New treatment shows promise for relief of inflammatory bowel disease

Inflammatory bowel disease (IBD) is chronic, often painful, and takes a toll on mental health and emotional well-being. In addition to depression and anxiety, emotional responses to living with a chronic illness can include denial of the disease, dependent behaviors, feeling overwhelmed, and having a poor self-image. IBD also affects family and friends.

There are two types of inflammatory bowel disease – ulcerative colitis and Crohn’s disease. People with IBD can develop inflammation of the intestine which causes thickening of the gut wall and life-threatening blockage of the bowel. Twenty to 50 percent of people are affected over their lifetime by this poorly understood condition called “fibrosis.”

“Currently, there are no approved treatments for this condition, except surgery to remove the blocked section of intestine,” says study co-author Dr. Simon Hirota, Canada Research Chair in Host-Microbe Interactions and Chronic Disease, in a statement. Hirota is also a member of the Snyder Institute for Chronic Diseases at the University of Calgary’s Cumming School of Medicine.

Researchers at the University of Calgary and the Albert Einstein College of Medicine in New York City are collaborating in a new study led by Hirota. Their work is a step toward a potential treatment for fibrosis. 

The researchers studied bacteria in the human gut that release chemical substances called microbial metabolites (products of metabolism). The metabolites block inflammation and gut wall thickening. People with IBD have reduced levels of these metabolites and of the natural sensors that the body uses to detect them.

Hirota explains that repair in the gut is necessary after injury, but the exuberant and constant repair characteristic of IBD leads to disease-causing changes in the gut wall.

“We’re now starting to think about not only the lining of the gut playing a role in sensing and responding to metabolites. The fibroblast cells just below the lining may also have a role,” Hirota says.

The researchers looked at a specific chemical receptor, or sensor, in the gut called PXR. It is involved in helping the gut heal. They focused on the interplay between this receptor and a metabolite called IPA.

Using cells from mice the researchers removed the PXR receptor, enabling them to determine which cells were involved in the interplay between the chemicals released by gut bacteria and the host. They used cells from the human gut to verify their findings in the animal model.

The findings suggest that drugs designed to target these sensors may provide a new treatment to prevent inflammation-associated gut blockage. Dr. Sridhar Mani, professor at the Albert Einstein College of Medicine, and his research group, have produced IPA-like synthetic compounds based on the structure of the metabolites shown to inhibit inflammation.

“This new research clearly implicates PXR as an important target for fibrosis,” says Mani. “We hope to now use microbial metabolite mimicry as a strategy to target PXR to prevent this dreaded complication of IBD.”

A next step will be clinical trials to see if the synthetic compounds have a beneficial effect on fibrosis and remodeling in the gut. Ideally, Hirota says, the synthetic metabolite could be ingested, pass through the stomach, and be released in affected areas of the gut.

The study is published in Cellular and Molecular Gastroenterology and Hepatology.

Leave a Comment