara Vieira-Silva, Justine Debelius, Tess Pallister, Massimo Mangino, Jeroen Raes, Rob Knight, Andrew Clark, Ruth Ley, Tim Spector, Jordana Bell. Heritable components of the human fecal microbiome are associated with visceral fat, Genome Biology, 2016, pp. 189, 17, DOI: 10.1186/s13059-016-1052-7