Harmful gut bacteria co-opt a genetic susceptibility to trigger Crohn’s disease

According to a new study led by Weill Cornell Medicine and NewYork-Presbyterian investigators, changes in a single gene open the door for harmful gut bacteria to stop the inflammation that drives Crohn’s disease. These findings may one day help physicians select better targeted treatments for patients with this immune disorder.

This special host gene, called AGR2, encodes part of the cell’s machinery that helps prepare new proteins correctly so they can help eliminate “bad” bacteria. When anything from microbes to inflammatory conditions disrupt this process, protein production backs up, stressing the cell. Extremes in the expression of AGR2 — when it becomes too active or silenced — 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.

Investigators have already suspected that the cell’s stress response plays a central role in the development of Crohn’s. In addition to AGR2, many other variants associated with Crohn’s are involved in this response, according to co-senior author Dr. Randy Longman, associate professor of gastroenterology and hepatology and director of the Jill Roberts Center for Inflammatory Bowel Disease at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center. .

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“What makes this study unique is that we discovered a link between one of these stress-related genetic sensitivities 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 United States suffer from Crohn’s disease, an inflammatory bowel disease (IBD) in which chronic inflammation damages the intestinal lining, usually in the small intestine and colon. A nebulous combination of factors can bring it on, including genetic susceptibility and the presence of certain bacteria.

The study began by chance when co-senior author Dr. Steven Lipkin, vice chair 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 block expression. AGR2 gene for a different project, and they developed Crohn’s-like inflammation. He and his colleagues linked that inflammation to a bacterium known as adherent-invasive Escherichia coli (AIEC), which is among the bacteria implicated in Crohn’s.

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“My lab started studying AGR2 more than 10 years ago. Now, there are more than 400 publications about the gene,” said Dr. Lipkin, who is also leader of the Cancer Genetics and Epigenetics Program at Weill Cornell Medicine’s Sandra and Edward Meyer Cancer Center. “This gene drives an important pathway relevant to IBD, cancer metastasis and other clinically relevant pathways and is a promising precision medicine therapy target and co-therapeutic.” Therapagnostics are treatment strategies that combine diagnostics and therapies.

Dr. Lipkin then contacted Dr. Longman, who researched these bacteria and their role in Crohn’s disease. Together, Dr. Cornell’s Ithaca campus. Dr. Kenneth Simpson and UNC. Along with a collaborative team, including Balfour Sartor, they linked changes in AGR2 activity levels to growth in the group of bacteria belonging to AIEC. Then in experiments with mice, they established that both AIEC and the wrong stress response are necessary to trigger inflammation. What’s more, their results suggested that the altered response encourages AIEC to proliferate, reinforcing the pathology.

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The team went on to identify the inflammatory pathway triggered by this interaction. Their tests linked it to the production of an immune signal known as IL-23, which plays a well-established role in Crohn’s.

IL-23 is an important driver of IBD and colorectal cancer tumorigenesis and an important therapy target. Our research has the potential to bring precision medicine to IBD and develop anti-metastasis cancer therapies for patients.”

Dr. Steven Lipkin, Vice Chair 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, including some that target specific aspects of its complex biology. However, they have little guidance on which treatment to use for a given patient. By linking AGR2 and AIEC to IL-23, this study provides context that may help guide these decisions, Dr. According to Longman.

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Journal Reference:

Villadomeau, M., etc (2022) Agr2-associated ER stress promotes adherent-invasive E. coli dysbiosis and triggers CD103+ dendritic cell IL-23-dependent ileocolitis. Cell report. doi.org/10.1016/j.celrep.2022.111637.

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