Changes in a single gene open the door for harmful gut bacteria to trigger the inflammation that causes Crohn’s disease, according to a new study led by Weill Cornell Medicine and NewYork-Presbyterian researchers. These findings could one day help doctors better select targeted treatments for patients with this immune disorder.
This particular host gene, called AGR2, codes for part of the cell machinery that helps properly prepare new proteins so they can repel “bad” bacteria. When anything from microbes to inflammatory conditions interferes with this process, protein production backs up, stressing the cell. Extremes in the expression of AGR2 – when it becomes too active or just quiet – are associated with such stress and the cell’s response to it, and formed the basis of the study described Nov. 15 in Cell Reports.
The researchers already suspected that the cell’s stress response plays a central role in the onset of Crohn’s disease. In addition to AGR2, according to co-senior author, many other variants associated with Crohn’s disease are involved in this response Dr Randy Longmanassociate professor of medicine in the Department of Gastroenterology and Hepatology and the director of the Jill Roberts Center for Inflammatory Bowel Disease at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center.
“What makes this study unique is that we discovered a link between one of these stress-related genetic susceptibility and changes in the gut microbial community that lead to the development of this disease,” he said.
More than half a million people in the US suffer from Crohn’s disease, a form of inflammatory bowel disease (IBD) in which chronic inflammation damages the lining of the gut, usually in the small intestine and colon. A vague combination of factors, including genetic susceptibility and the presence of certain bacteria, can cause this.
This study started by chance when co-senior author Dr Steven Lipkin, vice chairman for research in the Weill Department of Medicine at Weill Cornell Medicine and a medical geneticist at NewYork-Presbyterian/Weill Cornell Medical Center, genetically engineered mice to prevent expression of the AGR2 gene for another project, and found that they developed Crohn’s disease like inflammation. He and his collaborators linked that inflammation to microbes known as adherent-invasive Escherichia coli (AIEC), which are among the bacteria involved in Crohn’s disease.
“My lab started studying AGR2 more than 10 years ago. Now there are more than 400 publications on the gene,” said Dr. Lipkin, who also leads the Cancer Genetics and Epigenetics Program at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “This gene drives an important pathway relevant to IBD, cancer metastasis and other clinically relevant pathways, and is a promising target for precision medicine and co-theragnostic.” Theragnostics are treatment strategies that combine diagnostics and therapy.
Dr. Lipkin then approached Dr. Longman, that one studies these bacteria and their role in Crohn’s disease. Together, together with a collaborative team inclusive Dr Kenneth Simpson on Cornell’s Ithaca campus and Dr. Balfour Sartor at UNC, they associated changes in AGR2 activity levels with increases in the group of bacteria AIEC belonged to. Then, in experiments on mice, they determined that both AIEC and the wandering stress response are required to trigger the inflammation. In addition, their results suggested that the altered response encourages AIEC to multiply, amplifying the pathology.
The team went on to trace the inflammatory pathway triggered by this interaction. Their experiments linked it to the production of an immune signal known as IL-23, which has an established role in Crohn’s disease.
“IL-23 is an important driver of IBD and colorectal cancer tumor formation and an important therapy target,” said Dr. Lipkin. “Our research has the potential to bring precision medicine to IBD and develop anti-cancer metastasis therapies for patients.”
Doctors currently have numerous ways to treat Crohn’s disease, including some that target specific aspects of its complex biology. However, they have few guidelines on what treatment to use for any given patient. By connecting AGR2 and AIEC to IL-23, this study provides the kind of context that could help guide these decisions, said Dr. Longman.
Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with outside organizations to promote scientific innovation and provide expert guidance. The institution shall make these disclosures public to ensure transparency. For this information, see profiles for Doctor Lipkin and Dr. Longman.