Complex host genetics influence the microbiome in inflammatory bowel disease

Abstract

BackgroundHuman genetics and host-associated microbial communities have been associated independently with a wide range of chronic diseases. One of the strongest associations in each case is inflammatory bowel disease (IBD), but disease risk cannot be explained fully by either factor individually. Recent findings point to interactions between host genetics and microbial exposures as important contributors to disease risk in IBD. These include evidence of the partial heritability of the gut microbiota and the conferral of gut mucosal inflammation by microbiome transplant even when the dysbiosis was initially genetically derived. Although there have been several tests for association of individual genetic loci with bacterial taxa, there has been no direct comparison of complex genome-microbiome associations in large cohorts of patients with an immunity-related disease.MethodsWe obtained 16S ribosomal RNA (rRNA) gene sequences from intestinal biopsies as well as host genotype via Immunochip in three independent cohorts totaling 474 individuals. We tested for correlation between relative abundance of bacterial taxa and number of minor alleles at known IBD risk loci, including fine mapping of multiple risk alleles in the Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene exon. We identified host polymorphisms whose associations with bacterial taxa were conserved across two or more cohorts, and we tested related genes for enrichment of host functional pathways.ResultsWe identified and confirmed in two cohorts a significant association between NOD2 risk allele count and increased relative abundance of Enterobacteriaceae, with directionality of the effect conserved in the third cohort. Forty-eight additional IBD-related SNPs have directionality of their associations with bacterial taxa significantly conserved across two or three cohorts, implicating genes enriched for regulation of innate immune response, the JAK-STAT cascade, and other immunity-related pathways.ConclusionsThese results suggest complex interactions between genetically altered host functional pathways and the structure of the microbiome. Our findings demonstrate the ability to uncover novel associations from paired genome-microbiome data, and they suggest a complex link between host genetics and microbial dysbiosis in subjects with IBD across independent cohorts.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-014-0107-1) contains supplementary material, which is available to authorized users.

Captivity humanizes the primate microbiome

“…However, an important additional component of our study design is that we have controlled for host genetics at the species level by obtaining samples from wild and captive individuals within the same species, replicated across two different species (howler and douc). Although this does not control for within-species individual genetic variation that may cause dysbiosis (14), microbiome variation between captive individuals of the same species is smaller than variation between captive and wild individuals from the same species (Fig. 3B).…”

“…Specific environmental and genetic factors have been linked to the development of dysbiosis, including antibiotic use, stress, geography, race, host genetics, and diet (13,14). Of these factors, diet, gastrointestinal motility, and medication history most strongly shape the gut microbiome (13,(15)(16)(17)(18)(19).…”

Host genetics and microbiome associations from the lens of genome wide association studies

“…The first such studies in humans focused on specific genes and pathways, and have identified several significant microbiome-associated variants [41][42][43][44][45]. However, a potential shortcoming of the above studies is that they require previous knowledge of associated genes, and thus cannot discover new associations.…”

“…[37] and references therein for a comprehensive review). It has also been observed that many mGWAS hits are found near genes associated with complex diseases [24,[27][28][29]31,39,41,[47][48][49][50], and that multiple studies have implicated variants residing in the same genes, though the exact loci differed between studies [11,36,41].…”

Nature vs. Nurture: The Gut Microbiome and Genetics in the Development of Gastrointestinal Disease

“…For example CD patients have shown increased expression of a tumor necrosis factor ligand TNFSF15, which is a costimulator of T cells and also causes proinflammatory cytokine production. The TNFSF15 ligand shares overlap in receptor function with the closely related TNFSF14, which functions to activate STAT3 signaling in response to pathogenic bacteria [72]. Furthermore, STAT3 is an important effector of T cell differentiation through the binding of the interleukin (IL)-23 receptor and the RAR-related orphan receptor C (RORC), both of which are IBD risk alleles.…”