Pain-sensing intestinal neurons can prevent inflammation

According to a study by researchers at Weill Cornell Medicine, pain-sensing neurons protect the gut from inflammation and related tissue damage
by regulating the microbial communities that live in the gut.
The study was published Oct.
14 in
the journal Cell.
In a preclinical model, the researchers found that pain-sensing neurons in the gut secrete a molecule called substance P, which appears to prevent intestinal inflammation and related tissue damage
by increasing the number of beneficial microbes in the gut.
The researchers also found that in patients with inflammatory bowel disease (IBD), these pain-sensing nerves were reduced in number and their pain signaling genes were severely disrupted
.
IBD includes two different diseases, Crohn's disease and ulcerative colitis, which are believed to affect millions of people in the United States, often with medications
that directly target the immune system.
Scientists now recognize that gut bacteria and other microbes also help regulate gut inflammation
.

Research in recent years has shown that the nervous system, which is "connected" to most organs, appears to be another powerful regulator of the immune system on the surface of
the body's barrier.
In the new study, Dr.
Artis' team specifically looked at pain neurons
that innervate nerve endings in the gut.
These pain neurons that innervate intestinal nerves, whose cell bodies are located in the lower part of the spine, express a surface protein called TRPV1, which is a receptor
for pain-related signals.
For example, TRPV1 can be activated by the heat, acid, and cayenne pepper compound capsaicin, and the brain converts this activation into a burning sensation
.
The researchers found that silencing TRPV1 receptors in intestinal nerves, or deleting TRPV1-expressing neurons, led to more severe inflammation and tissue damage in mouse models of IBD, while activating these receptors had a protective effect
.

The researchers observed that in mice with TRPV1 blockade, the worsening of inflammation and tissue damage was associated
with changes in the relative populations of different species of gut bacteria.
When this altered bacterial population was transplanted into normal mice, it caused an equally worsening inflammation and susceptibility to injury
.
In contrast, broad-spectrum antibiotic therapy could even reverse this susceptibility of TRPV1-blocking mice
.
This result suggests that TRPV1-expressing nerves protect the gut
primarily by helping maintain a healthy gut microbial population.

The scientists found that this specific effect of TRPV1-expressing neurons on microbes is largely due to neurosecretion of a molecule called substance P—a substance that they observed itself could reverse most of the harmful effects
of blocking TRPV1.
The experiments also showed that the signals between neurons and microbes are bidirectional—some bacteria can activate TRPV1-expressing nerves, causing them to produce more P
.

To confirm its relevance to humans, the researchers examined the intestinal tissue of IBD patients and found that there were fewer signs of TRPV1 neurons overall, and that TRPV1 and substance P genes were not active properly
.
"These patients have disturbed pain nerves, which may have exacerbated their chronic inflammation," said
Dr.
Zhang, one of the authors of the article.

Exactly how substance P affects gut microbial populations and how these microbes "fight back" are questions
that researchers are currently trying to answer in the ongoing study.
But the current findings suggest that the next generation of anti-inflammatory drugs for inflammatory bowel disease and other diseases could be compounds
that target the nervous system.

"These findings reshape our understanding of chronic inflammatory diseases and open up a whole new approach to therapeutic interventions," said
David Artis, Ph.
D.
, senior author of the study, director of the Gil Roberts Institute for Inflammatory Bowel Diseases, director of the Friedman Center for Nutrition and Inflammation, and Michael Coles Professor of Immunology at Weill Cornell Medical College 。 "A lot of anti-inflammatory drugs are only effective for a subset of patients right now, and the pharmaceutical companies don't really know why," "Maybe it's because when it comes to chronic inflammation, we're only seeing some of it — and now, the rest, including the role of the nervous system, is starting to come into focus
.
" ”

Dr.
David Artis

Dr.
Zhang, lead author of the study and a postdoctoral researcher in Artis' lab, added: "Identifying a previously unknown sensory function of these specific neurons affecting the microbiota adds a new level of
understanding of host-microbiota interactions.
"

Dr.
Wen Zhang