Inhibiting a novel gut signaling pathway reversed colitis in mice

John Murphy, MDLinx | July 30, 2018

Scientists have identified a novel gut signaling pathway stemming from the enteric nervous system, and when they gave mice an inhibitor of NK2R—a signaling receptor involved in this pathway—it reduced inflammation and colitis development. Results of this study have been published in Cellular and Molecular Gastroenterology and Hepatology.

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A signaling pathway that connects enteric neurons and glia (shown here) underlies the effects of inflammation on GI disorders. Targeting this pathway could improve GI motility and reduce pain, researchers found. (Image: Michigan State University)

The scientists’ research focused on the role of tachykinins, which are important neuropeptide mediators that help carry out gut functions such as motility and secretion. But tachykinins can also contribute to gut inflammation and visceral pain. Tachykinin receptors, therefore, make an attractive therapeutic target for treating gastrointestinal (GI) disorders like irritable bowel syndrome (IBS) and colitis.

“Here, we tested the hypothesis that tachykinins contribute to enteric neuroinflammation through mechanisms that involve intercellular neuron-glia signaling,” wrote investigators led by Brian Gulbransen, PhD, associate professor, Department of Physiology, Michigan State University, East Lansing, MI. They used immunohistochemistry, molecular biology, and calcium (Ca2+) imaging to observe the expression and function of tachykinin peptides and receptors.

They found that glial cells—the supporting cells of the nervous system—are actively involved in much of the signaling implicated in GI inflammation. This increased signaling agitates quiescent glial cells, turning them into “angry” glial cells, Dr. Gulbransen noted.

“Post-inflammation, there are still many angry glial cells. Because they’ve amped up their signaling, they make you, and your gut, more sensitive,” he said. “We hope we can turn them back to happy glia, reduce the sensitivity, and return gut function to normal.”

To that end, the researchers tested the effect of the tachykinin inhibitor GR 159897 on the NK2 receptor in mice with induced colitis. This receptor plays a key role in neuron-to-glia signaling.

“By blocking the receptor with GR 159897, which is a known NK2 receptor antagonist drug, it disconnected the signaling between neurons and glia,” Dr. Gulbransen said. “It proved to be quite effective in accelerating recovery from inflammation.”

If proved effective in humans, this approach could lead to an important therapeutic treatment of functional GI disorders, the researchers concluded.

This research was funded by the National Institutes of Health and the Crohn’s and Colitis Foundation of America.

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