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Most inflammatory reactions in the body are accompanied by redness, swelling, heat and pain of local tissues and dysfunction
.
The body senses physiological pain mediated by adverse external stimuli through a group of receptors of the peripheral nervous system (Nociceptor sensory neurons, pain
receptors).
Pain receptors are highly expressive of the non-selective cation channel TRPV1, which can be excited by various physical and chemical stimuli (such as temperature above 43 °C, low pH (acidic environment) and capsaicin, the active ingredient of capsaicin, and activated pain receptors secrete corresponding neuropeptides (Neuropeptide) to transmit and regulate pain sensation to the central nervous system (Nociception) and the integration of various pain information (this research work was awarded the Nobel Prize in Medicine in 2021) [1-3].
Recent studies have found that pain receptors not only transmit and regulate pain sensation, but also have certain immunomodulatory functions [4,5].
Inflammatory bowel disease (IBD), the focus of this study, is a chronic inflammatory intestinal disease of the intestinal where the etiology is not fully understood, and its main symptoms include abdominal pain and diarrhea [6,7].
There is currently no cure for IBD, so further understanding of the pathology of inflammatory bowel disease plays an important role
in the development of new treatments.
On October 14, 2022, the team of David Artis Laboratory at Weill Cornell Medical College at Cornell University in the United States (Dr.
Wen Zhang is the first author) published a paper in the journal Cell Gut-innervating nociceptors regulate the intestinal microbiota to promote tissue protection, revealing for the first time the pain-perceptive neuron TRPV1+ Pain receptors play a key protective role
in intestinal injury and intestinal inflammation by regulating the gut microbiome.
To investigate the scientific question of what functions TRPV1+ pain-receptive neurons have in regulating intestinal inflammation and inflammatory bowel disease, the researchers used neurobiology and chemogenetics By specifically regulating the activity and function of TRPV1+ pain receptors, combined with the enteritis injury model of mice, it was found that after inhibiting the activity and function of pain receptors, the susceptibility of mice to enteritis injury was significantly increased
.
In addition, mice with pain receptors that were missing also had a higher susceptibility to enteritis damage after permanently removing TRPV1+ pain receptors by using a natural chemical resin toxin (Resiniferatoxin/RTX).
These data indicate that TRPV1+ pain receptors have a key tissue-protective function
in mouse enteritis injury models.
So, how exactly does TRPV1+ pain receptors mediate this tissue protection function? Through a series of immunological analyses and high-throughput sequencing studies in microbiology, the researchers found that the gut microbiota of mice missing pain receptors underwent significant changes
.
Using germ-free mice and mouse models with specific microbiota, the researchers found that if the gut microbiota of mice with missing pain receptors was transplanted into germ-free mice, recipient mice transplanted with microbiota of mice with missing pain receptors also gained higher susceptibility to enteritis damage
.
By using a range of antibiotics to specifically clear different microbial flora, the researchers found that dysbacteriosis of gram-positive bacteria (Gram+) is one of
the main reasons why mice with missing pain receptors have a higher susceptibility to enteritis injury.
Interestingly, the researchers also saw the same phenotype
as SPF mice in a single-flora mouse model of Clostridium Gram+ Clostridium spp.
These data suggest that TRPV1+ nociceptor protects intestinal tissue from external damage-induced enteritis by regulating homeostasis
of intestinal flora.
Among them, the gram-positive flora and Gram+ Clostridium spp.
are key targeted flora
that may be regulated by this group of neurons.
Next, does TRPV1+ pain receptors specifically regulate the gut microbiota and intestinal inflammation by secreting neuropeptides? The researchers found that pain receptors activate and secrete the neuropeptide Substance P in the mouse enteritis injury model, and the loss of Substance P also leads to intestinal dysbacteriosis in mice and more severe intestinal inflammation
.
Crucially, the susceptibility to intestinal inflammatory damage can be reduced to a certain extent by supplementing Substance P in mice without pain receptors, and it is also shown that pain receptors mediate their tissue protective function
in intestinal injury and intestinal inflammation by secreting Substance P.
Finally, the researchers observed a significant reduction in the levels of the pain receptor marker TRPV1 in intestinal biopsies of IBD patients, suggesting that the function of this group of pain-sensing neurons may also be regulated
by chronic inflammation or dysregulated gut flora in IBD patients.
In summary, this study reveals for the first time the new immune regulatory function of TRPV1+ pain receptors as pain-receptive neurons and the key role of neuron-microbiota crosstalk in intestinal immunity and gut microbial homeostasis.
It also provides an important theoretical reference and new ideas
for the clinical treatment of patients with intestinal diseases.
The research was mainly completed by the team of David Artis Laboratory at Weill Cornell Medical School at Cornell University, with Dr.
Wen Zhang as the first author
of the paper.
Several other research teams contributed to the study, including the Chun-Jun Guo lab at Cornell University's Weill Cornell School of Medicine and the Hongzhen Hu lab at
Washington University School of Medicine in St.
Louis.
At the same time, the team from Issac Chiu's lab at Harvard University also published a related research paper Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier The above study enriches the regulatory function of receptor neuronal TRPV1+ pain receptors in intestinal immunity, and makes important contributions
to the study of the mechanism of neuroimmune interaction in regulating intestinal homeostasis and intestinal inflammation.
Original link: https://doi.
org/10.
1016/j.
cell.
2022.
09.
008
Pattern maker: Eleven
References
1.
Basbaum, A.
I.
, Bautista, D.
M.
, Scherrer, G.
, and Julius, D.
(2009).
Cellular and molecular mechanisms of pain.
Cell 139, 267-284.
2.
Julius, D.
, and Basbaum, A.
I.
(2001).
Molecular mechanisms of nociception.
Nature 413, 203-210.
3.
Woolf, C.
J.
, and Ma, Q.
(2007).
Nociceptors--noxious stimulus detectors.
Neuron 55, 353-364.
4.
Baral, P.
, Udit, S.
, and Chiu, I.
M.
(2019).
Pain and immunity: implications for host defence.
Nat Rev Immunol 19, 433-447.
5.
Chu, C.
, Artis, D.
, and Chiu, I.
M.
(2020).
Neuro-immune Interactions in the Tissues.
Immunity 52, 464-474.
6.
Abraham, C.
, and Cho, J.
H.
(2009).
Inflammatory bowel disease.
N Engl J Med 361, 2066-2078.
7.
Chang, J.
T.
(2020).
Pathophysiology of Inflammatory Bowel Diseases.
N Engl J Med 383, 2652-2664.
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