Understanding the Interaction between Host Genetics, Immune response, and Gut Microbes in Post-operative Recurrence of Crohn's disease - Project Summary/Abstract Intestinal resection remains a common complication in Crohn's disease (CD) despite the advent of advanced biologics and small molecule therapies. Within one year after ileocolic resection, over 70% of patients with CD are known to have endoscopic recurrence. Even in patients treated with a biologic treatment, 30% develops recurrence of CD. Despite significant progress in the management of post-operative CD patients, there is still an unmet need in efficiently treating and preventing recurrence of CD following ileal resection. Since 2011, six participating Genetic Research Centres as part of the NIDDK Inflammatory Bowel Disease Genetic Consortium (IBDGC) have recruited patients for the CD Ileal Post-Operative Study. The consortium- wide effort has led to a creation of a large biobank of blood, stool, and biopsy samples during the peri-operative period and at each follow-up post-operative endoscopic procedures. Although these efforts led to important biomarker discoveries related to post-operative disease recurrence, the mechanism of intestinal inflammation initiation after ileal resection is still unknown. For this ancillary study proposal, we aim to better understand the pathophysiology of CD by leveraging the NIDDK IBDGC Post-operative CD cohort. We propose to make use of the latest high-throughput omics approaches to this cohort. First, an untargeted in-depth antibody repertoire profiling approach using phase display technology (PhIP-Seq) will help us identify novel anti-microbial antibodies associated with disease recurrence. Second, metagenome-assembled genome analysis (MAG) on stool and biopsy samples will help identify novel gut microbial functional genomic signatures associated with post-operative CD recurrence. Third, metabolomics analysis will help identify the downstream expression of various changes that occur in the genome, proteome, and transcriptome, that will ultimately closely represent the phenotypic fingerprints of CD recurrence. Additionally, the associations between anti-microbial antibodies, microbiome, and metabolome with post-operative CD recurrence can be assessed for their dependence on specific known ileal CD-associated genetic variants (e.g., located NOD2, ATG16L1, HLA-DRB1*07:01, LRRK2, MUC19) or combined CD-genetic risk variants (e.g., CD-polygenic risk score). Taken together, through the research proposed, we anticipate that significant advances will be made toward a better understanding of the mechanisms of intestinal inflammation following ileal resection of CD and the translation of these data into clinically meaningful tools that will lead to a lower recurrence of CD.
