Parasites trigger epithelial cell crosstalk to drive gut–brain signalling

Mar 26, 2026Nature

Parasites cause gut lining cells to communicate and influence gut-brain signaling

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Gut-Brain Axis on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

Tuft cells in the gut epithelium release acetylcholine through two distinct mechanisms during parasitic infections.

Cholinergic tuft cells are involved in initiating type 2 immune responses against parasites.
Serotonergic enterochromaffin cells detect irritants and communicate with nerve fibers to transmit pain signals.
Paracrine signaling between tuft cells and enterochromaffin cells facilitates neuro-immune interactions.
Acute release of acetylcholine occurs in response to metabolites from parasites, while a continuous 'leak-like' release happens during type 2 inflammation.
Only the sustained acetylcholine release from tuft cells is sufficient to trigger serotonin levels that activate vagal afferent neurons, leading to reduced food intake.
This mechanism illustrates the progression from asymptomatic parasitic infection to symptomatic disease, highlighting the collaboration of immune and sensory pathways in the gut-brain axis.

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Parasitic infections modulate both immune and sensory responses, but how these systems collaborate to elicit protective behaviours remains incompletely understood. The gut epithelium contains specialized sensory cells that detect pathogens and irritants. These include cholinergic tuft cells, which sense parasites and initiate type 2 immune responses, as well as serotonergic enterochromaffin (EC) cells, which detect irritants and communicate with afferent nerve fibres to transmit nociceptive signals. Here we show that paracrine signalling between these cells constitutes a mechanism for neuro-immune interaction and gut-brain communication. We find that tuft cells use two distinct mechanisms of acetylcholine (ACh) release despite lacking synaptic vesicles and excitable membranes. These include acute release in response to parasite-derived metabolites, followed by constitutive 'leak-like' release, which occurs with type 2 inflammation. Although both mechanisms can activate muscarinic receptors on crypt-residing EC cells, only the sustained mode of ACh release elicits levels of serotonin sufficient to stimulate vagal afferent neurons that suppress food intake. This two-phase paracrine signalling mechanism explains how parasitic infection progresses from an initial asymptomatic phase to symptomatic established disease, in which type 2 immune and sensory signalling pathways within the gut-brain axis collaborate to evoke protective behaviours. 1-3 4-6