Summary: Researchers have mapped the exact molecular “phone line” that lets the gut’s immune system signal the brain during parasitic infection. The study reveals a direct relay between two rare epithelial cell types—tuft cells and enterochromaffin (EC) cells—through which the immune system suppresses appetite by activating vagal nerve pathways.
When tuft cells detect parasite-derived metabolites, they release acetylcholine in a two-phase pattern. That acetylcholine stimulates nearby EC cells to release serotonin, which in turn activates vagal afferents that signal the brain to reduce food intake. This stepwise signaling explains why appetite loss often appears only days after infection, once the immune response becomes established.
Key Facts
- The Two-Cell Relay: Tuft cells act as sentinels that detect parasites; EC cells act as transmitters that communicate with nervous system fibers.
- Neuronal Mimicry: Tuft cells use acetylcholine to communicate, yet they lack the classic neuronal release machinery.
- Two-Phase Release: Tuft cells emit a rapid, transient acetylcholine burst first, followed by a sustained, low-level release after immune activation—only the latter is sufficient to drive serotonin release from EC cells and activate vagal pathways.
- Broader Relevance: Because tuft cells exist throughout the body—in the gut, airways, gallbladder and other mucosal surfaces—this pathway may contribute to chronic gut disorders such as irritable bowel syndrome (IBS), food intolerances and visceral pain.
Source: UCSF
Anyone who’s had a serious stomach bug knows the lingering appetite loss that can follow—sometimes lasting long after the initial symptoms. The same persistent appetite suppression is common in people chronically infected with parasitic worms. Until now, the molecular steps linking the immune response in the gut to those behavioral changes were unclear.
Scientists at the University of California, San Francisco (UCSF) have traced the molecular pathway that connects immune sensing in the gut to changes in brain-driven behavior. Their findings explain how an immune response to parasites triggers the nervous system to curb appetite.
“We wanted to understand not only how the immune system fights parasites, but how it recruits the nervous system to change behavior,” said co-senior author David Julius, PhD, professor and chair of Physiology at UCSF and a 2021 Nobel Prize laureate. “There’s an elegant molecular logic to how this communication unfolds.”
Published in Nature on March 25, the study identifies a previously unrecognized paracrine signaling axis between tuft cells and EC cells that mediates gut-to-brain communication during parasitic infection. The mechanism may also shed light on a range of gastrointestinal disorders involving chronic discomfort.
How tuft cells and EC cells communicate
The research focused on two specialized, relatively rare epithelial cell types in the intestinal lining. Tuft cells act as pathogen sensors and initiate type 2 immune responses, while enterochromaffin (EC) cells are known serotonin producers that communicate with afferent nerve fibers and can induce sensations such as nausea and pain.
Using genetically engineered sensor cells placed adjacent to tuft cells under microscopy, first author Koki Tohara, PhD, detected acetylcholine release from tuft cells when those cells encountered succinate—a metabolite released by parasitic worms. In laboratory gut tissues containing EC cells, acetylcholine exposure triggered serotonin release; that serotonin then activated vagal nerve fibers known to carry gut signals to the brain.
Tohara emphasized that tuft cells achieve acetylcholine signaling without the conventional vesicular release apparatus and excitable membranes characteristic of neurons. Instead, tuft cells employ two distinct release modes: an acute burst in immediate response to parasite-derived signals, and a later, constitutive “leak-like” release that accompanies type 2 inflammation and epithelial tuft cell expansion.
Only the sustained acetylcholine output was sufficient to stimulate EC cells to secrete serotonin at levels necessary to engage vagal afferents and suppress appetite. This two-step process provides a built-in confirmation mechanism: the gut waits for persistent evidence of infection before issuing a behavioral command to the brain.
“This explains why you may feel fine right after exposure but begin to feel sick once the infection is established,” Julius said. “The gut effectively verifies that a threat is real and persistent before prompting behavioral changes like appetite loss.”
Evidence and implications
To test the physiological importance of the pathway, the team infected mice with parasitic worms and measured feeding behavior. Wild-type mice with functional tuft cell acetylcholine signaling reduced food intake as infection progressed. Mice engineered to lack the acetylcholine-producing machinery in tuft cells continued to eat normally, confirming the molecular chain’s role in driving appetite loss.
These results point to potential routes for intervention. Modulating tuft cell output could help manage symptoms of parasitic infections and may offer therapeutic avenues for disorders in which similar epithelial-to-neural signaling contributes to chronic gut symptoms.
Because tuft cells are present across multiple organs, disruptions in this signaling axis could play a role in noninfectious conditions such as IBS, food intolerances and chronic visceral pain, making the pathway a candidate target for future research and drug development.
The work was conducted in collaboration with Stuart Brierly, PhD, and his laboratory at the University of Adelaide.
Key Questions Answered:
A: The gut “double-checks” the threat. Tuft cells emit a robust appetite-suppressing signal only after the infection is confirmed and the immune response progresses, preventing unnecessary behavioral changes from transient signals.
A: In part, yes. The study shows that immune-related epithelial cells can use neurotransmitter chemistry—acetylcholine and serotonin—to convey danger signals to the nervous system, producing sensations like nausea and discomfort.
A: Potentially. Because tuft cells and this signaling pathway are implicated in multiple gut disorders, targeting their output could help reduce chronic nausea, pain and other symptoms associated with IBS and related conditions.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The referenced journal paper was reviewed in full.
- Additional context was added by editorial staff to clarify implications and experimental evidence.
About this neurology and aging research news
Author: Laura Kurtzman
Source: UCSF
Contact: Laura Kurtzman – UCSF
Image: The image is credited to Neuroscience News
Original Research: Open access. “Parasites Trigger Epithelial Cell Crosstalk to Drive Gut-Brain Signaling” by Kouki K. Touhara et al., published in Nature. DOI:10.1038/s41586-026-10281-5
Abstract
Parasites Trigger Epithelial Cell Crosstalk to Drive Gut-Brain Signaling
Parasitic infections modify both immune and sensory responses, yet how these systems cooperate to produce protective behaviors is incompletely understood. The gut epithelium contains specialized sensory cells that detect pathogens and irritants. Among them are cholinergic tuft cells, which sense parasites and initiate type 2 immune responses, and serotonergic enterochromaffin (EC) cells, which detect irritants and communicate with afferent nerve fibers to transmit nociceptive signals.
This study demonstrates that paracrine signaling between tuft cells and EC cells provides a mechanism for neuro–immune interaction and gut–brain communication. Tuft cells employ two modes of acetylcholine release—an acute response to parasite metabolites and a constitutive, leak-like release during type 2 inflammation—despite lacking synaptic vesicles and excitable membranes. While both modes can stimulate muscarinic receptors on crypt EC cells, only the sustained acetylcholine release produces serotonin levels sufficient to activate vagal afferents that suppress food intake.
The described two-phase paracrine signaling mechanism explains the transition from an initially asymptomatic phase to an established symptomatic disease during parasitic infection, where coordinated type 2 immune and sensory signaling within the gut–brain axis drives protective behavioral responses.