Innate Immune Environment in Ileal Pouch Mucosa: α-5 Defensin up-Regulation As Predictor of Chronic/Relapsing Pouchitis
Marco Scarpa*1, Alessia R. Grillo2, Melania Scarpa2, Paola Brun2, Carlo Castoro1, Anna Pozza3, Diego Faggian4, Cesare Ruffolo5, Renata D'Incà3, Romeo Bardini3, Ignazio Castagliuolo2, Imerio Angriman3
1Department of Oncological Surgery, Venetian Oncology Institute (IOV-IRCCS), Padova, Italy; 2Dept. of Histology, Microbiology and Medical Biotechnologies, University of Padova, Padova, Italy; 3Dept. of Surgical and Gastroenterological Sciences, University of Padova, Padova, Italy; 4Dept. of Diagnostic Sciences and Special Therapy, University of Padova, Padova, Italy; 5Dept. of Surgery (Chirurgia IV), Ospedale “Ca’ Foncello”, Treviso, Italy
Background Defensins are small cationic peptides with antibacterial activity expressed only in Paneth cells (α-defensins) or generally in intestinal epithelial cells (β-defensins) that have a profound effect on gut microbiota. We have recently shown that chronic pouchitis, that occurs in 5% of patients after restorative proctocolectomy and can cause pouch failure, is associated to a significant increase Clostridiaceae spp. The aim of this study was to gain further insight in the pathogenesis of chronic/relapsing pouchitis by exploring the interplay between the microbiota adherent to the ileal pouch mucosa and defensin expression. Patients and methods Thirty-two consecutive patients coming for follow up endoscopy, were recruited. On pouch biopsies we determined bacteria adherent to the mucosa, by culture method, and mRNA for α-and β-defensins and Toll Like Receptor-4 and -2, by quantitative Real Time RT-PCR. Serum and mucosal levels of IL-1β, IL-6 and TNF-α were measured with immunometric assays. Faecal lactoferrin was analyzed by quantitative ELISA. After a median follow up of 23 (IQR 20-24) months the patients were contacted for a reassessment of current and past disease activity. Results During the follow up chronic/relapsing pouchitis was diagnosed in 6 patients. Mucosal level of α-5 and α-6 defensins correlated with chronic/relapsing pouchitis onset (tau=0.30, p=0.034 and tau=0.28, p=0.053, respectively). High levels of α-5 defensin resulted predictive of chronic/relapsing pouchitis [AUC=74%(95% CI=53-89%), p=0.052]. Patients with high level of α-5 and α-6 defensins had earlier pouchitis relapses (p=0.009 and p=0.034, respectively). High levels of α-5 defensin were associated to a significant risk of chronic/relapsing pouchitis [OR=10.6(95% CI=1.2-97.6), p=0.027]. At multivariate analysis mucosal levels of α-5 defensin and the number of CFU of mucosa-associated Clostridiaceae spp resulted to be independent predictors of chronic/relapsing pouchitis [tau=0.46(0.18), p=0.024 and tau=0.44(0.18), p=0.027, respectively].Conclusion Chronic/relapsing pouchitis is associated to increased expression of mucosal α-5 defensin. High levels of α-5 defensin may be the response to challenge of Clostridiaceae spp antigens or, alternatively they may favour Clostridiaceae spp decreasing other competing bacteria familiae.
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