Neurones in the gut help fight dangerous infections

Researchers have identified an unexpected role of pain neurones in eliciting the immune response within the gut.

The gut is one of the body’s main barriers to infection. It has the ability to discern food, harmless microbes and dangerous pathogens by looking at the differences in antigens. If an antigen molecule is recognised as ‘non-self’, an immune response is triggered to clear the invading pathogen. This recognition and neutralisation process requires the coordination of epithelial and immune cells, which gather within the intestinal walls in specific locations called Peter’s patches. These patches are especially prone to bacterial tissue invasion, therefore require the presence of these specialised cells. Without such defence mechanisms the body would be vulnerable to widespread infection, including sepsis.

The enteric nervous system is a division of the autonomic nervous system which governs the working of the gastrointestinal tract. It contains a variety of neural circuits which modulate specific functions such as muscle contraction, blood flow and mucosal transport. Although previously established, the exact role of gut pain neurones, known as nociceptors, in the immune response was not known. Nociceptors are found throughout the body, responsible for the perception of pain from potentially harmful stimuli including intense heat and mechanical injury. They can also sense the presence of pathogens through the detection of antigens, which can result in pain during an infection. Recent studies into gut nociceptor-mediated immunity have identified an additional role for these neurones in directly influencing the cellular composition of Peyer’s patches to modulate the gut barrier to infection.

Peyer’s patches are collections of follicles which contain specialised cells called M cells. These cells act as a net to catch antigens from pathogens or resident gut microbes, and transfer them to underlying immune cells to assess whether an immune response should be triggered. M cells are extremely important for correct immune surveillance, however bacteria such as Salmonella exploit these cells as a means of gaining entry into the tissue. This is extremely dangerous as it can cause widespread body infection and sepsis.

Peyer’s patches also have a good neural connection as they lie close to nociceptors. Working with mice, the researchers found a specific subpopulation of nociceptors surrounding these patches which specifically express ion-channel proteins TRPV1 and Nav1.8. Rather than encouraging the gut’s usual antimicrobial defence mechanisms such as activation of immune cells or release of antimicrobial peptides, the neurones send a signal in the form of a neuropeptide called CGRP to decrease the number of M cells within the Peyer’s patch. This reduces the chance of bacteria entering the surrounding tissue through the M cells and causing infection.

The scientists genetically engineered mice to lack either TRPV1 and Nav1.8 channels to determine the effect of removing these channels on immunity. What they found was that these mice had significantly less segmented filamentous bacteria (SBF), a type of resident gut microbe which coat gut epithelial cells, including M cells. These bacteria play an important role in gut immunity as they compete for gut colonisation with harmful pathogens, preventing them from multiplying on the intestinal surface and causing infection. They also found a link between M cell number and levels of SBF, suggesting a nociceptor-induced decrease in M cell number causes an increase in SBF to further increase protection against pathogens.

The researchers have successfully identified a novel role for nociceptors in gut immunity. Establishing this flow of interactions between multiple cell types and microbes has shone light on the complexity of gut immunity and our bodies in general. The enteric nervous system is an area of promising research as it could provide answers to multiple gastrointestinal diseases and vulnerability to infections which start in the gut.

Reference: Lai N.Y., Musser M.A., Pinho-Ribeiro F.A., Baral P. et al. (2020) Gut-Innervating Nociceptor Neurons Regulate Peyer’s Patch Microfold Cells and SFB Levels to Mediate Salmonella Host Defense. Cell 180(1):33-49.e22. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31813624?dopt=Abstract

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