Future Therapeutics Can Target Crohn’s Disease
Researchers from Brigham and Women’s Hospital (BWH), Harvard’s School of Public Health and Medical School and colleagues in Europe have found a new genetic pathway for the development of both of the major forms of inflammatory bowel disease (IBD); Crohn’s disease and ulcerative colitis. Alterations in the gene XBP1, (X box binding protein 1) which is involved in regulating cellular stress pathways, has been identified as a major risk factor for the development of these two IBDs and the researchers point to the epithelial cell as the cell type responsible for initiating IBD as a result of the genetic alterations. The findings appear in the Journal Cell.
It has long been suspected that the epithelium may play a critical role in the development of ulcerative colitis and Crohn’s disease. The epithelium that lines the inside surfaces of the intestine is the first set of cells to contact the environment and serves as the primary functional barrier to the outside world. This epithelium is strategically placed between the two major ingredients involved in the development of IBD, the largest concentrations of bacteria and immune cells in the human body.
To determine the role of XBP1 in the intestinal epithelium, the researchers developed mice in which that gene was deleted. The mice developed an IBD-like intestinal inflammation through a mechanism that involved an inability to regulate intestinal bacteria, together with a hypersensitivity of the epithelium to the products of the bacteria, culminating in spontaneous intestinal inflammation. To determine if XBP1 might be a genetic risk factor in the development of the human conditions, the researchers performed genetic analysis on nearly 5,000 IBD patients and controls which involved genetic sequencing through the XBP1 gene of 1,200 patients and controls and found that there was an association with both forms of IBD. They also found unique genetic alterations that were likely to be functional risk factors.
“The findings are very exciting and paint the first coherent picture of how a genetic encoded risk factor can emerge as inflammatory bowel disease,” said Richard Blumberg MD, senior author of the study and Chief of the Division of Gastroenterology, Hepatology and Endoscopy at BWH. He continued, “The therapeutic implications are huge because the findings allow us, for the first time, to rationally target a factor that we know is a risk factor for developing IBD.” Co-senior author Laurie Glimcher the Irene Heinz Given Professor of Immunology at Harvard School of Public Health comments, “We had no idea when we first discovered XBP1 that it would turn out to be such a key factor in a human disease.”