Intestinal innervating nociceptors regulate the intestinal microbiota and promote tissue protection

Intestinal innervating nociceptors regulate the intestinal microbiota and promote tissue protection

According to a recently published study in Cell Reports Substance P, produced by nociceptors in the intestinal lining, protects against inflammation and tissue damage by increasing the number of beneficial microbes.

Lernen: Darminnervierende Nozizeptoren regulieren die Darmmikrobiota, um den Gewebeschutz zu fördern. Bildnachweis: Explode/Shutterstock

The results also highlighted the presence of reduced numbers of nociceptors in patients with inflammatory bowel disease (IBD), along with significant disruptions in the pain-signaling gene expression profile.

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The immune system evolved alongside large microbial communities residing at 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, when the microbial population is disrupted, it causes stress and inflammatory diseases.

Several inflammatory diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis, and multiple sclerosis, cause suffering, reduce quality of life, and lead to chronic pain. The sensation of pain is triggered to warn of 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 the transient receptor 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 either enhance or inhibit the downstream inflammatory cascade. However, considerable uncertainty remains regarding the role of pain-sensing neurons in intestinal inflammatory conditions.

The present study investigated the innervation of TRPV1+ nociceptor cells in the intestine of mice and their function during homeostasis and inflammation. This study evaluated the susceptibility of TRPV1+ nociceptors in intestinally injured and inflamed mice 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 naive and inflamed mouse colons.

TRPV1-tdTomato was used in conjunction with the pan-neuronal marker βIII-tubulin to identify TRPV1+ nociceptor innervation in the inner lining of the colon at steady state and after dextran sodium sulfate (DSS) exposure in mice with intestinal injury and inflammation.

A chemogenetic strategy to acutely silence TRPV1 nociceptors in vivo by producing TRPV1hM4Di mice, in which TRPV1+ nociceptors exclusively express the inhibitory designer receptors, was activated.

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Dorsal root ganglia (DRG) nociceptor marker gene expression was assessed in steady-state DRGs obtained from B6 mice treated with DMSO or RTX. Mice treated with DMSO or RTX had their fecal microbial composition assessed by 16S rRNA gene sequencing and principal coordinate analysis.

DMSO- or RTX-treated mice administered vehicle or broad-spectrum antibiotic cocktail (ABX), vancomycin, or neomycin were exposed to DSS for five days while disease and recovery were monitored daily.

The colonic substance P and CGRP levels in mice treated with DSS, DMSO or RTX. Clinical disease score, colon length, H&E staining, and daily weight loss of the distal colon were used to track the disease and recovery of DSS-treated DMSO- or RTX-treated Tac1/mice.

The results

The researchers found that TRPV1+ nociceptors contribute to tissue protection after DSS-induced intestinal inflammation and injury by controlling the composition of the microbiome. A 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 higher susceptibility, suggesting that TRPV1+ nociceptors in the intestine protect against tissue damage.

When TRPV1+ nociceptors are transiently silenced or permanently abated, changes in the gut microbiota occur, and transplantation of microbes from mice with dysregulated nociception worsens gut injury and inflammation. TRPV1+ nociceptor-mediated tissue protective effects have been shown to be associated with Gram-positive bacterial modifications, and selective colonization of germ-free (GF) mice with Gram-positive Clostridium species improves tissue protection. Furthermore, chemogenetic silencing or pharmacological ablation of TRPV1+ nociceptors reduced levels of nociceptor-derived substance P, while therapeutic administration of substance P attenuated severe inflammation in animals with impaired nociception.

Compared to healthy controls, intestinal biopsies from IBD patients showed dysregulated TRPV1+ nociceptor innervation and altered nociceptor-associated gene expression, suggesting that this dysregulation likely evolved from an evolutionary process due to persistent chronic intestinal inflammation.

Thus, the nociceptors innervating the gut play a significant role in modulating microbiota composition to reduce intestinal inflammation and improve intestinal tissue health.

Limitations of the study

There are significant limitations to this research. Additional metabolomic and transcriptomic research is needed to determine the mechanisms underlying the control of Clostridium spp. underlie. through TRPV1+ nociceptors. Despite the specificity of the chemogenetic modification for colon-innervating TRPV1+ nociceptors, further research is needed to distinguish between the DRG and vagus nerve populations.

Further research using innovative gnotobiotic and chemogenetic mouse models is warranted to investigate the interaction between nociceptors and microbiota following acute neuronal stimulation.

Reference:

• Zhang, W., Lyu, M., Bessman, N., et al. (2022). Darminnervierende Nozizeptoren regulieren die Darmmikrobiota, um den Gewebeschutz zu fördern. Zelle. doi: 10.1016/j.cell.2022.09.008 https://admin.azonetwork.com/newsmedical/news-alt/new

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