Researchers discover a vital pathway that may serve as a potential treatment target for Crohn’s disease.
Among the list of chronic diseases, Crohn’s disease is a debilitating illness that affects over 1.6 million people in North America alone. It’s characterized by chronic inflammation within the gastrointestinal tract, with affected regions ranging from the mouth to the anus. The cause is unknown, but science believes that a mix of environmental and microbial factors may influence the origin of the disease in genetically susceptible individuals. No Crohn’s disease treatment or cure has been found yet and medical interventions largely only focus on the management of symptoms.
Recently, Cellular and Molecular Gastroenterology and Hepatology published a three-year study from Fabio Cominelli and his team that focused on a cellular pathway often expressed during chronic inflammation in Crohn’s disease patients: TWEAK and its binding receptor, Fn14.
In healthy tissues and cells, the pair are expressed at low levels. Previous studies showed their expression to be magnified only when responding to injured tissues or inflammation as a bodily defense mechanism. While their expression was proven to be beneficial during acute injuries, the persistent activation during chronic inflammation was hypothesized to actually cause more harm than protection. As the intestine is one of the most influenced tissues by TWEAK and Fn14, Cominelli focused the study around the expression of TWEAK and Fn14 in ileitis, the inflammation of the ileum of the small intestine, in hopes of finding a potential Crohn’s disease treatment.
Mice obtained from the National Institutes of Health P30 Cleveland Digestive Disease Research Core Center were genetically modified and raised with a strain called SAMP. This specific strain was chosen as it shared similar symptoms and characteristics with the human’s Crohn’s disease.
The mice were observed throughout the stages of the disease over a 30-week period. A control group of wild SAMP mice was used to compare against another group that had the Fn14 receptor genetically removed. At 10 weeks, both groups showed a similar severity in ileitis. However, at 20 to 30 weeks, the genetically removed Fn14 group showed a significant decrease in chronic ileitis when compared with its control counterpart. Moreover, the control group showed larger mesenteric lymph nodes (lymph nodes commonly affected in Crohn’s disease) when examined at death. Lastly, the Fn14 deleted group of mice produced a generation of mice with healthier intestinal structures.
The significance of these findings in the mice were then applied to human ileum tissue samples from patients with Crohn’s disease. With healthy tissues used for comparison, the researchers found that both TWEAK and Fn14 were notably upregulated during active inflammation in the disease-affected tissues. The implications of this research provide great future possibilities for targeted therapeutic Crohn’s disease treatment.
Alongside these discoveries, the deletion of Fn14 in mice without intestinal disease interestingly caused aggravation in the severity of acute colitis in the intestinal tract. This suggests that while TWEAK and Fn14 directly contribute to the consequences of Crohn’s disease, they still remain a vital defensive response to acute challenges to the body. Nonetheless, the expression of TWEAK and Fn14 are believed to be vital in targeting Crohn’s disease treatment and potentially other chronic diseases.
Written by Stephanie Tsang, BHSc
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Gogol, A. (2019, August 8). A new pathway: Researchers identify potential treatment target for Crohn’s disease. Retrieved from https://www.eurekalert.org/pub_releases/2019-08/cwru-anp080819.php
Martino, L. D., Osme, A., Kossak-Gupta, S., Pizarro, T. T., & Cominelli, F. (2019). TWEAK/Fn14 Is Overexpressed in Crohn’s Disease and Mediates Experimental Ileitis by Regulating Critical Innate and Adaptive Immune Pathways. Cellular and Molecular Gastroenterology and Hepatology. doi:10.1016/j.jcmgh.2019.05.009