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

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ABSTRACT

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.

Electronic supplementary material: The online version of this article (doi:10.1186/s13059-016-1052-7) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus

Distribution and heritability of adiposity phenotypes. a Scatterplot matrix showing the distribution and correlation between six adiposity measures in 3666 twins. The distribution of each phenotype (prior to normalisation) is shown along the diagonal. The lower panel shows scatterplots for each pair of adiposity phenotypes, and the upper panel denotes the coefficients of determination. b Heritability of six adiposity measures in the TwinsUK cohort, as well as visceral fat measures in three independent cohorts: Framingham [39], Quebec [41] and Heritage [40]. The total variance of each adiposity phenotype is decomposed into variance components attributed to additive genetics (A) or narrow-sense heritability (h2), common environment (C) and unique environment (E)
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Fig1: Distribution and heritability of adiposity phenotypes. a Scatterplot matrix showing the distribution and correlation between six adiposity measures in 3666 twins. The distribution of each phenotype (prior to normalisation) is shown along the diagonal. The lower panel shows scatterplots for each pair of adiposity phenotypes, and the upper panel denotes the coefficients of determination. b Heritability of six adiposity measures in the TwinsUK cohort, as well as visceral fat measures in three independent cohorts: Framingham [39], Quebec [41] and Heritage [40]. The total variance of each adiposity phenotype is decomposed into variance components attributed to additive genetics (A) or narrow-sense heritability (h2), common environment (C) and unique environment (E)

Mentions: We studied six adiposity measures in total, and these included three measures of abdominal adiposity (visceral fat mass (VFM), subcutaneous fat mass (SFM), percentage trunk fat (pTF)), two measures of body fat distribution (android/gynoid ratio (AGR) and waist/hip ratio (WHR)) and one measure of overall obesity, BMI. Adiposity was estimated using DXA-derived measures, which have been shown to be reliable alternatives [35–38] to traditional computed tomography (CT) and magnetic resonance imaging scan-based measures of adiposity. The majority of these adiposity measures have been previously explored in the TwinsUK cohort; however, VFM and AGR are newly obtained phenotypes. The new measure of VFM was highly correlated with other abdominal and overall adiposity measures, including BMI (Fig. 1a). Twin-based heritability analysis of VFM showed evidence of a significant additive genetic component, or heritability (h2), contributing to 0.70 (95 % CI = 0.58–0.74) of the total variance in VFM. The VFM heritability estimate remained high after adjustment for BMI (0.64, see Additional file 2). We obtained comparable estimates for the heritability of SFM (h2 = 0.72 (95 % CI = 0.60–0.77)), pTF (h2 = 0.66 (95 % CI = 0.55–0.77), AGR (h2 = 0.65 (95 % CI = 0.55–0.76)), BMI (h2 = 0.75 (95 % CI = 0.68–0.80) and a slightly lower estimate for WHR (h2 = 0.32 (95 % CI = 0.24–0.40)), in line with previous studies [39–41] (Fig. 1b).Fig. 1


Heritable components of the human fecal microbiome are associated with visceral fat
Distribution and heritability of adiposity phenotypes. a Scatterplot matrix showing the distribution and correlation between six adiposity measures in 3666 twins. The distribution of each phenotype (prior to normalisation) is shown along the diagonal. The lower panel shows scatterplots for each pair of adiposity phenotypes, and the upper panel denotes the coefficients of determination. b Heritability of six adiposity measures in the TwinsUK cohort, as well as visceral fat measures in three independent cohorts: Framingham [39], Quebec [41] and Heritage [40]. The total variance of each adiposity phenotype is decomposed into variance components attributed to additive genetics (A) or narrow-sense heritability (h2), common environment (C) and unique environment (E)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5036307&req=5

Fig1: Distribution and heritability of adiposity phenotypes. a Scatterplot matrix showing the distribution and correlation between six adiposity measures in 3666 twins. The distribution of each phenotype (prior to normalisation) is shown along the diagonal. The lower panel shows scatterplots for each pair of adiposity phenotypes, and the upper panel denotes the coefficients of determination. b Heritability of six adiposity measures in the TwinsUK cohort, as well as visceral fat measures in three independent cohorts: Framingham [39], Quebec [41] and Heritage [40]. The total variance of each adiposity phenotype is decomposed into variance components attributed to additive genetics (A) or narrow-sense heritability (h2), common environment (C) and unique environment (E)
Mentions: We studied six adiposity measures in total, and these included three measures of abdominal adiposity (visceral fat mass (VFM), subcutaneous fat mass (SFM), percentage trunk fat (pTF)), two measures of body fat distribution (android/gynoid ratio (AGR) and waist/hip ratio (WHR)) and one measure of overall obesity, BMI. Adiposity was estimated using DXA-derived measures, which have been shown to be reliable alternatives [35–38] to traditional computed tomography (CT) and magnetic resonance imaging scan-based measures of adiposity. The majority of these adiposity measures have been previously explored in the TwinsUK cohort; however, VFM and AGR are newly obtained phenotypes. The new measure of VFM was highly correlated with other abdominal and overall adiposity measures, including BMI (Fig. 1a). Twin-based heritability analysis of VFM showed evidence of a significant additive genetic component, or heritability (h2), contributing to 0.70 (95 % CI = 0.58–0.74) of the total variance in VFM. The VFM heritability estimate remained high after adjustment for BMI (0.64, see Additional file 2). We obtained comparable estimates for the heritability of SFM (h2 = 0.72 (95 % CI = 0.60–0.77)), pTF (h2 = 0.66 (95 % CI = 0.55–0.77), AGR (h2 = 0.65 (95 % CI = 0.55–0.76)), BMI (h2 = 0.75 (95 % CI = 0.68–0.80) and a slightly lower estimate for WHR (h2 = 0.32 (95 % CI = 0.24–0.40)), in line with previous studies [39–41] (Fig. 1b).Fig. 1

View Article: PubMed Central - PubMed

ABSTRACT

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.

Electronic supplementary material: The online version of this article (doi:10.1186/s13059-016-1052-7) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus