Pain-sensing intestinal neurons protect against inflammation.newsroom

Pain-sensing neurons protect the gut from inflammation and associated tissue damage by regulating the microbial community that lives in the gut, according to a study by researchers at Weill Cornell Medicine.

The researcher report Published Oct. 14 in Cell, it was discovered in a preclinical model in which pain-sensing neurons in the gut secrete a molecule called substance P. Substance P appears to protect against intestinal inflammation and associated tissue damage by increasing the number of beneficial microorganisms in the gut. The researchers also found that the number of these pain-sensing nerves was reduced and pain-transmitting genes were significantly disrupted in patients with inflammatory bowel disease (IBD).

“These findings reshape how we think about chronic inflammatory diseases and open up entirely new approaches to therapeutic intervention,” said the study’s senior author. Dr. David Artist,director Jill Roberts Inflammatory Bowel Disease Institute,director Friedman Nutrition and Inflammation Center and Michael Kors Professor of Immunology at Weill Cornell Medicine.

Dr. David Artist

The lead author of this study, Dr. Zhang WenPostdoctoral fellow at the Artis Institute.

IBD covers two different disorders, Crohn’s disease and ulcerative colitis, and is thought to be: affect millions in the United States. It is usually treated with drugs that directly target elements of the immune system. Scientists now recognize that gut bacteria and other microbes also help regulate gut inflammation.

As Dr. Artis’ lab and others have shown in recent years, the nervous system, which is “wired” to most organs, appears to be yet another potent regulator of the immune system at the body’s barrier surfaces. It seems. In a new study, Dr. Artis and his team specifically looked at pain neurons that innervate (extend nerve endings) the gut.

Dr. Zhang Wen

These gut-innervating pain neurons, whose cell bodies are located in the lower spine, express a surface protein called TRPV1. It acts as a receptor for pain-related signals. TRPV1 can be activated by high heat, acid, the pepper compound capsaicin, etc., and the brain translates this activation into a burning sensation. The researchers found that silencing these TRPV1 receptors in enteric nerves or deleting TRPV1-expressing neurons far exacerbated inflammation and tissue damage in a mouse model of IBD, whereas the receptors had a protective effect when activated.

The researchers observed that exacerbation of inflammation and tissue damage in TRPV1-blocked mice was associated with changes in the relative populations of different types of gut bacteria. Transplanting this altered bacterial population into normal mice similarly exacerbated susceptibility to inflammation and injury. In contrast, broad-spectrum antibiotic treatment can reverse this susceptibility even in TRPV1-blocked mice. This result indicates that TRPV1-expressing neurons protect the gut, primarily by helping maintain a healthy gut microbial community.

Scientists have found strong evidence that most of the effects of TRPV1-expressing neurons on this microbe come from a neuron-secreted molecule called substance P. They observed that most of the detrimental effects of blocking TRPV1 could be reversed by itself. rice field. Some bacterial species can activate TRPV1-expressing neurons to produce more substance P.

To confirm the human relevance, the researchers examined intestinal tissue from IBD patients and found aberrant TRPV1 and substance P gene activity and overall fewer TRPV1 neuronal manifestations.

“These patients have destroyed pain-sensing nerves, which may contribute to chronic inflammation,” Dr. Zhang said.

How Substance P affects gut microbial populations and how these microbes “counteract” is a question researchers are trying to answer in ongoing research. The results suggest that the next generation of anti-inflammatory drugs for IBD and other disorders may be compounds that target the nervous system.

“Many current anti-inflammatory drugs only work in some patients, and pharmaceutical companies had no idea why,” Dr. Artis said. “Perhaps because we were only seeing part of the picture when it came to chronic inflammation, but now the focus is beginning to focus on the rest, including the role of the nervous system.”

This work at Weill Cornell Medicine was supported in part by a grant from the National Government. Institute of Health (AI172027, AI151599, AI095466, AI095608, AR070116, DK126871, DK132244, F32AI124517), LEO Foundation, CURE for IBD, Jill Roberts Institute, The Saunders Family, The Roseanne H. Silverman Family Foundation, and Crohn’s Disease and Colitis Foundation Research Fellowship Award.