New research may have solved a mystery surrounding Crohn’s disease, a type of inflammatory bowel disease in which the immune system is designed to attack invading microbes and mistakenly targets the body’s digestive tract instead. Norovirus is a common infection that causes vomiting and diarrhea. It’s also one of several viruses and bacteria thought to trigger the onset of the disease in people with Crohn’s disease, but the field doesn’t know why.
Norovirus is a highly contagious virus that causes vomiting and diarrhea. Anyone can contract and become ill with norovirus, and outbreaks are common. You may hear norovirus disease referred to as “food poisoning,” “stomach bug,” or “stomach flu.” Although norovirus is the leading cause of foodborne illness, other germs and chemicals can also cause foodborne illness.
A clue emerged when previous studies found that a specific genetic change (mutation) is present in most people with the condition. This genetic mutation makes gut lining cells more susceptible to damage. But the mystery deepened again when it was revealed that half of all Americans carry the same risk-causing genetic mutation, but fewer than half a million will develop Crohn’s disease.
Published in the magazine on October 5, 2022 Nature, new research using mice and human tissue revealed for the first time that in healthy individuals, immune defenders called T cells secrete a protein called apoptosis inhibitor 5 (API5), which signals the immune system to stop attacking gut lining cells. This protein adds an extra layer of protection against immune damage, allowing even those with the mutation to have healthy guts. However, the scientists also discovered that norovirus infection blocked T-cell secretion of API5 in mice bred with a rodent form of Crohn’s disease, killing gut lining cells in the process.
Led by scientists at NYU Grossman School of Medicine, the research supports the theory that API5 protects most people with the mutation from the disease until a second trigger, such as norovirus infection, pushes some past the disease threshold.
In experiments that focused on mice genetically modified to have the mutation associated with human Crohn’s disease, mice injected with API5 survived, while half of the untreated group died. This confirmed the hypothesis that the protein protects gut cells, the study authors say. In human tissue, the researchers found that people with Crohn’s disease had between 5 and 10 times fewer API5-producing T cells in their gut tissue than people without the disease.
“The results of our research help explain why the genetic links to Crohn’s disease are much broader than the actual number of people who have the disease.” Shhei Koide, PhD
“Our results provide new insights into the key role played by apoptosis inhibitor 5 in Crohn’s disease,” said Yu Matsuzawa-Ishimoto, MD, PhD, study lead author and gastroenterologist. “This molecule could represent a new target for the treatment of this chronic autoimmune disease that has proven difficult in the long term.”
according to dr Matsuzawa-Ishimoto, a postdoctoral researcher at NYU Langone Health, current therapies that suppress the immune system put patients at high risk of infection and often lose effectiveness after a few years of use. A treatment method that targets API5, he adds, could avert these problems.
In another set of experiments, the researchers created organ-like structures from tissue collected from people who tested positive for the mutation. Remarkably, these structures consisted only of the cells lining the gut. Then the research team dropped API5 into these “mini-guts” and found that this treatment protected the cells lining the gut. In addition, the addition of API5-producing T cells also protected the intestinal mucosa.
“Our study suggests that when norovirus infects those with a compromised ability to produce the apoptosis inhibitor 5, it tips the balance toward full-blown autoimmune disease.” Ken H. Cadwell, PhD
“The results of our research help explain why the genetic links to Crohn’s disease are much broader than the actual number of people who have the disease,” says Shohei Koide, PhD, study co-author and biochemist. dr Koide is a professor in the Department of Biochemistry and Molecular Pharmacology and a member of the Perlmutter Cancer Center at NYU Langone.
“Our study suggests that when norovirus infects those with a compromised ability to produce the apoptosis inhibitor 5, it tips the balance toward full-blown autoimmune disease,” adds Ken H. Cadwell, study co-author and microbiologist, PhD , the Recanati family added a professor of microbiology at NYU Langone.
dr Cadwell notes that while the study authors obtained the API5 protein from human tissue and not rodents, it remains unclear whether the injection treatment can be safely administered in humans.
Next, the research team plans to study the long-term effects of API5 injections to better understand whether prospective treatment can effectively treat Crohn’s disease, which can flare up repeatedly over a long period of time.
Reference: “The γδ-IEL Effector API5 Masks Genetic Vulnerability to Paneth Cell Death” By Yu Matsuzawa-Ishimoto, Xiaomin Yao, Akiko Koide, Beatrix M. Ueberheide, Jordan E. Axelrad, Bernardo S. Reis, Roham Parsa, Jessica A Neil , Joseph C Devlin, Eugene Rudensky, M Zahidunnabi Dewan, Michael Cammer, Richard S Blumberg, Yi Ding, Kelly V Ruggles, Daniel Mucida, Shohei Koide and Ken Cadwell 5 October 2022, Nature.
In addition to Dr. Matsuzawa-Ishimoto, Dr. Koide and Dr. Cadwell were other NYU investigators involved in the study Langone Xiaomin Yao, PhD; Akiko Koide, PhD; Beatrix M. Überheide, PhD; Jordan E. Axelrad, MD, MPH; Jessica Neil, PhD; Joseph Devlin, PhD; Eugene Rudensky, PhD; M Zahidunnabi Dewan, PhD; Michael Cammer, PhD; Kelly V Ruggles, PhD; and Daniel Mucida, PhD. Other study researchers were Bernardo Reis, PhD, and Roham Parsa, PhD, at Rockefeller University in New York City; Richard Blumberg, PhD, at Harvard Medical School in Boston; and Yi Ding, PhD, at Geisinger Health in Danville, Pennsylvania.
Funding for the study was provided by National Institutes of Health grants R0IL123340, R0IDK093668, R0IAI140754, R0IAI121244, R0IAI130945, R0IDK124336, and R0IDK088199. Additional funding was provided by the Howard Hughes Medical Institute, the Kenneth Rainin Foundation, the Crohn’s & Colitis Foundation, and the Takeda-Columbia-NYU Alliance.
dr Cadwell has received research support from Pfizer, Takeda, Pacific Biosciences, Genentech and Abbvie and has served as a consultant to Puretech Health, which develops microbiome therapies, as well as to GentiBio and Synedge. dr Koide has received research support from Argenx BVBA, Black Diamond Therapeutics and Puretech Health and has served as a consultant to Black Diamond Therapeutics. NYU Langone has pending patents (10,722,600, 62/935,035 and 63/157,225) for therapies developed from this treatment approach, of which Dr. Cadwell, Dr. Koide, Dr. Matsuzawa-Ishimoto and NYU Langone could benefit financially. The terms and conditions of these relationships will be managed in accordance with NYU Langone policies.