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

Abstract

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

Strains, functions and dynamics in the expanded Human Microbiome Project

“…Population-scale studies have aided in understanding the functional consequences of its remarkable inter-individual diversity, the earliest of which include MetaHIT 5,6 and the Human Microbiome Project 1 (referred to here as HMP1). Studies continue to focus on the gut 7–9 , with fewer population-scale cohorts investigating vaginal 10 , oral 11 , or skin 12 microbial communities. HMP1 remains the largest body-wide combined amplicon and metagenome survey of the healthy microbiome to date.…”

The Relationship Between the Human Genome and Microbiome Comes into View

“…The association of Christensenellaceae with a lean phenotype was also observed in Missouri twins (64), the Dutch LifeLines- DEEP population (17), Koreans (40) and Japanese individuals (51). Christensenellaceae was subsequently linked to visceral fat phenotypes in the TwinsUK cohort (3), as well as with healthy levels of triglycerides in the Dutch LifeLines- DEEP cohort (17). Furthermore, the Christensenellaceae increased in relative abundance in stool of subjects consuming resistant starch, and correlated with levels of specific SCFAs in stool (66).…”

“…Genetic variants near the genes PLD1 and LINGO2 , which have been implicated in obesity GWAS (42, 50), associated with the abundance of Akkermansia (10) and Blautia (5) respectively. Both Akkermansia and Blautia have been linked to obesity related phenotypes (3, 14, 21). The overlap observed between genetic variants associated with both microbiome attributes and complex diseases motivates further investigation to better understand how human genetic variation impacts the microbiome in the context of these diseases.…”

Alterations in Gut Microbiome Composition and Barrier Function Are Associated with Reproductive and Metabolic Defects in Women with Polycystic Ovary Syndrome (PCOS): A Pilot Study

“…Recent large-scale studies and meta-analyses support an association between the gut microbiome and obesity in humans, though this association may be weaker than previously assumed [12–14]. Furthermore, a link between gut bacteria, obesity, and host genetics is emerging, suggesting that certain bacteria predisposing to a healthy or unhealthy metabolic state may be heritable [13–15]. …”