The work fits into a broader effort to understand how the immune system maintains balance – a theme underscored by this year's Nobel Prize in Physiology or Medicine for discoveries in immune tolerance.
"The gut isn't just a tube that digests food – it's a highly active organ where the nervous and immune systems are in constant conversation", says Henrique Veiga-Fernandes, senior author of the study and Principal Investigator of CF's Immunophysiology Lab. Published in Nature Immunology, the study not only eavesdrops on a previously unknown three-way dialogue in the gut between the nervous system, the epithelial cells that line it, and the immune system, but also decodes the molecular language that makes those exchanges possible.
To Kill or Repair?
The story began with a simple question: how does the immune system know when to go on the offensive and when to heal?
"The immune system has to perform two opposite functions", says Veiga-Fernandes. "It needs to kill infected or tumour cells – but also promote repair and regeneration when tissues are damaged. We wanted to understand how the body decides between these two very different programmes".
The researchers focused on a neurochemical messenger called VIP – short for vasoactive intestinal peptide – which is released by certain neurons in the gut. They found that neighbouring epithelial cells possess a receptor for VIP, called VIPR1, which acts like a receiver antenna. These epithelial cells form the front line between the body and the outside world, constantly exposed to food, microbes, and potential pathogens.
The Gut's Levers
When the team experimentally activated VIP-releasing neurons in mice, the gut's epithelial cells began producing cytokines that stimulate a type 1 immune response – the body's "killer mode", used to destroy bacteria and infected cells. But when they blocked the receptor VIPR1 in epithelial cells, the balance flipped: the killer response weakened, while a type 2 immune response – the one that drives repair and fights parasites – grew stronger.
The shift was striking. Mice lacking VIPR1 in their epithelial cells became more vulnerable to bacterial infections like Salmonella, yet more resistant to parasitic worms. "This was the big surprise", says Roksana Pirzgalska, first author of the study. "We realised the neurons of the gut are not just fine-tuning immunity locally – they are orchestrating completely different immune programmes".
In other words, the gut's nervous system sits at the railway switch, sensing the environment and deciding which track the immune system should take. When the "killer" track is active, immune cells patrol the intestinal lining, eliminating bacteria and tumour cells. When the "repair" track is engaged, the same tissue focuses on regeneration – rebuilding the delicate epithelial barrier that keeps harmful microbes out.
But how do epithelial cells pass on the message once they've received the VIP signal? "We found that these cells translate the nerve signal into a set of molecular instructions – a cocktail of 'cytokines', the chemical messengers of the immune system", explains Pirzgalska. "You can think of cytokines as the language that epithelial cells use to talk to immune cells. Different immune cells have different receptors for these cytokines, so depending on which ones are released, the immune system knows whether to attack or repair".
Civilisation Diseases
The team found that this neuronal switch is closely linked to feeding behaviour – and therefore to our daily biological rhythms. Eating stimulates the production of the VIP neuropeptide, which makes sense from an evolutionary perspective: every meal brings a risk of ingesting pathogens, so activating the killer track at that time helps protect the gut.
"The problem", says Veiga-Fernandes, "is that modern life has disrupted this rhythm. When people eat late at night or work irregular shifts, they keep the immune system stuck in killer mode. That means the gut doesn't get its normal period of rest and repair".
This, he adds, could contribute to the growing burden of so-called "civilisation diseases" – chronic inflammation, metabolic disorders, and cancer. "Our findings suggest that when circadian rhythms and feeding patterns are out of sync, the gut's neuro-immune switch may be mis-timed, preventing the intestine from properly regenerating".
From Mice to Humans – and Beyond the Gut
Although the experiments were carried out in mice, the researchers confirmed that human intestinal epithelial cells also express the VIPR1 receptor, suggesting that the same neuro-epithelial communication system exists in people. Clinicians at the Champalimaud Clinical Centre, including Ricardo Rio Tinto, helped validate these findings in human tissue.
"This is the first clear evidence that neurons in the gut, which respond to behavioural signals like feeding, can directly coordinate immune responses through epithelial cells – not just locally, but at an organism-wide level", says Veiga-Fernandes. "It's a beautiful example of how closely intertwined behaviour and immunity really are", adds Pirzgalska.
Veiga-Fernandes' lab is now exploring how signals from the brain interact with neuro-epithelial circuits along the so-called brain-body axis, and what similar "railway-switch" mechanisms the nervous system might be operating in other organs, especially in the context of cancer and obesity. "We're realising more and more that nothing in our body works in isolation", he says. "The nervous system, the immune system, the microbiome, metabolism – they're all in continuous dialogue, day and night".
So the next time you sit down for a midnight snack, spare a thought for the silent trains in your gut, switching tracks in the dark.
