Innate Immunity Activation in Newly Diagnosed Ileocolonic Crohn's Disease: A Cohort Study

Background: Recent studies showed that early surgery for Crohn's disease leads to a lower recurrence rate. However, the underlying mechanism is unknown. Objective: The study aims to analyze the innate immunity microenvironment in ileal mucosa according to Crohn's disease duration. Design: A prospective cohort study. Settings: Tertiary referral center for IBD surgery. Patients: A total of 88 consecutive Crohn's disease patients undergoing ileocolonic resection were prospectively enrolled. Mucosal samples were obtained from both healthy and inflamed ileum. Data from a public dataset were analyzed as an external validation cohort. Main outcome measures: Neutrophil infiltration was evaluated at histology and macrophage subpopulation at immunohistochemistry. Expression of TLR2, TLR4, TLR5, DEFB1, DEFB4A, DEFB103, DEFA5 and DEFA6 was quantified by Real-Time qPCR. Concentrations of BDNF, CCL11, ICAM1, IL1A, IL1B, IL1RN, IL12 p40, IL12 p70, IL15, IL17A, IL23A, MMP3, CCL3, KITLG, VEGFA were determined with immunometric assay. Results: Neutrophil infiltration is inversely correlated with disease duration. DEFB4A mRNA expression tended to be higher in late-stage Crohn's disease (p = 0.07). A higher number of macrophages expressed CD163 at low intensity in the late stage (p = 0.04). The concentration of IL15 (p = 0.02) and IL23A (p = 0.05) was higher in healthy ileal mucosa of early-stage patients. In the external cohort, expression of DEFB1 (p = 0.03) and DEFB4A (p = 0.01), IL2 (p = 0.04), and IL3 (p = 0.03) increased in late-stage patients. Limitations: A relatively small number of patients, especially in the newly diagnosed group. Conclusions: In newly diagnosed Crohn's disease, high levels of IL-15 and IL-23 in healthy mucosa suggest that innate immunity is the starter of acute inflammation. Moreover, M2 macrophages increase in healthy mucosa of late-stage Crohn's disease patients suggesting that reparative and profibrotic processes are predominant in the long term and in this phase, anti-inflammatory therapy may be less efficient. See Video Abstract.