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Crohn's disease recurrence after ileocolonic resection: high expression of TLR2 and TLR4 is associated to prolonged disease free interval
Imerio Angriman*1, Melania Scarpa2, Claudia Mescoli3, Andromachi Kotsafti2, Giovanni Bordignon1, Giovanni Tagliente1, Mario Gruppo1, Renata D'Inca4, Romeo Bardini1, Carlo Castoro5, Massimo Rugge3, Ignazio Castagliuolo2, Marco Scarpa5
1Surgery, University of Padova, Vicenza, Italy; 2Molecular Medicine, University of Padova, Padova, Italy; 3Dept of Medicine, University of Padova, Padova, Italy; 4Surgical, Oncological & Gastroenterological, University of Padova, Padova, Italy; 5Surgery, Veneto Istitute of Oncology, Padova, Italy
Introduction. Impaired intestinal barrier function and innate immunity are demonstrated to have a role in Crohn's disease (CD). Surgical treatment is required in about 70% of CD patients during the course of disease, but recurrence occurs in at least 35-40% often because of fibrotic stenosis of previous anastomosis. Standardized criteria to determine which patients should receive medical prophylaxis are lacking.
Aim of the study. The aim of the study is to identify inflammatory markers in the intestinal microenvironment associated to bowel fibrosis and those associated to a short recurrence interval.
Patients and methods. Thirty-five consecutive CD patients who underwent ileo-colonic resection were enrolled. Mucosal samples were obtained from both healthy and inflamed ileum. Clinical records with pre- and post-operative details were retrieved. Fibrosis grade was evaluated with a pathological score. CD68, CD163 and iNOS were evaluated with immunohistochemistry. Expression of TLR2, TLR4, TLR5, HBD1, HBD2, HBD3, HD5 and HD6 was quantified through Real-Time qPCR. Concentrations of Eotaxin-1, ICAM-1, IL-1a, IL-1b, IL-1ra, IL-12p40, IL-12p70, IL-15, IL-17, IL-23, MMP-3, SCF, VEGF were determined with immunometric assay. Clinical recurrence was defined as Harvey-Bradshaw Index (HBI)>8 (moderate-to-severe activity). Comparisons and correlations were carried out with non-parametric tests.
Results. Ileal wall fibrosis grade was directly correlated to concentrations of IL-1a (r=0,501; p=0,04), IL-1b (r=0,508; p=0,04), IL-12p40 (r=0,537, p=0,03) and VEGF (r=0,485; p=0,05). During the 29 months of follow-up, moderate-to-severe clinical postoperative recurrence occurred in 20% of patients (7/35). Recurrence-free interval directly correlated with expression of TLR2 (r=0,486; p=0,013) and TLR4 (r=0,524; p=0,008) in healthy ileum and inversely with CD163+ macrophage infiltration in healthy ileum (r=-0,356; p=0,06) and preoperative HBI (r=-0,377; p=0,07).
Conclusions. Pro-inflammatory and pro angiogenic cytokines are associated to ileal fibrosis in CD. High levels of TLR2 and TLR4 expression are associated to longer recurrence free interval while high infiltration of CD163+ macrophages (M2), involved in wound repairing and possibly fibrosis, seemed associated to a shorter recurrence free interval.
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