Crohn’s Disease (CD) is a chronic inflammatory disorder characterized by transmural and segmental lesions, which can occur in any part of the alimentary tract, even though they are more common in the terminal ileum and/or right colon. [
1] Despite recent advances in the management of CD, nearly half of the patients undergo surgery within 10 years after diagnosis, mainly due to failure of medical therapy or development of local complications, such as strictures and/or fistulae. [
2,
3] Ileocolonic end-to-end anastomoses and side-to-side anastomoses are the standard surgical treatments for most CD patients who undergo ileocecal resection. [
4] Unfortunately, however, surgery does not cure CD, and almost all the patients will experience endoscopic recurrence at the site of anastomosis, which inevitably leads to clinical exacerbation. [
5] Some demographic, lifestyle-related and clinical factors have been related to increased risk of post-operative recurrence in CD, [
6,
7] but the exact basic mechanism underlying CD recurrence remains unknown. In this context, we have recently shown that the mucosa of the neo-terminal ileum after ileocecal resection is infiltrated with immune cells secreting high levels of inflammatory T-helper (Th) type-1-related cytokines before the manifestation of endoscopic recurrence (“early CD”). [
8] A similar temporally regulated cytokine profile was seen in mouse models of colitis, where the early stage of the colonic inflammation was driven by Th1-cytokines. [
9] These findings, together with the demonstration that blockers of tumor necrosis factor alpha (TNF-α) are useful in the management of CD recurrence [
10], support the hypothesis that Th type-1-related cytokines, such as IFN-γ and TNF-α, may play a role in driving the postoperative recurrence of CD.
Although the cause of CD remains unknown, epidemiological and experimental studies support the hypothesis that CD is due to multiple environmental factors, which in genetically-predisposed individuals trigger an excessive inflammatory response directed against components of the gut microflora. [
11,
12] It has also been demonstrated that defects in counter-regulatory mechanisms contribute to amplify the ongoing mucosal inflammation. For instance, in CD, there is diminished activity of transforming growth factor (TGF)-β1, a regulatory cytokine that inhibits inflammatory signals in many immune cells. [
13] Such a defect is secondary to elevated levels of Smad7, an intracellular protein that binds to TGF-β receptor type I and inhibits TGF-β1-induced signalling. [
14‐
16] Consistently, inhibition of Smad7 with a specific antisense oligonucleotide (AS) restored TGF-β1 activity and suppressed inflammatory pathways in both in vitro and in vivo models of intestinal inflammation. Phase 1 and phase 2 studies showed that knockdown of Smad7 with a pharmaceutical compound containing the Smad7 AS induced clinical and endoscopic improvement in CD patients, [
17,
18] even though a recent phase 3 study was discontinued following a futility analysis showing no benefit in patients treated with such a drug as compared to those receiving placebo. [
19]
The functional relevance of the TGF-β1 defects in the pathogenesis of CD is also supported by studies in mice showing that lack of the cytokine activity is sufficient to promote the development of gut inflammation. [
20] Altogether, these observations raise the possibility that induction of Smad7 and consequent defective TGF-β1 activity can occur early in the sequence of molecular events that lead to tissue damage. The aim of this study was to assess whether Smad7 induction occurs early and/or late in CD.