According to a recent study published in Cell Reports, substance P produced by nociceptors in the intestinal lining confers protection against inflammation and tissue damage by increasing the number of beneficial microbes.
Study: Nociceptors innervating the gut regulate gut microbiota to promote tissue protection. Image credit: Explode/Shutterstock
The findings also highlighted the presence of a reduced number of nociceptors in patients with inflammatory bowel disease (IBD), along with significant disruptions in the pain signaling gene expression profile.
background
The immune system evolved alongside large microbial communities that inhabit barrier sites, collectively known as the microbiota. It is becoming clear that microbial antigens and metabolites constantly interact with the immune system, resulting in microbiota-specific immune responses without inflammation. However, if the microbial population is disrupted, it causes distress and inflammatory disorders.
Several inflammatory disorders, including inflammatory bowel disease (IBD), rheumatoid arthritis, and multiple sclerosis, cause distress, impair quality of life, and precipitate chronic pain. The sensation of pain is activated to warn against tissue damage or injury.
In peripheral tissues, such as the gastrointestinal tract, lungs, and skin, pain-sensitive neurons transmit environmental signals to the central nervous system.
A nociceptor is a sensory neuron that expresses transient receptor potential vanilloid 1 (TRPV1), a nonselective cation channel activated by various stimuli, including capsaicin, heat, and inflammatory mediators. When nociceptors are activated, they release neuropeptides that increase or inhibit the downstream inflammatory cascade. However, there is considerable uncertainty about the role of pain-sensitive neurons in inflammatory conditions of the gut.
The present study investigated the innervation of TRPV1+ nociceptor cells in the intestines of mice and their function during homeostasis and inflammation. This study assessed the vulnerability of TRPV1 + nociceptors in injured and inflamed mice by using targeted chemogenetic silencing, adenoviral-mediated colon-specific silencing, or pharmacological ablation.
The study
The researchers crossed Trpv1-Cre mice with reporter mice of the tdTomatofl/stop/fl cell line to analyze the location of TRPV1+ nociceptors in naïve and inflamed mouse colons.
TRPV1-tdTomato, together with the panneuronal marker βIII-tubulin, was used to identify TRPV1+ nociceptor innervation in the inner lining of the colon at steady state and after exposure to dextran sodium sulfate (DSS), in injured mice intestinal and inflammation. .
A chemogenetic strategy was uniquely activated to acutely silence TRPV1 nociceptors in vivo by producing TRPV1hM4Di mice in which TRPV1+ nociceptors express inhibitory designer receptors.
Dorsal root ganglia (DRG) nociceptor marker gene expression was assessed in steady-state DRGs obtained from DMSO- or RTX-treated B6 mice. Mice treated with DMSO or RTX had their faecal microbial composition assessed by 16S rRNA gene sequencing and principal coordinate analysis.
Mice treated with DMSO or RTX and given vehicle or a broad-spectrum antibiotic cocktail (ABX), vancomycin, or neomycin were exposed to DSS for five days while disease and recovery were observed daily .
Colonic substance P and CGRP levels in mice treated with DSS, DMSO, or RTX. Clinical disease score, colon length, H&E staining, and daily distal colon weight loss were used to track disease and recovery in Tac1/DMSO-treated or DSS-treated RTX mice .
the findings
The researchers noted that TRPV1+ nociceptors contribute to tissue protection after DSS-induced intestinal inflammation and injury by controlling microbiome composition. Vancomycin-susceptible gram-positive bacterial population increases the susceptibility of mice to colitis in the absence of TRPV1+ nociceptors.
In a murine model of intestinal damage and inflammation, targeted chemogenetic silencing, adenoviral-mediated colon-specific silencing, or pharmacological ablation of TRPV1+ nociceptors resulted in increased susceptibility, suggesting that TRPV1+ nociceptors in the gut protect against tissue damage.
When TRPV1+ nociceptors are transiently silenced or permanently ablated, changes in the intestinal microbiota occur, and transplantation of microbes from mice with dysregulated nociception worsens intestinal injury and inflammation. TRPV1+ nociceptor-mediated tissue protective actions have been shown to be associated with Gram+ bacterial modifications, and selective colonization of germ-free (GF) mice with Gram-positive Clostridium species enhances tissue protection. Furthermore, chemogenetic silencing or pharmacological ablation of TRPV1 + nociceptors decreased levels of nociceptor-derived substance P, whereas therapeutic administration of substance P mitigated severe inflammation in animals with defective nociception.
Compared with healthy controls, intestinal biopsies from IBD patients showed dysregulated TRPV1 + nociceptor innervation and altered nociceptor-associated gene expression, suggesting that this dysregulation likely developed through an evolutionary process due to sustained chronic intestinal inflammation.
Thus, nociceptors innervating the gut play an important role in modulating the composition of the microbiota to reduce gut inflammation and improve gut tissue health.
Limitations of the study
There are important limitations to this research. Additional metabolomic and transcriptomic investigations are required to determine the mechanisms underlying the control of Clostridium spp. by TRPV1+ nociceptors. Further research is needed to differentiate DRG and vagus nerve populations, despite the specificity of chemogenetic modification to TRPV1+ nociceptors innervating the colon.
Further research with innovative gnotobiotic and chemogenetic mouse models is warranted to address the cross-talk between nociceptors and microbiota, following acute neuronal stimulation.