A single genetic change opens the door for harmful gut bacteria to trigger Crohn’s disease-causing inflammation, according to new research led by researchers at Weill Cornell Medicine and New York-Presbyterian. It may help doctors choose better targeted treatments for patients with this immune disorder.
This particular host gene, called AGR2, encodes part of the cellular machinery that helps to properly prepare new proteins and helps fight off “bad” bacteria. When anything, from microbes to inflammatory conditions, perturbs this process, it backs up protein production and puts the cell under stress. , related to such stress and the cellular response to it, formed the basis of the study described November 15 in Cell Reports.
Researchers already suspected that cellular stress responses play a central role in the development of Crohn’s disease. In addition to AGR2, many other variants associated with Crohn’s disease are involved in this response, says Jill Roberts, co-lead author and associate professor in the Department of Gastroenterology and Hepatology, Inflammatory. Disease at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center, according to Dr. Randy Longman, director of the Bowel 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 that lead to the development of this disease.
More than 500,000 people in the United States suffer from Crohn’s disease. Crohn’s disease is a type of inflammatory bowel disease (IBD) in which chronic inflammation damages the intestinal lining (usually the small intestine and colon). It can be caused by a vague combination of factors, including genetic susceptibility and the presence of certain bacteria.
The study coincided with co-lead author Stephen Lipkin, Ph.D., vice chair of research at the Weill School of Medicine at Weill Cornell Medicine and a medical geneticist at the New York-Presbyterian/Weill Cornell Medical Center, in another study. When we examined the AGR2 gene in the project, we found that Crohn’s disease-like inflammation occurred. He and his collaborators linked the inflammation to an organism known as adherent invasive E. coli (AIEC), one of the bacteria implicated in Crohn’s disease.
“My lab started working on AGR2 more than a decade ago. Today, there are over 400 publications on this gene,” says the Cancer Genetics and Epigenetics Program at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. said Dr. Lipkin, leader of “This gene drives key pathways associated with IBD, cancer metastasis, and other clinically relevant pathways, and is a promising precision medicine therapeutic target and co-theragnostic.” is a treatment strategy that combines diagnosis and treatment.
Dr. Lipkin then contacted Dr. Longman, who is studying these bacteria and their role in Crohn’s disease. With a collaborative team that included Dr. Kenneth Simpson of Cornell University’s Ithaca Campus and Dr. Balfour Sartor of UNC, he linked changes in AGR2 activity levels with an increase in the bacterial population to which he belongs AIEC. Later experiments in mice demonstrated that both AIEC and a false stress response are required to trigger inflammation. Moreover, their results suggest that the altered response drives proliferation of his AIEC, reinforcing his pathology.
The team traced the inflammatory pathways initiated 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 a key driver of IBD and colorectal cancer tumorigenesis and an important therapeutic target. Our research has the potential to bring precision medicine to IBD and develop anti-metastatic cancer treatments for patients. “
Stephen Lipkin, Ph.D., Weill School of Medicine, Weill Cornell Medical School, New York Presbyterian/Weill Cornell Medical Center, Vice Chair of Weill Cornell Medicine and Medical Geneticists
Physicians now have many methods to treat Crohn’s disease, including those that target specific aspects of its complex biology. Very little guidance. According to Dr. Longman, the study, by linking AGR2 and AIEC with her IL-23, provides a context that might help guide those decisions.
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Journal reference:
Villadomieu M. and others. (2022) Agr2-associated ER stress promotes dysbiosis in adherent invasive E. coli and causes CD103+ dendritic cell IL-23-dependent ileocolitis. cell report. doi.org/10.1016/j.celrep.2022.111637.
