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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.


Associations between fecal microbiome 16S OTUs and visceral fat in the TwinsUK and replication datasets. a The inner circle denotes the phylogenetic tree of OTUs, produced using iTOL [93] based on Greengenes May 2013 tree filtered for the OTUs in the sample. Tree leaves are coloured according to the direction of association with visceral fat, where blue indicates a negative association, while red indicates a positive association. The outer circle denotes the significance of each OTU-visceral fat association, where P values are plotted as –log10 (P value), and the red line shows the Bonferroni significance threshold. The figure highlights the most-associated OTU in the sample (OTU 372146), as well as the two closed-reference OTUs that were significantly associated with host genetic variants in genes FHIT (OTU 181702) and ELAVL4 (194733). It also highlights the heritable Christensenellaceae OTU 176318. The figure also denotes the tree branches containing members of Clostridiales, Bacteroides and Christensenellaceae to accompany results and discussion in the main text. b Forest plot of beta coefficients with confidence intervals of eight OTUs that replicated robustly in a meta-analysis of three independent cohorts (TUK-R, AG and FGFP)
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Fig3: Associations between fecal microbiome 16S OTUs and visceral fat in the TwinsUK and replication datasets. a The inner circle denotes the phylogenetic tree of OTUs, produced using iTOL [93] based on Greengenes May 2013 tree filtered for the OTUs in the sample. Tree leaves are coloured according to the direction of association with visceral fat, where blue indicates a negative association, while red indicates a positive association. The outer circle denotes the significance of each OTU-visceral fat association, where P values are plotted as –log10 (P value), and the red line shows the Bonferroni significance threshold. The figure highlights the most-associated OTU in the sample (OTU 372146), as well as the two closed-reference OTUs that were significantly associated with host genetic variants in genes FHIT (OTU 181702) and ELAVL4 (194733). It also highlights the heritable Christensenellaceae OTU 176318. The figure also denotes the tree branches containing members of Clostridiales, Bacteroides and Christensenellaceae to accompany results and discussion in the main text. b Forest plot of beta coefficients with confidence intervals of eight OTUs that replicated robustly in a meta-analysis of three independent cohorts (TUK-R, AG and FGFP)

Mentions: We investigated the association of each OTU with all adiposity traits, including BMI, across individuals. Of the approximately 12,000 OTU-phenotype associations considered, 3217 were nominally significant, and 149 OTU results surpassed the Bonferroni correction (P = 3.90 × 10−6). The 149 significant microbial-adiposity associations involved 97 unique OTUs (Additional file 1: Table S2), and these fell within either the Firmicutes or Bacteroidetes phylum, and most within the Ruminococcaceae family. Visceral fat (VFM) associations made up the highest proportion of significant results surpassing the Bonferroni threshold (45 %, Fig. 3a). The peak result was an OTU classified as Oscillospira (Greengenes OTU 372146), which was associated with VFM (P = 1.93 × 10−12). Ruminococcaceae OTUs featured prominently in the top significant results, along with a number of other OTUs within the Lachnospiraceae family. Given the importance of VFM and AGR in cardiovascular risk, we were interested in determining potential microbial markers of cardiovascular risk. OTUs within Oscillospira, Lachnospira and Ruminococcus all showed negative associations with VFM and AGR, suggesting a potential protective role for these bacteria in cardiovascular risk (Fig. 3, Additional file 1: Table S2). Blautia OTUs showed a positive association with VFM and AGR and may be a microbial marker candidate for cardiovascular risk (Fig. 3a, Additional file 1: Table S2). These results support the crucial role of the microbiome towards visceral fat as a marker of adiposity and cardio-metabolic disease risk.Fig. 3


Heritable components of the human fecal microbiome are associated with visceral fat
Associations between fecal microbiome 16S OTUs and visceral fat in the TwinsUK and replication datasets. a The inner circle denotes the phylogenetic tree of OTUs, produced using iTOL [93] based on Greengenes May 2013 tree filtered for the OTUs in the sample. Tree leaves are coloured according to the direction of association with visceral fat, where blue indicates a negative association, while red indicates a positive association. The outer circle denotes the significance of each OTU-visceral fat association, where P values are plotted as –log10 (P value), and the red line shows the Bonferroni significance threshold. The figure highlights the most-associated OTU in the sample (OTU 372146), as well as the two closed-reference OTUs that were significantly associated with host genetic variants in genes FHIT (OTU 181702) and ELAVL4 (194733). It also highlights the heritable Christensenellaceae OTU 176318. The figure also denotes the tree branches containing members of Clostridiales, Bacteroides and Christensenellaceae to accompany results and discussion in the main text. b Forest plot of beta coefficients with confidence intervals of eight OTUs that replicated robustly in a meta-analysis of three independent cohorts (TUK-R, AG and FGFP)
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Fig3: Associations between fecal microbiome 16S OTUs and visceral fat in the TwinsUK and replication datasets. a The inner circle denotes the phylogenetic tree of OTUs, produced using iTOL [93] based on Greengenes May 2013 tree filtered for the OTUs in the sample. Tree leaves are coloured according to the direction of association with visceral fat, where blue indicates a negative association, while red indicates a positive association. The outer circle denotes the significance of each OTU-visceral fat association, where P values are plotted as –log10 (P value), and the red line shows the Bonferroni significance threshold. The figure highlights the most-associated OTU in the sample (OTU 372146), as well as the two closed-reference OTUs that were significantly associated with host genetic variants in genes FHIT (OTU 181702) and ELAVL4 (194733). It also highlights the heritable Christensenellaceae OTU 176318. The figure also denotes the tree branches containing members of Clostridiales, Bacteroides and Christensenellaceae to accompany results and discussion in the main text. b Forest plot of beta coefficients with confidence intervals of eight OTUs that replicated robustly in a meta-analysis of three independent cohorts (TUK-R, AG and FGFP)
Mentions: We investigated the association of each OTU with all adiposity traits, including BMI, across individuals. Of the approximately 12,000 OTU-phenotype associations considered, 3217 were nominally significant, and 149 OTU results surpassed the Bonferroni correction (P = 3.90 × 10−6). The 149 significant microbial-adiposity associations involved 97 unique OTUs (Additional file 1: Table S2), and these fell within either the Firmicutes or Bacteroidetes phylum, and most within the Ruminococcaceae family. Visceral fat (VFM) associations made up the highest proportion of significant results surpassing the Bonferroni threshold (45 %, Fig. 3a). The peak result was an OTU classified as Oscillospira (Greengenes OTU 372146), which was associated with VFM (P = 1.93 × 10−12). Ruminococcaceae OTUs featured prominently in the top significant results, along with a number of other OTUs within the Lachnospiraceae family. Given the importance of VFM and AGR in cardiovascular risk, we were interested in determining potential microbial markers of cardiovascular risk. OTUs within Oscillospira, Lachnospira and Ruminococcus all showed negative associations with VFM and AGR, suggesting a potential protective role for these bacteria in cardiovascular risk (Fig. 3, Additional file 1: Table S2). Blautia OTUs showed a positive association with VFM and AGR and may be a microbial marker candidate for cardiovascular risk (Fig. 3a, Additional file 1: Table S2). These results support the crucial role of the microbiome towards visceral fat as a marker of adiposity and cardio-metabolic disease risk.Fig. 3

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.