Etiopathogenesis of inflammatory bowel diseases

Background Intestinal fibrosis resulting in stricture formation and obstruction in Crohn’s disease (CD) and increased wall stiffness leading to symptoms in ulcerative colitis (UC) is among the largest unmet needs in inflammatory bowel disease (IBD). Fibrosis is caused by a multifactorial and complex process involving immune and non-immune cells, their soluble mediators and exposure to luminal contents, such as microbiota and environmental factors. To date, no antifibrotic therapy is available. Some progress has been made in creating consensus definitions and measurements to quantify stricture morphology for clinical practice and trials, but approaches to determine the degree of fibrosis within a stricture are still lacking. Objective We herein describe the current state of stricture pathogenesis, measuring tools and clinical trial endpoints development. Design Data presented and discussed in this review derive from the past and recent literature and the authors’ own research and experience. Results and conclusions Significant progress has been made in better understanding the pathogenesis of fibrosis, but additional studies and preclinical developments are needed to define specific therapeutic targets.

Background and aims: Crohn’s disease is a life-long form of inflammatory bowel disease (IBD) mediated by mucosal immune abnormalities. Understanding of the pathogenesis is limited because it is based on data from adults with chronic Crohn’s disease. We investigated mucosal T-cell immunoregulatory events in children with early Crohn’s disease. Methods: Mucosal biopsies and T-cell clones were derived from children experiencing the first attack of Crohn’s disease, children with long-standing Crohn’s disease, infectious colitis, and children without gut inflammation. Results: As in acute infectious colitis, interleukin (IL) 12 induced T cells from early Crohn’s disease to acquire a strongly polarised T helper (Th) type 1 response characterised by high IFN-γ production and IL12Rβ2 chain expression. Th1 polarisation was not induced in clones from late Crohn’s disease. Mucosal levels of IL12p40 and IL12Rβ2 messenger RNA were significantly higher in children with early than late Crohn’s disease. These results demonstrate that susceptibility to IL12-mediated modulation is strongly dependent on the stage of Crohn’s disease. Conclusions: At the onset of Crohn’s disease mucosal T cells appear to mount a typical Th1 response that resembles an acute infectious process, and is lost with progression to late Crohn’s disease. This suggests that mucosal T-cell immunoregulation varies with the course of human IBD. Patients with the initial manifestations of IBD may represent an ideal population in which immunomodulation may have optimal therapeutic efficacy.

Fibrosis is a serious condition complicating chronic inflammatory processes affecting the intestinal tract. Advances in this field that rely on human studies have been slow and seriously restricted by practical and logistic reasons. As a consequence, well-characterized animal models of intestinal fibrosis have emerged as logical and essential systems to better define and understand the pathophysiology of fibrosis. In point of fact, animal models allow the execution of mechanistic studies as well as the implementation of clinical trials with novel, pathophysiology-based therapeutic approaches. This review provides an overview of the currently available animal models of intestinal fibrosis, taking into consideration the methods of induction, key characteristics of each model, and underlying mechanisms. Currently available models will be classified into seven categories: spontaneous, gene-targeted, chemical-, immune-, bacteria-, and radiation-induced as well as postoperative fibrosis. Each model will be discussed in regard to its potential to create research opportunities to gain insights into the mechanisms of intestinal fibrosis and stricture formation and assist in the development of effective and specific antifibrotic therapies.