Changes in a single gene open the door for harmful gut bacteria to trigger the inflammation that leads to 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, encodes part of the cellular machinery that helps make new proteins properly ready so they can help fend off “bad” bacteria. When anything, from microbes to inflammatory conditions, disrupts this process, protein production is backed up, stressing the cell. Extremes in the expression of AGR2 – when it becomes overactive or simply silent – are associated with such stress and the cell’s response to it, and formed the basis of the study described on 15 November in Cell Reports.
Researchers already suspected that the cell’s stress response plays a central role in the development of Crohn’s disease. In addition to AGR2, many other Crohn’s disease-related variants are implicated in this response, according to co-lead author Dr. Randy Longman, associate professor of medicine in the Division of Gastroenterology and Hepatology and director from 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 found a link between one of these stress-related genetic susceptibilities and changes in the gut microbial community leading to the development of this disease,” he said. .
More than half a million people in the United States suffer from Crohn’s disease, a form of inflammatory bowel disease (IBD) in which chronic inflammation damages the lining of the intestine, usually in the small intestine and colon. A nebulous combination of factors, including genetic susceptibility and the presence of certain bacteria, can cause it.
This study began by chance when co-lead author Dr. Steven Lipkin, vice chair of research in Weill’s Department of Medicine at Weill Cornell Medicine and medical geneticist at NewYork-Presbyterian/Weill Cornell Medical Center, genetically engineered mice to suppress expression of the AGR2 gene for a different project, and found that they developed Crohn-like inflammation. He and his collaborators have linked this inflammation to microbes known as adherent-invasive Escherichia coli (AIEC), which are among the bacteria implicated in Crohn’s disease.
“My lab started studying AGR2 more than 10 years ago. Today, there are over 400 publications on the gene,” said Dr. Lipkin, who is also program manager for cancer genetics and epigenetics at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “This gene directs an important pathway relevant to IBD, cancer metastasis, and other clinically relevant pathways, and is a promising therapeutic target in precision and co-theragnostic medicine.” Theragnostics are treatment strategies that combine diagnostics and therapies.
Dr. Lipkin then approached Dr. Longman, who studies these bacteria and their role in Crohn’s disease. Together, with a collaborative team including Dr. Kenneth Simpson of Cornell’s Ithaca campus and Dr. Balfour Sartor of UNC, they linked changes in AGR2 activity levels to increases in the group of bacteria to which AIEC belonged. . Then, in experiments with mice, they established that AIEC and the wandering stress response are required to trigger inflammation. Moreover, their results suggest that the impaired response encourages the AIEC to proliferate, reinforcing the pathology.
The team then traced the inflammatory pathway triggered by this interaction. Their experiments linked it to the production of an immune signal called IL-23, which plays a well-established role in Crohn’s disease.
IL-23 is an important driver of IBD and colorectal cancer tumorigenesis and an important therapeutic target. Our research has the potential to bring precision medicine to IBD and to develop anti-metastasis cancer therapies for patients.
Dr. Steven Lipkin, Vice Chairman of Research, Weill Department of Medicine, Weill Cornell Medicine and Medical Geneticist, NewYork-Presbyterian/Weill Cornell Medical Center
Doctors currently have many ways to treat Crohn’s disease, some of which target specific aspects of its complex biology. However, they have little guidance on what treatment to use for a given 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. Longman.
Viladomiu, M., et al. (2022) Agr2-associated ER stress promotes invasive dysbiosis in adherent E. coli and triggers IL-23-dependent ileocolitis of CD103+ dendritic cells. Cell reports. doi.org/10.1016/j.celrep.2022.111637.
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