Recent insights into the molecular pathogenesis of Crohn's disease: a review of emerging therapeutic targets

Abstract

Chronic inflammatory bowel diseases (IBDs) are a subject of great interest in gastroenterology, due to a pathological mechanism that is difficult to explain and an optimal therapeutic approach still undiscovered. Crohn’s disease (CD) is one of the main entities in IBD, characterized by clinical polymorphism and great variability in the treatment response. Modern theories on the pathogenesis of CD have proven that gut microbiome and environmental factors lead to an abnormal immune response in a genetically predisposed patient. Genome-wide association studies in patients with CD worldwide revealed several genetic mutations that increase the risk of IBD and that predispose to a more severe course of disease. Gut microbiota is considered a compulsory and an essential part in the pathogenesis of CD. Intestinal dysmicrobism with excessive amounts of different bacterial strains can be found in all patients with IBD. The discovery of Escherichia coli entero-invasive on resection pieces in patients with CD now increases the likelihood of antimicrobial or vaccine-type treatments. Recent studies targeting intestinal immunology and its molecular activation pathways provide new possibilities for therapeutics. In addition to antitumor necrosis factor molecules, which were a breakthrough in IBD, improving mucosal healing and resection-free survival rate, other classes of therapeutic agents come to focus. Leukocyte adhesion inhibitors block the leukocyte homing mechanism and prevent cellular immune response. In addition to anti-integrin antibodies, chemokine receptor antagonists and SMAD7 antisense oligonucleotides have shown encouraging results in clinical trials. Micro-RNAs have demonstrated their role as disease biomarkers but it could also become useful for the treatment of IBD. Moreover, cellular therapy is another therapeutic approach under development, aimed for severe refractory CD. Other experimental treatments include intravenous immunoglobulins, exclusive enteral nutrition, and granulocyte colony-stimulating factors.

Role ofPTPN2/22polymorphisms in pathophysiology of Crohn’s disease

“…Thus, understanding the key elements of CD pathogenesis (genetic SNPs and environmental triggers), it is possible to find new treatment targets for the disease and new diagnosis techniques as well. CD pathogenesis is very dependent on the overproduction of pro-inflammatory cytokines such as TNF-α and IFN-γ, which promote chronic inflammation, increased granuloma formation, and increased apoptosis of intestinal tissues[ 8 , 9 , 20 , 21 ]. Since the majority of CD medications are blocking pro-inflammatory cytokines such as TNF-α and IFN-γ, other types of targets has been ignored[ 6 - 10 , 20 , 21 ].…”

Enteric Neuronal Regulation of Intestinal Inflammation

“…Most earlier investigations of IBD, whether of pathogenesis or therapy, have, understandably, concentrated on innate and adaptive immunity [110]. The neuronal component has not yet been exploited for insight into causation, contributions to severity, or especially to therapy.…”

Differential Intestinal Mucosa Transcriptomic Biomarkers for Crohn’s Disease and Ulcerative Colitis

“…These are chronic diseases characterized by a relapsing remitting course with an increasingly high incidence and prevalence worldwide [ 1 ]. The current accepted model for IBD etiology implies the existence of a genetic predisposition, perturbations in the intestinal barrier components, and altered microbiota, which combined will lead to an aberrant immune response [ 2 ]. Distinguishing between the two diseases represents a problem in clinical practice due to some similarities in endoscopic and morphological aspects which in turn will lead to a change in diagnosis throughout the course of disease [ 3 ].…”