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Novel Gene Discoveries Could Mean the End of IBD

Immunosuppressants are standard treatment for inflammatory bowel disease (IBD) but they’re only effective in 30% to 50% of patients, with just 20% of patients achieving remission. That’s why Luis Sifuentes-Dominguez, M.D., and his colleagues at Children’s Health℠ and UT Southwestern are working to identify new genes and pathways that contribute to IBD and may ultimately lead to development of novel therapeutic agents.

Dr. Sifuentes-Dominguez’s team recently published a study that identified a gene mutation that drives ulcerative colitis, and was also the first research to implicate neuroendocrine cells as potential mediators of chronic intestinal inflammation. In a separate study, the researchers identified a genetic change associated with early-onset Crohn’s disease that impacted a specific anti-inflammatory pathway that could be targeted by the drug tofacitinib.

“We’re working to identify and understand genetic factors that may explain chronic intestinal inflammation,” says Dr. Sifuentes-Dominguez, a gastroenterologist at Children’s Health and Assistant Professor at UT Southwestern Medical Center. “That could open the door to novel therapies that stop IBD or lessen its effects, with potentially fewer side effects and risks than long-term immunosuppression.”

A New Mechanism of Intestinal Inflammation


Gastroenterologists at Children’s Health and UT Southwestern collectively follow approximately 3,000 people with IBD, including around 600 pediatric patients.

“We follow a large, ethnically diverse IBD patient population, which increases our opportunity to identify patients whose disease likely has a strong genetic component,” Dr. Sifuentes-Dominguez says. “That includes patients who have multiple family members with IBD, and children who are diagnosed with it before 6 years of age.”

In an October 2019 study published in eLife, Dr. Sifuentes-Dominguez and his colleagues conducted whole exome sequencing on a family where three siblings were diagnosed with early-onset ulcerative colitis, while two other siblings were unaffected. The researchers identified that the affected siblings share a rare mutation in the SCGN gene. This mutation leads to loss of function of SCGN.

“We used cell and mouse models to show that, when you lose the protein altogether or have the mutation that these patients have, it leads to an inability to appropriately secrete hormones from enteroendocrine cells in the intestine,” Dr. Sifuentes-Dominguez says.

The researchers also demonstrated that SCGN-deficient mice have increased susceptibility to chemical induced models of intestinal inflammation.

 “Everything validated our initial suspicion,” Dr. Sifuentes-Dominguez says. “The mutation leads to poor hormone secretion caused by abnormal migration of certain proteins to the cell surface membrane, which leads to disease.”

Because SCGN is only found in neuroendocrine cells, the researchers suspect that abnormalities in these cells may drive IBD and potentially other diseases.

“It’s possible that many immune, environmental and/or dietary pathways that lead to disease are mediated or controlled by these cells,” says Ashish Patel, MD, who coauthored the study, “and it might be possible to mitigate disease by creating therapies that modulate these cells, as an alternative to blanket immune suppression.”

Dr. Patel is the founder and Director of the Southwestern IBD Program at Children’s Health and is an associate professor at UT Southwestern.

Mosaic Tetrasomy 9P Associated With IBD

Dr. Sifuentes-Dominguez led a separate study, published in the Journal of Crohn’s and Colitis, that centered on a patient who underwent clinical genetic testing after suffering symptoms similar to Crohn’s disease. The research team identified that the patient had four copies of the short arm of chromosome 9 instead of two.

This region harbors the type 1 interferon gene cluster, and the researchers found that the type 1 interferon pathway is significantly overactive in this patient. Dr. Sifuentes-Dominguez and his colleagues also evaluated intestinal tissue samples from the patient. They were able to prove that the phenomena replicated at the intestinal level. They did so by finding substantial elevation of type 1 interferon-related genes compared to samples from healthy controls.

“This is particularly exciting because there is a new medication, tofacitinib, that targets this pathway,” Dr. Sifuentes-Dominguez says. “Our research validates the idea that this medication could be potentially effective in patients with IBD.”

Pursuing Next-Generation Diagnostics and Treatments

This research brings the field one step closer to a new generation of IBD diagnostics and treatments that can be far more personalized than ever before.

“We’re getting closer to the day when we routinely use genetic testing to identify what’s causing a patient’s intestinal inflammation, and then match patients with treatments that target that specific cause,” Dr. Sifuentes-Dominguez says.

This cutting-edge research is part of Children’s Health’s and UT Southwestern’s collaborative push to provide excellent gastroenterology care and innovations in diagnostics, treatment and care. Children’s Health delivers GI care and surgery to more than 24,000 patients a year—making us one of the nation’s busiest pediatric GI programs. This GI expertise, combined with our push to improve care through research, landed us a no. 10 U.S. News & World Report ranking in 2019-20.