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

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

Microbial functional analysis in obesity. a Microbial PICRUSt-predicted KEGG functions relevant to metabolism in the twin dataset, and their association with the six adiposity measures. The heatmap denotes the direction of association between each microbial PICRUSt-predicted KEGG function and adiposity measures, where blue indicates a negative association, while red indicates a positive association. Bonferroni-significant associations are highlighted (*). b Five KO genes that are differentially abundant between high and low visceral fat individuals in glyoxylate and dicarboxylate metabolism, as tested by a two-sided Welch’s t test. FDR-adjusted P values are reported at the right of the image, and stars indicate Bonferroni-significant associations. Figure was produced using STAMP [45]
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Fig4: Microbial functional analysis in obesity. a Microbial PICRUSt-predicted KEGG functions relevant to metabolism in the twin dataset, and their association with the six adiposity measures. The heatmap denotes the direction of association between each microbial PICRUSt-predicted KEGG function and adiposity measures, where blue indicates a negative association, while red indicates a positive association. Bonferroni-significant associations are highlighted (*). b Five KO genes that are differentially abundant between high and low visceral fat individuals in glyoxylate and dicarboxylate metabolism, as tested by a two-sided Welch’s t test. FDR-adjusted P values are reported at the right of the image, and stars indicate Bonferroni-significant associations. Figure was produced using STAMP [45]

Mentions: Of the 233 KEGG pathway associations with six adiposity measures, 13 associations surpassed Bonferroni correction (P = 3.6 × 10−5), and 218 associations were significant after false discovery rate (FDR) correction (FDR 5 %). Four of the 13 Bonferroni-significant associations were with KEGG functions related to metabolism, as well as 98 of the FDR 5 % significant results (Fig. 4a). Functions within carbohydrate metabolism were positively associated with adiposity, in particular, glyoxylate and dicarboxylate metabolism, which had a Bonferroni-significant association with VFM (P = 1.19 × 10−06) and FDR 5 % significant associations with the remaining adiposity measures. Five groups within the glyoxylate and dicarboxylate metabolism pathway were significantly differentially abundant in high visceral fat and low visceral fat individuals (Fig. 4b). Two of these five groups remained significant following Bonferroni correction, and these were K03779 (ttdA, Q = 2.87 × 10−3) and K03780 (ttdB, Q = 1.79 × 10−3); both increased in subjects with high visceral fat. The remaining 3 pathways that surpassed Bonferroni correction were obtained between pTF and dioxin degradation, prenyltransferases and N-glycan biosynthesis.Fig. 4


Heritable components of the human fecal microbiome are associated with visceral fat
Microbial functional analysis in obesity. a Microbial PICRUSt-predicted KEGG functions relevant to metabolism in the twin dataset, and their association with the six adiposity measures. The heatmap denotes the direction of association between each microbial PICRUSt-predicted KEGG function and adiposity measures, where blue indicates a negative association, while red indicates a positive association. Bonferroni-significant associations are highlighted (*). b Five KO genes that are differentially abundant between high and low visceral fat individuals in glyoxylate and dicarboxylate metabolism, as tested by a two-sided Welch’s t test. FDR-adjusted P values are reported at the right of the image, and stars indicate Bonferroni-significant associations. Figure was produced using STAMP [45]
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: Microbial functional analysis in obesity. a Microbial PICRUSt-predicted KEGG functions relevant to metabolism in the twin dataset, and their association with the six adiposity measures. The heatmap denotes the direction of association between each microbial PICRUSt-predicted KEGG function and adiposity measures, where blue indicates a negative association, while red indicates a positive association. Bonferroni-significant associations are highlighted (*). b Five KO genes that are differentially abundant between high and low visceral fat individuals in glyoxylate and dicarboxylate metabolism, as tested by a two-sided Welch’s t test. FDR-adjusted P values are reported at the right of the image, and stars indicate Bonferroni-significant associations. Figure was produced using STAMP [45]
Mentions: Of the 233 KEGG pathway associations with six adiposity measures, 13 associations surpassed Bonferroni correction (P = 3.6 × 10−5), and 218 associations were significant after false discovery rate (FDR) correction (FDR 5 %). Four of the 13 Bonferroni-significant associations were with KEGG functions related to metabolism, as well as 98 of the FDR 5 % significant results (Fig. 4a). Functions within carbohydrate metabolism were positively associated with adiposity, in particular, glyoxylate and dicarboxylate metabolism, which had a Bonferroni-significant association with VFM (P = 1.19 × 10−06) and FDR 5 % significant associations with the remaining adiposity measures. Five groups within the glyoxylate and dicarboxylate metabolism pathway were significantly differentially abundant in high visceral fat and low visceral fat individuals (Fig. 4b). Two of these five groups remained significant following Bonferroni correction, and these were K03779 (ttdA, Q = 2.87 × 10−3) and K03780 (ttdB, Q = 1.79 × 10−3); both increased in subjects with high visceral fat. The remaining 3 pathways that surpassed Bonferroni correction were obtained between pTF and dioxin degradation, prenyltransferases and N-glycan biosynthesis.Fig. 4

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