Parasites trigger a gut-to-brain signal that cuts food intake during infection

By Vijay Kumar MalesuReviewed by Susha Cheriyedath, M.Sc.Mar 29 2026

A new Nature study shows how parasite-driven inflammation in the gut activates a tuft cell to serotonin to vagus nerve pathway, helping explain why infection can suppress appetite.

Study: Parasites trigger epithelial cell crosstalk to drive gut–brain signalling. Image Credit: Chizhevskaya Ekaterina / Shutterstock

In a recent study published in the journal Nature, a group of researchers investigated how intestinal epithelial cells interact to trigger gut-brain signaling and changes in food intake during parasitic infections.

Did you know that gut infections can influence how much you eat or even how you feel? The gastrointestinal tract acts as a sensory system that detects harmful stimuli and communicates with the brain.

Specialized epithelial cells, such as enterochromaffin (EC) cells and tuft cells, are important in sensing irritants and parasites. EC cells release serotonin (5-HT), which activates nerve pathways linked to pain and nausea, while tuft cells detect parasites and initiate immune responses. However, how these cells coordinate to influence brain signaling remains unclear.

Further research is needed to explain how the gut-brain connection influences feeding-related responses during infection.

Tuft Cell and EC Cell Study Design

The study used a combination of cellular, molecular, and animal-based experimental approaches to examine communication between intestinal tuft cells and EC cells. Gut epithelial structure and functionality were replicated using organoids of mouse intestinal tissue.

Calcium imaging techniques were applied to monitor cellular activation, using genetically encoded indicators such as genetically encoded calcium indicator (GCaMP) and serotonin sensors like genetically encoded GPCR-Activation-Based 5-HT sensor (gGRAB5-HT).

To evaluate acetylcholine release during the experiment, biosensor cells were created that express different receptors (e.g., the muscarinic acetylcholine receptor (mAChR) subtype 1 (M1R) and the 5-hydroxytryptamine receptor 3 (5-HT3)). They were then studied using electrophysiological methods, including the patch-clamp technique, to evaluate tuft cell electrophysiological properties and demonstrate that tuft cells do not exhibit conventional forms of excitability. Several pharmacological agents were used to separate the functional muscarinic and nicotinic receptor pathways involved in acetylcholine release from the biosensor cells.

Genetically modified mice missing tuft cells or lacking choline acetyltransferase, the enzyme needed to make acetylcholine, were included as the animal models. Type 2 immune responses were induced with interleukin-25, while parasitic infection was modeled using Nippostrongylus brasiliensis.

Researchers recorded neural activity in vagal afferent fibers ex vivo from gut-nerve preparations. Food intake and other spontaneous behaviors were measured to evaluate the physiological effects of gut-brain signaling.

Tuft Cell Acetylcholine Activates Serotonin Release

The findings revealed a previously unrecognized communication pathway between tuft cells and EC cells that links immune responses to neural signaling. Tuft cells were shown to release acetylcholine through two distinct mechanisms. Tuft cells were shown to release acetylcholine through two distinct mechanisms. First, they released acetylcholine acutely in response to succinate, a protist-derived signal, through TRPM5-dependent signaling. Later, during type 2 inflammation induced by interleukin 4 or interleukin 25, they exhibited a sustained, “leak-like” release of acetylcholine.

Tuft cells can release acetylcholine without having synaptic vesicles or being electrically excitable. This means that tuft cells have their own special way of releasing neurotransmitters. Instead of activating all mAChRs, acetylcholine released from tuft cells can activate only muscarinic receptors on EC cells in crypts, predominantly activating mAChR subtype 3 (M3R). Activation of M3R leads to the production of intracellular calcium and the subsequent stimulation of serotonin release.

It was observed that the magnitude and duration of acetylcholine release controlled the effects. Acute acetylcholine release generated limited serotonin output, insufficient to strongly activate vagal nerve fibers. In contrast, sustained acetylcholine release during inflammation elevated serotonin levels, which robustly activated vagal afferent neurons via 5-HT3 receptors.

This signaling pathway was demonstrated experimentally in genetically modified mice, which relied on tuft cells and the synthesis of acetylcholine. Mice lacking tuft cells or choline acetyltransferase showed reduced serotonin release and diminished neural activation. Also, pharmacological inhibition of muscarinic receptors decreased EC cell stimulation, underscoring the significance of cholinergic stimulation.

Parasite Infection Reduces Food Intake

Nippostrongylus brasiliensis parasitic infection further confirmed these findings in a physiological setting. This included increased serotonin levels in intestinal crypts, augmented vagal nerve activity, and receptor activation in brainstem areas, including the nucleus of the solitary tract. This pathway was either absent or severely attenuated in mice with tuft cell dysfunction or acetylcholine synthesis deficiency.

Sustained activation of the gut-brain connection can reduce food intake. While acute stimulation of tuft cells had minimal effects, type 2 inflammation reduced food intake, especially during the peak inflammatory phase rather than immediately after infection. This suggests that the gut uses prolonged signaling to communicate ongoing infection to the brain, triggering adaptive responses that may help limit nutrient availability to parasites.

Gut-Brain Axis and Feeding Implications

This study demonstrates that intestinal tuft cells and EC cells form a critical communication network that links immune detection of parasites to brain-mediated changes in feeding behavior. The pathway drives serotonin release when tuft-cell-derived acetylcholine activates muscarinic receptors on crypt EC cells, and the released serotonin then stimulates vagal afferent neurons and influences feeding behavior during infectious states. Acetylcholine being released in two distinct time phases supports the idea that the gastrointestinal tract has a mechanism to differentiate between short- and long-term threats.

These findings provide new insights into the gut-brain axis and have important implications for understanding changes in feeding behaviors and gastrointestinal disease processes, as well as neuro-immune interactions. Therapeutic strategies targeting the identified pathway may eventually provide an innovative approach to treating symptoms and metabolic disturbances associated with infection.