Researchers explore 'completely novel, nontoxic' IBD treatment

Gastrointestinal problems — from diarrhea to issues caused by food allergies to inflammatory bowel disease — have one common characteristic. A new study suggests an innovative way of tackling it to both prevent and treat gastrointestinal conditions.

Inflammatory bowel disease (IBD), as well as other gastrointestinal problems, are characterized by impaired function in the intestinal epithelial barrier. This is the tissue layer that prevents harmful "leakages" between the inside of intestines (intestinal lumen) and the space surrounding the guts.

Damage of the epithelial barrier has links to disease, but it is still unclear what causes impairments in this necessary defense layer.

Nevertheless, research has shown that an enzyme called the myosin light chain kinase (MLCK) plays a key role in the regulation of the epithelial barrier. Scientists think it may also have something to do with gastrointestinal inflammation.

Because MLCK is important to epithelial barrier function, acting on it directly to try and prevent gastrointestinal problems could have unwanted effects.

Now, however, researchers have come up with a new approach that may allow them to circumvent these difficulties.

The team — which is made up of specialists from Harvard Medical School in Boston, MA, the University of Illinois at Chicago, the University of Chicago in Illinois, and the First Affiliated Hospital of Soochow University in Suzhou, China — has found that targeting the MLCK1 version of MLCK could help prevent and treat IBD and other gastrointestinal problems.

The researchers write about their experiments and their findings in a study paper that now appears in the journal Nature Medicine.

Discovering a useful molecule

In their new study, the scientists, first of all, aimed to identify a way in which they could safely address the issue of epithelial barrier damage. To do so, they mapped out the structure of an element called "the IgCAM3 domain," which differentiates MLCK1 from other forms of MLCK.

Then, they searched for a molecule that could take MLCK1's specific place without upsetting the delicate balance of the intestinal cells that line the small intestine lumens — which normally express MLCK1.

Eventually, the researchers managed to find an appropriate molecule, which they named "Divertin" because it works by diverting MLCK1 from the spots at which it would usually act on the epithelial barrier.

When they tested Divertin in mouse models of both diarrhea and IBD, the scientists found that the molecule was able to prevent inflammation-related damage to the epithelial barrier without stopping MLCK from doing its maintenance work in that tissue.

Moreover, Divertin both corrected epithelial barrier dysfunction and stopped IBD from progressing further in the animal models. The molecule also worked as a method of preventing the disease from developing in the first place.

The researchers believe that these experimental findings are promising and that they could, in the future, lead the way to better strategies for both the treatment and prevention of IBD and other gastrointestinal problems.

"This represents a completely novel, nontoxic approach to intestinal barrier restoration and treatment of inflammatory bowel disease."

Study author Dr. Jerrold Turner

Furthermore, the team argues that targeting MLCK1 to treat epithelial barrier loss could also work in addressing other medical issues that threaten barrier integrity.

Such issues, they note, include celiac disease, atopic dermatitis, pulmonary infection, and even multiple sclerosis. Scientists could also use this approach to help prevent graft versus host disease, which can occur when the host tissue rejects transplanted tissue.

In another study — conducted by the same research team and published in The Journal of Clinical Investigation — the investigators have already found evidence that MLCK has implications in the development of graft versus host disease.

Based on those results, Dr. Turner and colleagues contend that Divertin could act on some of the mechanisms that drive the rejection of transplanted tissue, too.

"Our study indicates that MLCK1 is a viable target for preserving epithelial barrier function in intestinal diseases and beyond," explains Dr. Turner.

"This therapeutic approach may help break the cycle of inflammation that drives so many chronic diseases," he suggests.