Large-scale association analyses identify host factors influencing human gut microbiome composition

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P <5 x 10(-8)) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 x 10(-20)), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 x 10(-10) <P <5 x 10(-8)) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis

Meta-analysis of human genome-microbiome association studies: the MiBioGen consortium initiative

Abstract Background In recent years, human microbiota, especially gut microbiota, have emerged as an important yet complex trait influencing human metabolism, immunology, and diseases. Many studies are investigating the forces underlying the observed variation, including the human genetic variants that shape human microbiota. Several preliminary genome-wide association studies (GWAS) have been completed, but more are necessary to achieve a fuller picture. Results Here, we announce the MiBioGen consortium initiative, which has assembled 18 population-level cohorts and some 19,000 participants. Its aim is to generate new knowledge for the rapidly developing field of microbiota research. Each cohort has surveyed the gut microbiome via 16S rRNA sequencing and genotyped their participants with full-genome SNP arrays. We have standardized the analytical pipelines for both the microbiota phenotypes and genotypes, and all the data have been processed using identical approaches. Our analysis of microbiome composition shows that we can reduce the potential artifacts introduced by technical differences in generating microbiota data. We are now in the process of benchmarking the association tests and performing meta-analyses of genome-wide associations. All pipeline and summary statistics results will be shared using public data repositories. Conclusion We present the largest consortium to date devoted to microbiota-GWAS. We have adapted our analytical pipelines to suit multi-cohort analyses and expect to gain insight into host-microbiota cross-talk at the genome-wide level. And, as an open consortium, we invite more cohorts to join us (by contacting one of the corresponding authors) and to follow the analytical pipeline we have developed

Meta-analysis of human genome-microbiome association studies: The MiBioGen consortium initiative

Background: In recent years, human microbiota, especially gut microbiota, have emerged as an important yet complex trait influencing human metabolism, immunology, and diseases. Many studies are investigating the forces underlying the observed variation, including the human genetic variants that shape human microbiota. Several preliminary genome-wide association studies (GWAS) have been completed, but more are necessary to achieve a fuller picture. Results: Here, we announce the MiBioGen consortium initiative, which has assembled 18 population-level cohorts and some 19,000 participants. Its aim is to generate new knowledge for the rapidly developing field of microbiota research. Each cohort has surveyed the gut microbiome via 16S rRNA sequencing and genotyped their participants with full-genome SNP arrays. We have standardized the analytical pipelines for both the microbiota phenotypes and genotypes, and all the data have been processed using identical approaches. Our analysis of microbiome composition shows that we can reduce the potential artifacts introduced by technical differences in generating microbiota data. We are now in the process of benchmarking the association tests and performing meta-analyses of genome-wide associations. All pipeline and summary statistics results will be shared using public data repositories. Conclusion: We present the largest consortium to date devoted to microbiota-GWAS. We have adapted our analytical pipelines to suit multi-cohort analyses and expect to gain insight into host-microbiota cross-talk at the genome-wide level. And, as an open consortium, we invite more cohorts to join us (by contacting one of the corresponding authors) and to follow the analytical pipeline we have developed

T Cell Repertoire and Inflammatory Bowel Disease

The diversity of the T cell receptor repertoire is generated through rearrangement of the variable, junctional and constant region genes. Selection processes in the thymus and periphery serve to eliminate self-reacting T cells, thereby preventing autoimmune disease. The possibility that inflammatory bowel disease (IBD) is an autoimmune disease has led to the search for an auto-antigen. In addition, studies are exploring the T cell receptor repertoire in IBD patients for changes that may provide clues regarding etiopathogenesis. Using monoclonal antibodies to T cell receptor variable-gene products or polymerase chain reaction analysis of variable-gene mRNA expression, the mucosal T cell repertoire has been examined in humans. The intestinal intraepithelial lymphocytes show a significant degree of oligoclonal expansion that may represent local antigen exposure or unique selection processes. This is in keeping with studies that show that murine intestinal intraepithelial lymphocytes undergo positive and possibly negative selection independent of the thymus. In the inflamed human gut, shifts in the T cell receptor repertoire may also reflect recruitment of peripheral T cells to the gut. In one study, a subset of Crohn’s disease patients was shown to have an increase in the proportion of variable β8 peripheral blood lymphocyte and mesenteric lymph node cells, suggesting a superantigen effect. The authors hypothesized that changes in the functional T cell receptor repertoire can also occur which might be independent of changes in the distribution of T cells expressing variable β T cell receptors. In fact, the authors have shown there is a selective decrease in the cytotoxic function of peripheral variable β8 T cells in Crohn’s disease. Furthermore, stimulation with the variable β8 selective bacterial enterotoxin staphylococcal enterotoxin E failed to increase the cytotoxic function in this subset of Crohn’s disease patients compared with controls. This suggests that in Crohn’s disease, variable β8 T cells have undergone an alteration in function that may reflect previous exposure to a superantigen-like stimulus. The relationship to the etiology and pathogenesis of IBD remains to be defined

Nod2 activates NF-kB in CD4+ T cells but its expression is dispensable for T cell-induced colitis.

Although the etiology of Crohn's disease (CD) remains elusive this disease is characterized by T cell activation that leads to chronic inflammation and mucosal damage. A potential role for maladaptation between the intestinal microbiota and the mucosal immune response is suggested by the fact that mutations in the pattern recognition receptor Nod2 are associated with higher risks for developing CD. Although Nod2 deletion in CD4(+) T cells has been shown to impair the induction of colitis in the murine T cell transfer model, the analysis of T cell intrinsic Nod2 function in T cell differentiation and T cell-mediated immunity is inconsistent between several studies. In addition, the role of T cell intrinsic Nod2 in regulatory T cell (Treg) development and function during colitis remain to be analyzed. In this study, we show that Nod2 expression is higher in activated/memory CD4(+) T cells and its expression was inducible after T cell receptor (TCR) ligation. Nod2 stimulation with muramyl dipeptide (MDP) led to a nuclear accumulation of c-Rel NF-kB subunit. Although functionally active in CD4(+) T cells, the deletion of Nod2 did not impair the induction and the prevention of colitis in the T cell transfer model. Moreover, Nod2 deletion did not affect the development of Foxp3(+) Treg cells in the spleen of recipient mice and Nod2 deficient CD4 T cells expressing the OVA specific transgenic TCR were able to differentiate in Foxp3(+) Treg cells after OVA feeding. In vitro, CD25(+) Nod2 deficient T cells suppressed T cell proliferation as well as wild type counter parts and T cell stimulation with MDP did not affect the proliferation and the cytokine secretion of T cells. In conclusion, our data indicate that Nod2 is functional in murine CD4(+) T cells but its expression is dispensable for the T cell regulation of colitis

Serum Zonulin Measured by Commercial Kit Fails to Correlate With Physiologic Measures of Altered Gut Permeability in First Degree Relatives of Crohn's Disease Patients

Intestinal epithelial cell tight junctions (TJs) contribute to the integrity of the intestinal barrier allowing for control of the physical barrier between external antigens or bacterial products and the internal environment. Zonula occludens-1 (ZO-1) is a protein that modulates intestinal TJs, and serum levels of ZO-1 has been suggested as a biomarker of disrupted barrier function in humans. Previous studies suggested that increased intestinal permeability was associated with evidence of TJ abnormalities. However, there is limited information on the serological measurement of ZO-1 and its relation to other tests of barrier function in healthy subjects. We investigated the correlation of serum ZO-1, with physiologic measures of intestinal permeability (as the ratio of the fractional excretion of lactulose-mannitol or LMR) in a cohort of 39 healthy FDRs of Crohn's disease (CD) patients. No significant correlation was found between LMR and ZO-1 levels ( r 2 = 0.004, P < 0.71), or intestinal fatty acid binding proteins (I-FABP) ( r 2 = 0.004, P < 0.71). In conclusion, our data show that ZO-1 and I-FABP are not a marker of gut permeability as defined by LMR