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

By Emma Yasinski and Madeline McCurry-Schmidt

chen-sundrud
The study was led by TSRI Graduate Student Mei Lan Chen and biologist Mark Sundrud (photo by Jeremy Pyle / The Scripps Research Institute)

Researchers on the Florida campus of The Scripps Research Institute (TSRI) are studying how immune cells adapt as they enter different tissues—with the goal of spurring the design of better, more specific medicines.

“We need therapeutic strategies that specifically target chronic inflammation in the gut, skin or other tissues,” says Mark Sundrud, PhD, a TSRI biologist, “instead of just generally suppressing the entire immune system.”

Now, Sundrud’s team has published a new study in the journal Immunity, showing how a subset of circulating immune cells, called TH17 cells, adapt when they enter different tissues. Importantly, the researchers found that an inability to adapt may lead to Crohn's disease.

When cells can’t adapt, disease follows

TH17 cells protect many types of tissues from infection, but they can also promote chronic inflammatory conditions like Crohn’s disease, which specifically targets the intestinal tract. The the contrasting roles of TH17 cells led Sundrud’s team to wonder if these cells might use different tools to behave normally in one tissue than they’d use in another. Perhaps activating one gene could be useful in the lungs, while activating another would be useful in the gut.

This study built on previous research from the Sundrud Lab, which showed that when TH17 cells entered the intestine in human tissue samples, they increased the expression of a gene called MDR1. But MDR1 is only known to transport chemotherapeutic drugs out of tumor cells, so why would it be expressed in immune cells in the gut?

The new study suggests that MDR1 is responsible for protecting TH17 cells in the gut from bile acids—detergent-like molecules produced by the liver that break down fats. Normally, the liver secretes bile acids after we eat to aid digestion. As food moves through the digestive tract, these acids are reabsorbed when they reach the ileum—the final portion of the small intestine—and the site of ileal Crohn’s disease, the most common form of Crohn’s.

“T cells only see high levels of bile acids in the ileum. They know this, and they adapt once they get there,” says Sundrud.

This discovery led the researchers to identify a mechanism where ileal Crohn's disease appears to be induced by bile acids when T cell adaptation does not occur the way it should.

The team used a genetically modified mouse model to observe the expression and function of MDR1 in mice. They found that the gene’s expression increased when the cells entered the ileum. But, in mice where the gene couldn’t be activated in the gut, TH17 cells that were exposed to bile acids suffered severe oxidative stress. This stress caused the TH17 cells to become overactive, leading to Crohn’s disease-like intestinal inflammation in mice.

Using bile acid sequestrants, an FDA-approved class of drugs used in transplant patients that absorb bile acids like a sponge, scientists were able to restore normal T cell function in the ileum and attenuate Crohn’s disease in mice.

To establish the relevance of their findings, the team tested blood samples from healthy humans, as well as those with a variety of inflammatory bowel diseases, including Crohn’s. They found a subset of patients with ileal Crohn’s disease had severely impaired MDR1 expression.

Not only does this suggest that the cause of Crohn’s disease in these patients may be oxidative stress due to dysfunctional MDR1, but that for the subset of patients with this dysfunction, bile acid sequestrants may be an effective treatment. Together with his collaborators, Sundrud hopes to fund a clinical study to test exactly that.

In addition to Sundrud, co-authors of the study, "The Xenobiotic Transporter Mdr1 Enforces T Cell Homeostasis in the Presence of Intestinal Bile Acids," 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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