Understanding the Etiology of Inflammatory Complications Following Ileal Pouch-Anal Anastomosis

• Main Author: Tyler, Andrea
• Other Authors: Silverberg, Mark
• Language: en_ca
• Published: 2014
• Subjects: Microbiome; Inflammatory bowel disease; Genetics; ileal pouch-anal anastomosis; 0369; 0410
• Online Access: http://hdl.handle.net/1807/66295

Introduction: Inflammatory pouch complications, including pouchitis, chronic pouchitis (CP) and a Crohn’s disease-like phenotype (CDL) of the pouch following ileal pouch-anal anastomosis (IPAA), are relatively common, and arise via unknown mechanisms. The phenotypic similarities between pouch inflammation and inflammatory bowel disease (IBD) suggest there may be common pathways involved in both disorders. The aim of this thesis is to investigate the serological, genetic and microbial factors contributing to the development of pouch inflammation in a large, well characterized patient cohort. Methods: Subjects with IPAA were recruited, and clinical and demographic information was obtained through medical chart review and patient questionnaire, allowing patients to be grouped based on post-surgical phenotype. Blood and tissue was collected for genetic, serological and microbial analyses. Anti-microbial antibodies were detected using enzyme-linked immunosorbent assay (ELISA), genotyping was carried out using the Illumina Goldengate custom SNP assay and Sequenome iPLEX platform, and tissue-associated microbial communities were assessed using 454 pyrosequencing. Results: Among our cohort, smoking was associated with CDL (P=0.003) and Ashkenazi Jewish heritage with CP (P<0.008). NOD2insC (rs2066847) (P=7.4x10-5), anti-CBir1 (P<0.0001) and ASCA (IgG) (P=0.03) were significantly associated with inflammatory pouch outcomes. Additional SNPs in NOX3, DAGLB, and NCF4 were also marginally associated with pouch outcome. A multi-variable risk model combining clinical, serologic and genetic markers was constructed and could differentiate between chronic pouch inflammatory phenotypes and no pouchitis. Genus level microbial analysis demonstrated that several organisms (Bacteroides, Parabacteroides, Blautia and Moryella) were detected less frequently among the inflammatory outcome groups (P<0.05). These associations remained significant even following adjustment for antibiotic use, smoking, country of birth and gender. Conclusions: CD-associated anti-microbial antibodies and genetic markers are associated with chronic inflammatory pouch phenotypes. Additionally, changes in the composition of the pouch associated microbiome are associated with inflammation. These observations suggest that similar mechanisms may be involved in non-surgical IBD and pouchitis.