Affecting roughly 1 million Americans, ulcerative colitis is a chronic inflammatory bowel disease in which the lining of the colon (mucosa) becomes inflamed and leaky. Rheumatoid arthritis is an autoimmune disease in which the body’s immune system attacks the joints. Roughly 2 millions of american people, instead, is affected by the condition. In each case a severe impairment of the quality of life of the affected subjects is everealy impaired and it reflects on the psychological and social sides. A research team led by biomedical scientists at the University of California, Riverside, has found that a drug approved by the FDA to treat rheumatoid arthritis and ulcerative colitis can repair permeability defects in the gut’s epithelium. The study is the first to show the drug, tofacitinib, also called Xeljanz, has a direct effect on cells lining the gut by correcting defects that occur in inflammation. The epithelium is a thin layer that lines the alimentary canal. The gastrointestinal epithelium is comprised of cells that have gaps between them, making them selectively permeable and providing a barrier that keeps out pathogens, toxins, and antigens from entering the gut, while allowing the absorption of nutrients. In ulcerative colitis, this epithelial permeability becomes leaky, allowing bacterial products to cross into the gut and nutrients and water to leak out. This, in turn, triggers immune responses, resulting in fluid loss and diarrhea.
Until now, the effects of tofacitinib on intestinal epithelial cell functions were largely unknown. Increased intestinal permeability — or leakiness — is a feature of ulcerative colitis and plays a critical role in promoting inflammation. The team tested tofacitinib in human intestinal epithelial cell lines, as well as in organoids, or colonoids, that were derived from primary human colonic stem cells isolated from human subjects — primarily patients undergoing elective colonoscopy for colon cancer screening — and found tofacitinib repaired inflammation-induced permeability defects in both. Declan McCole, a professor of Biomedical sciences at the UCR School of Medicine, explained the reseach: “We found tofacitinib fixes the leakiness in the intestinal barrier. 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. Our work increases our understanding of how this drug is useful for treating ulcerative colitis. We now better understand where in the gut the drug is working, and how. By targeting specific molecules, the drug inhibits a pathway that is activated by inflammation. Our study shows tofacitinib is not just acting on immune cells, as was first thought, but can have a direct effect on the epithelial cells that are the key factor in maintaining gut barrier function.”
A major focus of McCole’s lab topic is PTPN2, a protein-coding gene associated with autoimmune diseases such as rheumatoid arthritis, Crohn’s disease and ulcerative colitis. Individuals with mutations in this gene that cause it to lose function have an increased risk of getting these diseases. The gene econdes a protein phosphatase that deactivates protein kinases involved in cell growth and replication, celluar differentiation and oncogenic transformation. Epidermal growth factor receptor (EGFR) and the adaptor protein Shc p66 were reported to be substrates of this enzyme, which suggested his role in growth factor-mediated cell signaling. EGFR indeed control mucosal cel proliferation and repair. McCole’s research group was the first to identify PTPN2 normally helps to protect the barrier function of the epithelial cells that line the gut. A patient that has a PTPN2 loss-of-function mutation is predicted to have a leakier gut. Rather than trying to repair PTPN2, were successful in inhibiting some of the consequences of the loss-of-function mutation in this gene. Indeed PTPN2 deactivates the same signaling pathway as tofacitinib and the researchers thought tofacitinib might be a very effective way of correcting the defects that occur from the loss-of-function mutations of PTPN2 without having to introduce new genes into a cell, animal or patient.
Next, the researchers plan to identify specific patients who may derive the greatest benefit from the drug. This will allow more targeted treatment of patients likely to be good responders to tofacitinib in a “personalized medicine” approach to treating this disease.
- Edited by Dr. Gianfrancesco Cormaci, PhD; specialist in Clinical Biochemistry.
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