Tofacitinib Found to Repair Permeability Defects in the Gut for Patients with Ulcerative Colitis

Tofacitinib (Xeljanz, Pfizer), an FDA-approved treatment for rheumatoid arthritis (RA) and ulcerative colitis (UC), can repair permeability defects in the gut’s epithelium, according to researchers at the University of California—Riverside.

The study is the first to show that tofacitinib has a direct effect on cells lining the gut by correcting defects that occur in inflammation. Until now, the effects of tofacitinib on intestinal epithelial cell functions were largely unknown.

Increased intestinal permeability, or leakiness, is a feature of UC and promotes inflammation. The study authors tested tofacitinib in human intestinal epithelial cell lines, as well as in organoid, or colonoids, derived from primary human colonic stem cells isolated from patients undergoing elective colonscopy for colon cancer screening. Tofacitinib repaired inflammation-induced permeability defects in both, according to the study.

The epithelium is a thin layer that lines the alimentary canal and is comprised of cells that have gaps between them, making them selectively permeable and providing a barrier that keeps out pathogens. In UC, this epithelial permeability becomes leaky, allowing bacterial products to cross into the gut and nutrients and water to leak out.

By targeting specific molecules, the drug inhibits a pathway that is activated by inflammation, according to the study authors.

UC is a chronic inflammatory bowel disease of the large intestine in which the lining of the colon becomes inflamed and leaky. It affects approximately 1 million Americans. RA, which affects approximately 2 million Americans, is an autoimmune disease in which the body’s immune system attacks the joints, according to the press release.

Another major focus of the research team is PTPN2, a protein-coding gene associated with autoimmune diseases such as Crohn disease, UC, and RA. Individuals with mutations in this gene that cause it to lose function have an increased risk of having these diseases. The study authors were the first to identify that PTPN2 normally helps to protect the barrier function of the epithelial cells that line the gut.

Tofacitinib was used as a way of correcting the defects that occur from the loss-of-function mutations of PTPN2 without having to introduce new genes into a cell or patient.

The study authors plan to identify specific patients who may gain the greatest benefit from the drug, allowing more targeted treatment of patients with UC.

Reference

Drug Decreases Gut Leakiness Associated with Ulcerative Colitis [press release]. UC Riverside website. Published December 4, 2019. https://news.ucr.edu/articles/2019/12/04/drug-decreases-gut-leakiness-associated-ulcerative-colitis. Accessed January 13, 2020.