Dysfunctional gene may be culprit in some Crohn’s disease cases

A study from the lab of biologist Mark Sundrud, Ph.D., on the Florida campus of The Scripps Research Institute (TSRI), has shown that genetics plays a role for some people with Crohn’s disease, a potentially powerful discovery for people with a specific mutation. An inexpensive and effective treatment may already be readily available for them, Sundrud said.

Additional trials in the clinic are planned to help refine who can benefit, and develop a diagnostic test that could enable some Crohn’s patients to forego costlier, less effective treatments like steroids, Sundrud said.

“Our data suggests this could be life-changing for a group of Crohn’s patients,” Sundrud said. “People with severe, chronic Crohn’s who are not helped by current medications could benefit.”

Crohn’s disease involves inflammation of the digestive tract. It can become so severe that patients can develop malnutrition, weight loss and fatigue from the severe diarrhea and pain. Difficult and even life-threatening complications such as bowel obstructions, colon cancer, blood infections, or sepsis can develop. A common treatment, corticosteroids by pill or IV, can cause serious side-effects such as weight gain, osteoporosis, unstable blood sugar and other problems. Approximately 360,000 people in the United States suffer from Crohn’s disease, causing nearly 190,000 hospitalizations annually, according to the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health.

A subset of those patients has a type that involves an inability to reabsorb excess digestive fluids in the ileum, or the last section of the small intestine, Sundrud said. The imbalance can lead to intestinal injury and pain—sometimes severe. The culprit is a digestive acid called bile. Made in the liver, it seeps into the gut during consumption of a big meal. Bile helps with the digestion of fats, releasing important nutrients into the body.

Bile is chemically similar to detergent, however, so too much can lead to inflammation and potentially injure the intestinal lining. Some probiotics have been shown to help a bit with maintaining the appropriate amount of digestive fluids, but it wasn’t known if genetic factors played a role, too, Sundrud said.

Sundrud’s team discovered that a type of circulating immune system cell called a T helper cell 17, or TH17, can play an important role in digestion. When those circulating cells reach the end part of the small intestine, if they encounter too much bile, they adapt by switching on production of a gene called MDR1, Sundrud said. That was a surprise. Previously, MDR1 was known to transport chemotherapeutic drugs out of tumor cells, he said, but its role in aiding digestion wasn’t understood. Sundrud and his team found that if the MDR1 gene is not present in those circulating immune cells, or is mutated in a way that makes it ineffective, bile acids can accumulate in the ilium and injure the intestine. The research was published Dec. 19, 2017, in the journal Immunity.

“About 10 percent of patients with Crohn’s disease have disease that is driven by bile reabsorption issues,” Sundrud said.

Sundrud is hoping to attract funding for a clinical study to take the work further. Sundrud and his graduate student, Mei Lan Chen, are continuing to study how TH17 cells adapt within the body. And working with a team of clinicians at the University of Miami, he hopes to recruit Crohn’s patients to discern the healthy vs. disease-promoting range for MDR1 mutations, potentially giving doctors more options to help Crohn’s patients.

 “You can efficiently prevent this with a type of medication called a bile acid sequestrant. It’s a packet of powder that goes on food,” Sundrud said. “This could be much a less expensive therapy for those patients than other alternatives.”

In addition to Sundrud,  co-authors of the study were Wei Cao, Mei Lan Chen, Amber Delmas, Erumbi S. Rangarajan, Kelly McKevitt, Cody B. Jackson, Tina Izard and Gogce Crynen, all of The Scripps Research Institute; Hisako Kayama and Kyoshi Takeda of Osaka University; Amy Sun, Sergei B. Koralov and Sang Yong Kim of New York University Medical Center; Amanda P. Beck of MD Anderson Cancer Center; Angelos Oikonomopoulos, Precious N. Lacey and Daniel W. Hommes of University of California, Los Angeles; Gustavo Martinez of Rosalind Franklin University of Medicine and Science; Robin G. Lorenz of University of Alabama; Alex Rodriguez-Palacios and Fabio Cominelli of Case Western Reserve University; and Mari T. Abreu of the University of Miami.

This work was funded by TSRI Florida via the State of Florida, the National Institute of Allergy and Infectious Diseases (grant R21AI119728.), the National Institute of Diabetes and Digestive and Kidney Diseases (5R01DK099076-07 andP01DK071176), the Crohn’s and Colitis Foundation of America (#422515, #3786 and #26971), the Broad Medical Foundation (#IBD-0389R), and the Core Research for Evolutional Science and Technology, Japan Science and Technology Agency; the Ministry of Education, Culture, Sports, Science and Technology; and the Ministry of Health, Labour and Welfare, a Lotte Research Promotion Grant and the Nagao Memorial Fund.

Mari T. Abreu and Daniel W. Hommes have received research grants and consultancy fees from: AbbVie, Amgen, Asana Medical, Inc., Ferring Pharmaceuticals, Focus Medical Communications, Genentech, Genova Diagnostics, GI Health Foundation, Gilead, GSK Holding Americas, Inc., Hospira, Inc., Janssen, Mucosal Health Board, Pfizer, Prometheus Laboratories, Prova Education, Inc., Sanofi Aventis, Shire, Takeda, UCB and WebMD Health. 

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