Alterations in a single gene open the door for harmful gut bacteria to trigger the inflammation that drives Crohn’s disease, according to a new study led by Weill Cornell Medicine and New York-Presbyterian researchers. These findings could one day help doctors select more targeted treatments for patients with this immune disorder.
This particular host gene, called AGR2, encodes part of the cell machinery that helps properly prime new proteins so they can help fight off “bad” bacteria. When anything from microbes to inflammatory conditions interferes with this process, protein production is aided and the cell stressed. Extremes in the expression of AGR2 — when it becomes too active or just silent — are linked to 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 stress response of the cell plays a central role in the development of Crohn’s disease. In addition to AGR2, according to co-senior author Dr. Randy Longman, Associate Professor of Medicine in the Department of Gastroenterology and Hepatology and Director of the Jill Roberts Center for Inflammatory Bowel, many other variants involved in this reaction are associated with Crohn’s disease at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center.
“What makes this study unique is that we discovered an association between one of these stress-related genetic vulnerabilities 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 have 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 large intestine. A nebulous combination of factors, including genetic susceptibility and the presence of certain bacteria, can lead to it.
This study began coincidentally when co-senior author Dr. Steven Lipkin, vice chair for research in the Weill Division of Medicine at Weill Cornell Medicine and medical geneticist at New York-Presbyterian/Weill Cornell Medical Center, genetically engineered mice to prevent expression of the AGR2 gene for another project and hired found they developed Crohn’s-like inflammation. He and his collaborators linked this inflammation to microbes known as adherent-invasive Escherichia coli (AIEC), one of the bacteria implicated in Crohn’s disease.
“My lab started researching AGR2 more than 10 years ago. There are now more than 400 publications about the gene,” said Dr. Lipkin, who is also the director of the Cancer Genetics and Epigenetics Program at the Sandra and Edward Meyer Cancer Center at Weill-Cornell Medicine. “This gene controls an important signaling pathway relevant to IBD, cancer metastasis and other clinically relevant signaling pathways and is a promising target for precision medicine therapy and co-theragnostics.” Theragnostics are treatment strategies that combine diagnostics and therapy.
dr Lipkin then turned to Dr. Longman, who studies these bacteria and their role in Crohn’s disease. Along with a collaborative team including Dr. Kenneth Simpson of the Ithaca campus at Cornell and Dr. Balfour Sartor of UNC, they linked changes in AGR2 activity levels to an increase in the bacterial group to which AIEC belonged. Then, in experiments with mice, they found that both AIEC and the faulty stress response are necessary to trigger inflammation. Furthermore, their results suggested that the altered response stimulates AIEC to proliferate, which amplifies the pathology.
The team further tracked the inflammatory pathway triggered by this interaction. Their experiments linked it to the production of an immune signal known as IL-23, which has a well-established role in Crohn’s disease.
“IL-23 is an important factor in the development of IBD and colorectal cancer and an important therapeutic target,” said Dr. Lipkin. “Our research has the potential to bring precision medicine to IBD and to develop anti-metastatic cancer therapies for patients.”
Physicians currently have numerous options for treating Crohn’s disease, including some that target specific aspects of its complex biology. However, they have little guidance as to which treatment to use for any particular patient. By linking AGR2 and AIEC to IL-23, this study provides the kind of context that could help guide these decisions, according to Dr. long man