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BACKGROUND & AIMS Genome-wide association studies (GWAS) have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn’s disease (CD) and ulcerative colitis (UC) remains incompletely defined. Here we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip. METHODS Genotyping was performed in 10,523 IBD cases and 5,726 non-IBD controls. 91,713 functional single nucleotide polymorphism (SNP) loci in coding regions were analyzed. A novel identified association was further replicated in two independent cohorts. We further examined the association of the identified SNP with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface (MLI) cohort measured using 16S sequencing. RESULTS We identified an association between CD and a missense variant encoding alanine (Ala) or threonine (Thr) at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 Ala391Thr, rs13107325) and replicated the association with CD in two replication cohorts (combined meta-analysis p=5.55×10−13). This variant has previously been associated with distinct phenotypes including obesity, lipid levels, blood pressure and schizophrenia. We subsequently determined that the CD-risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (p=0.009) and CD cases (p=0.0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (p=9.24×10−16) and overweight individuals (p=6.73×10−16). CONCLUSIONS Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD.

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Healthy 1 st degree IBD relatives Pre-UC Post-UC Matched HC Follow-up Proteolytic activity Microbiotahumanized mice Proteolytic activity Low-grade colonic inflammation Fecal proteolytic activity as early biomarker Microbiota composition BACKGROUND & AIMS: Altered gut microbiota composition and function have been associated with inflammatory bowel diseases, including ulcerative colitis (UC), but the causality and mechanisms remain unknown. METHODS: We applied 16S ribosomal RNA gene sequencing, shotgun metagenomic sequencing, in vitro functional assays, and gnotobiotic colonizations to define the microbial composition and function in fecal samples obtained from a cohort of healthy individuals at risk for inflammatory bowel diseases (pre-UC) who later developed UC (post-UC) and matched healthy control individuals (HCs). RESULTS: Microbiota composition of post-UC samples was different from HC and pre-UC samples; however, functional analysis showed increased fecal proteolytic and elastase activity before UC onset. Metagenomics identified more than 22,000 gene families that were significantly different between HC, pre-UC, and post-UC samples. Of these, 237 related to proteases and peptidases, suggesting a bacterial component to the pre-UC proteolytic signature. Elastase activity inversely correlated with the relative abundance of Adlercreutzia and other potentially beneficial taxa and directly correlated with known proteolytic taxa, such as Bacteroides vulgatus. High elastase activity was confirmed in Bacteroides isolates from fecal samples. The bacterial contribution and functional significance of the proteolytic signature were investigated in germ-free adult mice and in dams colonized with HC, pre-UC, or post-UC microbiota. Mice colonized with or born from pre-UC-colonized dams developed higher fecal proteolytic activity and an inflammatory immune tone compared with HC-colonized mice. CONCLU-SIONS: We have identified increased fecal proteolytic activity that precedes the clinical diagnosis of UC and associates with gut microbiota changes. This proteolytic signature may constitute a noninvasive biomarker of inflammation to monitor at-risk populations that can be targeted therapeutically with antiproteases.