Inflammation of the intestine occurs in people with inflammatory bowel illnesses, which can thicken the gut wall and result in a potentially fatal blockage of the intestinal tube. This mysterious ailment known as "fibrosis" affects 20 to 50% of persons with Crohn's disease and ulcerative colitis during the course of their lifespan.
"Currently there are no approved treatments for this condition, beyond surgery, to remove the blocked section of intestine," 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 latest research, which was published in the journal Cellular and Molecular Gastroenterology and Hepatology, paves the way for the creation of a fibrosis treatment that might be effective. Researchers from the Albert Einstein College of Medicine in New York and the University of Calgary participated in the study.
The study teams looked at the bacteria that live in the human gut, which has been referred to as "the inner tube of life," and that produce microbial metabolites, which are metabolic byproducts that prevent inflammation and gut wall thickening. These metabolites, as well as the body's inherent receptors for detecting them, are less prevalent in persons with inflammatory bowel illnesses.
Hirota noted that although the gut has to heal itself after an injury, the "over-exuberant" continual healing seen with inflammatory bowel illnesses results in alterations to the gut wall that fuel disease.
"We're now beginning to suspect that the fibroblast cells right below the lining may also play a role in sensing and responding to metabolites," Hirota said.
The study focused on a particular chemical sensor or receptor in the gut called PXR, which is crucial in promoting gut healing. They concentrated on how this receptor and a metabolite known as IPA interact.
In order to identify the cells engaged in the interaction between the host and the compounds generated by gut bacteria, the researchers used cells from mice in which the PXR receptor had been deleted. To validate their findings in the animal model, they used intestinal cells from humans.
According to the research, medications made to specifically target these sensors might offer a fresh approach to treating inflammation-related intestinal obstruction. Similar to how the natural IPA inhibits inflammation, co-author Dr Sridhar Mani, MD, and his research team have created synthetic molecules based on the structure of the IPA metabolite.
"This new research has produced a field-driving publication that clearly implicates PXR as an important target for fibrosis," says Mani, a professor at the Albert Einstein College of Medicine. "We hope to now use microbial metabolite mimicry as a strategy to target PXR to prevent this dreaded complication of IBD."
Clinical trials would be the next step to determine whether synthetic chemicals have a positive impact on fibrosis and the remodeling of the human gut. According to Hirota, the "synthetic metabolite" should ideally be in a form that can be consumed, pass through the stomach, and then be released in the damaged sections of the gut.
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