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Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.

ABSTRACT: Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

SUBMITTER: Jostins L

PROVIDER: S-EPMC3491803 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.

Jostins Luke L Ripke Stephan S Weersma Rinse K RK Duerr Richard H RH McGovern Dermot P DP Hui Ken Y KY Lee James C JC Schumm L Philip LP Sharma Yashoda Y Anderson Carl A CA Essers Jonah J Mitrovic Mitja M Ning Kaida K Cleynen Isabelle I Theatre Emilie E Spain Sarah L SL Raychaudhuri Soumya S Goyette Philippe P Wei Zhi Z Abraham Clara C Achkar Jean-Paul JP Ahmad Tariq T Amininejad Leila L Ananthakrishnan Ashwin N AN Andersen Vibeke V Andrews Jane M JM Baidoo Leonard L Balschun Tobias T Bampton Peter A PA Bitton Alain A Boucher Gabrielle G Brand Stephan S Büning Carsten C Cohain Ariella A Cichon Sven S D'Amato Mauro M De Jong Dirk D Devaney Kathy L KL Dubinsky Marla M Edwards Cathryn C Ellinghaus David D Ferguson Lynnette R LR Franchimont Denis D Fransen Karin K Gearry Richard R Georges Michel M Gieger Christian C Glas Jürgen J Haritunians Talin T Hart Ailsa A Hawkey Chris C Hedl Matija M Hu Xinli X Karlsen Tom H TH Kupcinskas Limas L Kugathasan Subra S Latiano Anna A Laukens Debby D Lawrance Ian C IC Lees Charlie W CW Louis Edouard E Mahy Gillian G Mansfield John J Morgan Angharad R AR Mowat Craig C Newman William W Palmieri Orazio O Ponsioen Cyriel Y CY Potocnik Uros U Prescott Natalie J NJ Regueiro Miguel M Rotter Jerome I JI Russell Richard K RK Sanderson Jeremy D JD Sans Miquel M Satsangi Jack J Schreiber Stefan S Simms Lisa A LA Sventoraityte Jurgita J Targan Stephan R SR Taylor Kent D KD Tremelling Mark M Verspaget Hein W HW De Vos Martine M Wijmenga Cisca C Wilson David C DC Winkelmann Juliane J Xavier Ramnik J RJ Zeissig Sebastian S Zhang Bin B Zhang Clarence K CK Zhao Hongyu H Silverberg Mark S MS Annese Vito V Hakonarson Hakon H Brant Steven R SR Radford-Smith Graham G Mathew Christopher G CG Rioux John D JD Schadt Eric E EE Daly Mark J MJ Franke Andre A Parkes Miles M Vermeire Severine S Barrett Jeffrey C JC Cho Judy H JH

Nature 20121101 7422

Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge ...[more]

PMID: 23128233

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Project description:Reactive Arthritis (ReA), a rare seronegative inflammatory arthritis, lacks exquisite classification under rheumatic autoimmunity. ReA is solely established using differential clinical diagnosis of the patient cohorts, where pathogenic triggers linked to enteric and urogenital microorganisms e.g. Salmonella, Shigella, Yersinia, Campylobacter, Chlamydia have been reported. Inflammatory Bowel Disease (IBD), an idiopathic enteric disorder co-evolved and attuned to present gut microbiome dysbiosis, can be correlated to the genesis of enteropathic arthropathies like ReA. Gut microbes symbolically modulate immune system homeostasis and are elementary for varied disease patterns in autoimmune disorders. The gut-microbiota axis structured on the core host-microbe interactions execute an imperative role in discerning the etiopathogenesis of ReA and IBD. This study predicts the molecular signatures for ReA with co-evolved IBD through the enveloped host-microbe interactions and microbe-microbe 'interspecies communication', using synonymous gene expression data for selective microbes. We have utilized a combinatorial approach that have concomitant in-silico work-pipeline and experimental validation to corroborate the findings. In-silico analysis involving text mining, metabolic network reconstruction, simulation, filtering, host-microbe interaction, docking and molecular mimicry studies results in robust drug target/s and biomarker/s for co-evolved IBD and ReA. Cross validation of the target/s or biomarker/s was done by targeted gene expression analysis following a non-probabilistic convenience sampling. Studies were performed to substantiate the host-microbe disease network consisting of protein-marker-symptom/disease-pathway-drug associations resulting in possible identification of vital drug targets, biomarkers, pathways and inhibitors for IBD and ReA.Our study identified Na(+)/H(+) anti-porter (NHAA) and Kynureninase (KYNU) to be robust early and essential host-microbe interacting targets for IBD co-evolved ReA. Other vital host-microbe interacting genes, proteins, pathways and drugs include Adenosine Deaminase (ADA), Superoxide Dismutase 2 (SOD2), Catalase (CAT), Angiotensin I Converting Enzyme (ACE), carbon metabolism (folate biosynthesis) and methotrexate. These can serve as potential prognostic/theranostic biomarkers and signatures that can be extrapolated to stratify ReA and related autoimmunity patient cohorts for further pilot studies.

Project description:Interactions among the gut microbiome, dysregulated immune responses, and genetic factors contribute to the pathogenesis of inflammatory bowel disease (IBD). Nlrx1-/- mice have exacerbated disease severity, colonic lesions, and increased inflammatory markers. Global transcriptomic analyses demonstrate enhanced mucosal antimicrobial defense response, chemokine and cytokine expression, and epithelial cell metabolism in colitic Nlrx1-/- mice compared to wild-type (WT) mice. Cell-specificity studies using cre-lox mice demonstrate that the loss of NLRX1 in intestinal epithelial cells (IEC) recapitulate the increased sensitivity to DSS colitis observed in whole body Nlrx1-/- mice. Further, organoid cultures of Nlrx1-/- and WT epithelial cells confirm the altered patterns of proliferation, amino acid metabolism, and tight junction expression. These differences in IEC behavior can impact the composition of the microbiome. Microbiome analyses demonstrate that colitogenic bacterial taxa such as Veillonella and Clostridiales are increased in abundance in Nlrx1-/- mice and in WT mice co-housed with Nlrx1-/- mice. The transfer of an Nlrx1-/--associated gut microbiome through co-housing worsens disease in WT mice confirming the contributions of the microbiome to the Nlrx1-/- phenotype. To validate NLRX1 effects on IEC metabolism mediate gut-microbiome interactions, restoration of WT glutamine metabolic profiles through either exogenous glutamine supplementation or administration of 6-diazo-5-oxo-l-norleucine abrogates differences in inflammation, microbiome, and overall disease severity in Nlrx1-/- mice. The influence NLRX1 deficiency on SIRT1-mediated effects is identified to be an upstream controller of the Nlrx1-/- phenotype in intestinal epithelial cell function and metabolism. The altered IEC function and metabolisms leads to changes in barrier permeability and microbiome interactions, in turn, promoting greater translocation and inflammation and resulting in an increased disease severity. In conclusion, NLRX1 is an immunoregulatory molecule and a candidate modulator of the interplay between mucosal inflammation, metabolism, and the gut microbiome during IBD.

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Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.

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Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.

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