Gut infections can train the brain’s immune defences

New study led by CITIID researchers at the University of Cambridge reveals that gut infections can influence immune responses in the brain and its protective lining, creating a long-lasting defence against life-threatening blood infections. 

Protected inside the solid bone of the skull, the brain is surrounded by a watertight layer of tissue called the meninges. It has long been unclear how the body defends the brain against microbial invasion and infection, as many immune cells and antibodies circulating in the bloodstream are largely kept out of the brain by protective barriers. 

Published today in Nature Neuroscience, the study has shown that CD4+ T helper cells, white blood cells that coordinate immune defence, migrate from the gut to the brain and meninges after an intestinal infection.¹  

Professor Menna Clatworthy's group at CITIID previously discovered that antibody-producing immune cells can travel from the gut to the meninges.² In this new study, the team investigated whether other key immune defenders follow the same path. 

Using animal models infected with various gut pathogens, Aaron Fleming and Karen Neish from the lab found that gut infections not only changed the type of CD4+ T cells in the gut, but also altered cells in the meninges and the brain. 

To find out how CD4+ T cells affect the meninges and brain, the team challenged the mice with bacteria directly into the bloodstream, the route which pathogens use to reach the brain during meningitis. They found that these cells in mice that had experienced a gut infection mounted a faster, stronger local immune response in the brain and meninges, preventing the bacteria from invading deeper into brain tissue.  

These findings reveal a link between the immune system of the gut and the meninges and brain. An infection in the gut can establish long-lasting immune memory at the brain borders, strengthening the brain’s defence against blood-borne pathogens.

Professor Menna Clatworthy, senior author and CITIID Director from the Department of Medicine, University of Cambridge

Beyond protecting against infection, the findings offer a potential biological explanation for mood disorders linked to bowel disease, such as the Crohn’s disease and ulcerative colitis. 

CD4+ T helper cells coordinate immune responses by producing signals called cytokines. Recent studies have shown that some nerve cells (neurons) can directly recognize CD4+ T cell cytokines, and in animal models, an excess of these signals can lead to anxiety-type behaviour. This new study shows that gut-derived CD4+ T cells can migrate to the brain and its surrounding membrane, providing a local source of cytokines right next to neurons.

Reference 

1. Fleming, A., Neish, K., Di Marco Barros, R. et al. Intestinal infections establish antigen-specific, long-lived memory CD4+ T cells in the brain and meninges. Nat Neurosci (2026). https://doi.org/10.1038/s41593-026-02428-4 
2. Fitzpatrick, Z., Frazer, G., Ferro, A. et al. Gut-educated IgA plasma cells defend the meningeal venous sinuses. Nature 587, 472–476 (2020). https://doi.org/10.1038/s41586-020-2886-4