University of California, Riverside investigators—driven by biomedical scientists—has uncovered that tofacitinib (Xeljanz) an FDA approved drug to treat rheumatoid arthritis and ulcerative colitis, can repair permeability defects in the gut’s epithelium.
The study revealed that tofacitinib has a direct effect on cells lining the gut by correcting defects that occurs in inflammation. Until now, the effects of tofacitinib on intestinal epithelial cell functions were largely unknown.
What is Tofacitinib?
The drug was approved by ulcerative colitis in 2018. The drug improved a clinical readout called mucosal healing but this was thought to be through effects on immune cells. This U.C. Riverside-led study reveals that tofacitinib improves epithelial barrier function, an essential function of epithelial cells and a requirement for mucosal healing.
Leakiness a Feature of Ulcerative Colitis & Promotes Inflammation
UC Riverside team members mentioned that intestinal permeability (Leakiness) is a feature of ulcerative colitis and plays a critical role in promoting inflammation. His team tested tofacitinib in human intestinal epithelial cell lines, as well as organoids, or colonoids, that were derived from primary human colonic stem cells isolated from human subjects—primarily patients undergoing colonoscopy for colon cancer screening—and found tofacitinib repaired inflammation-induced permeability defects in both.
What is the epithelium and why does it matter?
A thin layer that lines the alimentary canal, the gastrointestinal epithelium is made up of cells that have gaps between them, making them selectively permeable and offering a barrier that blocks pathogens, toxins, and antigens from entering the gut while also allowing for absorption of nutrients. In ulcerative colitis, this epithelial permeability becomes leaky, hence enabling bacteria products to cross into the gut and nutrients and water to leak out. Consequently, this triggers immune responses, which results in fluid loss and diarrhea.
What does the Drug do to Stop this?
The researchers found that the drug actually fixes the leakiness in the intestinal layer, reported Declan McCole of UC Riverside. He continued, “Specifically it fixes intestinal epithelial permeability defects caused by ‘interferon-gamma’, an inflammatory cytokine involved in autoimmune diseases such as ulcerative colitis and rheumatoid arthritis.”
The team plans on identifying specific patients who may derive the greatest benefit from the drug. This will offer more targeted treatment of patients likely to be good responders to tofacitinib in a “personalized medicine” approach to treating disease.
This research was funded by the National institute of Diabetes and Digestive and Kidney Diseases of the NIH as well as Pfizer, the makers of tofacitinib.
Declan McCole, Professor Biomedical Sciences, UC Riverside