DOP70 Crohn’s Disease Like Inflammation of The Pouch is a Distinct Type of Pouchitis

Abstract

Abstract Background Pouchitis occurs in up to 80% of patients with ulcerative colitis (UC) after total proctocolectomy (TPC) with ileal pouch anal anastomosis (IPAA). The pathogenesis of pouchitis is unclear, but is thought to involve a complex interaction between the microbiome and mucosal immune system. To examine the underlying pathophysiological mechanisms of pouchitis, the present study aims to simultaneously define immuno-histological and microbial parameters associated with different pouch phenotypes. Methods Endoscopic biopsies from the pre-pouch ileum (PI) and the pouch body (PB) were obtained from 51 subjects age>18 who underwent TPC with IPAA, n=48 for UC and n=3 for familial adenomatous polyposis (FAP). Mucosal mononuclear cells (MMC) were isolated from the intra-epithelial compartment (IEC) and lamina propria (LP) and examined for lymphoid, myeloid and innate immune subsets by multiparameter flow-cytometry (FC). Histological sections were examined by two pathologists, blinded to clinical identifiers and scored for inflammatory parameters that included neutrophilic activity, lymphoplasmacytic infiltration, eosinophilia, villous atrophy and submucosal fibrosis. Metagenomic sequencing of stool was performed and analyzed for microbial beta and alpha diversity. Results IPAA subjects were classified into the following phenotypes: normal pouch (NP) n=15 (29.4%), acute pouchitis (AP) n=9 (17.6%), chronic antibiotic dependent pouchitis (CADP) n=9 (17.6%), Crohn’s disease like pouch inflammation (CDLPI) n=15 (29.4%), and FAP NP n=3 (5.9%). Among subjects with NP, the PB had a higher frequency of naïve-CD4+ and CD8+ T cells, central memory- CD4+ T cells, and naïve B cells and a lower frequency of homeostatic IELs relative to the PI (Fig. 1A). Immune remodeling of the PB was further confirmed on histology that demonstrated increased lymphoid aggregates and decreased IELs. Subjects with CDLPI had significantly higher levels of inflammation, chronicity, and lymphoid aggregates but decreased IELs in the PI than NP or AP patients (Fig. 1B and 1C). In contrast to immune parameters, the composition of the microbiota in non-inflamed UC pouches was more similar to inflamed UC pouches than to FAP pouches. Alpha diversity and genus relative abundance differences between UC and FAP pouch stool samples were not statistically significant (Fig. 1D). Conclusion CDLPI represents a distinct entity of pouchitis that is associated with heightened levels of chronic inflammation relative to AP despite similarities in microbiota.