In persons with inflammatory bowel disease, the intestine becomes inflamed, which can thicken the gut wall and result in a potentially deadly obstruction of the intestinal tube. This mystery condition known as “fibrosis” affects 20 to 50% of Crohn’s disease and ulcerative colitis patients throughout the course of their lives. “Aside from surgery to remove the blocked section of intestine, there are currently no approved treatments for this condition,” said Dr. Simon Hirota, PhD, Canada
Research Chair in Host-Microbe Interactions and Chronic Disease and member of the Snyder Institute for Chronic Diseases at the University of Calgary’s Cumming School of Medicine. Hirota’s recent study, which was published in the journal Cellular and Molecular Gastroenterology and Hepatology, sets the door for the development of a potentially viable fibrosis therapy. The study included researchers from the Albert Einstein College of Medicine in New York and the University of Calgary.
The researchers looked at the bacteria that dwell in the human gut, dubbed “the inner tube of life,” and create microbial metabolites, which are metabolic byproducts that prevent inflammation and gut wall thickening. These compounds, as well as the body’s natural receptors for detecting them, are less common in those suffering from inflammatory bowel disease.
Hirota observed that, while the gut must mend itself after an injury, the “over-exuberant” continuous healing seen in inflammatory bowel diseases causes changes to the gut wall that feed disease.
“We’re now suspecting that the fibroblast cells just under the lining may also play a role in perceiving and reacting to metabolites,” Hirota added.
The study focused on PXR, a chemical sensor or receptor in the gut that is important in aiding gut repair. They focused on the interaction between this receptor and a metabolite known as IPA.
The researchers employed cells from mice with the PXR receptor removed to identify the cells involved in the interaction between the host and the chemicals produced by gut bacteria. They employed human intestinal cells to confirm their findings in the animal model.
Medication designed to directly target these sensors, according to the study, may offer a novel strategy to treating inflammation-related intestinal blockage.
Co-author Dr Sridhar Mani, MD, and his research team produced synthetic compounds based on the structure of the IPA metabolite in the same way as natural IPA reduces inflammation.
“This novel research has resulted in a field-leading article that clearly implicates PXR as a crucial target for fibrosis,” adds Mani, an Albert Einstein College of Medicine professor. “We now seek to leverage microbial metabolite mimicry as a way to target PXR in order to avert this terrible IBD consequence.” Clinical studies would be the next stage in determining if synthetic compounds have a good effect on fibrosis and human gut remodelling. The “synthetic metabolite,” according to Hirota, should ideally be in a form that can be digested, passed through the stomach, and then released in the injured portions of the gut.
