When a parasitic worm takes up residence in your gut, your body takes a few days to decide it is actually a problem worth acting on. At first you feel fine. Then you do not — nausea sets in, appetite drops, and food becomes less appealing precisely when the infection is establishing itself. Nobody understood why the delay, until a team at the University of California, San Francisco traced the molecular chain of events that makes that happen.
David Julius, the 2021 Nobel laureate in Physiology or Medicine for his work on temperature-sensing receptors, and Richard Locksley, a UCSF immunologist, led a study published in Nature that maps a two-step relay between gut cells most people have never heard of. The first is a tuft cell — a chemosensory cell lining the intestinal tract that detects parasitic intruders. The second is an enterochromaffin cell, which lives nearby in the gut crypts and produces serotonin when activated. The conversation between them, the team found, is what tells the brain to stop eating.
The finding matters because it offers the first clean mechanistic target for irritable bowel syndrome symptoms in years. IBS affects an estimated 4.7 to 6.1 percent of the U.S. population — roughly 15 to 20 million people — based on the largest population-based study of IBS epidemiology published to date, a Rome IV survey of nearly 89,000 U.S. adults published in Gastroenterology in 2023. Yet the current treatment toolkit is largely unchanged from antispasmodics, fiber supplements, and the clinical equivalent of crossed fingers. FDA-approved IBS drugs exist, including rifaximin, eluxadoline, alosetron, and linaclotide — but none of them target the specific tuft cell-to-enterochromaffin cell relay via the Chrm3 muscarinic receptor that this paper describes.
The first author is Koki Tohara, a postdoctoral researcher at UCSF. The work appeared in the journal Nature on March 25, 2026.
How tuft cells talk to enterochromaffin cells — and why that matters for IBS
Tuft cells are named for the tiny hair-like projections on their surface, and they sit throughout the gut, airways, gallbladder, and reproductive tract. When they detect parasitic molecules — specifically the metabolites that worms release — they do not fire a neuron. They release acetylcholine, the same neurotransmitter neurons use, but without any of the usual cellular machinery that neurons rely on to package and release it. They lack synaptic vesicles and the choline transporters that neurons use to replenish their supply. They do it anyway, through two distinct phases: an acute burst the moment a parasite is detected, followed by a slower, continuous leak-like release that persists during type 2 inflammation.
The acetylcholine does not travel far. It acts locally on enterochromaffin cells in the adjacent crypts, which express a specific muscarinic receptor — Chrm3 — that responds only to muscarinic signals, not nicotinic ones. When atropine, a muscarinic blocker, was applied to these cells, the signal vanished. Mecamilamine, a nicotinic blocker, had no effect. That specificity matters: it rules out a class of potential off-target interactions and narrows down which receptor is doing the actual work.
The researchers engineered mice to lack acetylcholine-producing machinery in their tuft cells. Those mice kept eating normally during parasitic worm infection, while normal mice ate significantly less as the infection took hold. The behavioral change disappeared entirely when the molecular chain was broken — confirming that the tuft-to-enterochromaffin relay, and not some parallel pathway, drives the appetite response.
The delay in feeling sick, the team found, is not accidental. The gut appears to wait until it has confirmed a threat is real and persistent before committing to the behavioral change. "This explains why you feel fine at first, but then start to feel sick as the infection becomes established," Locksley said in a UCSF News release. "The gut is essentially waiting to confirm that the threat is real and persistent before it tells the brain to change your behavior." It is a calibration mechanism, not a reflex.
Stuart Brierly and his lab at the University of Adelaide in Australia participated in the research.
The IBS connection — and why it is not a stretch
IBS is not a parasitic infection. But the signaling pathway the team mapped — tuft cells talking to enterochromaffin cells via Chrm3, producing serotonin that influences gut-brain communication — is not specific to parasites. It is a general feature of how the gut monitors and reports distress. If that pathway is hypersensitive, overactive, or misfiring in the absence of any real threat, it could produce the chronic visceral pain, nausea, and altered appetite that define IBS.
"The pathway we have identified is a communication channel that exists in everyone," Julius said in the UCSF release. "Disruptions in this channel could contribute to conditions like IBS, food intolerances, and chronic visceral pain." He was careful not to claim the science directly translates to a human treatment — this is a mouse study, and the distance from mouse gut to human IBS is long and littered with failures. But the target itself — Chrm3, specifically located in crypt-residing enterochromaffin cells — is now a named, characterized mechanism rather than a black box.
The interest from a drug development standpoint is obvious: Chrm3 is a well-characterized muscarinic receptor with existing pharmacology. Several muscarinic receptor drugs are already on the market or in development, which means the medicinal chemistry path from target to candidate is more tractable than starting from scratch.
The funding list for the study runs long — NIH, the BRAIN Initiative, the Howard Hughes Medical Institute, the National Natural Science Foundation of China, the New Cornerstone Science Foundation, the XPLORER PRIZE, Australia's NHMRC, the Damon Runyon Cancer Research Foundation, and a Larry L. Hillblom Fellowship all supported the work. That breadth reflects how basic the science is: it is not a pipeline bet, it is a map of an undermapped corner of human physiology.
What to watch next
The obvious next question is whether any lab or company is already working on Chrm3-targeted enteric agents for IBS or related conditions. A muscarinic receptor in the gut is a known object of pharmaceutical interest, but the specific crypt-residing enterochromaffin cell localization adds a precision that was not available before. If someone is already targeting this, they are working with a better address than they had last month.
The deeper bet here is on the tuft cell — a cell type that has gone from curiosity to central player in gut immunology over the past decade. These cells exist throughout the mucosal surfaces of the body. If controlling tuft cell output can modulate the gut-brain axis in the way this paper describes, the scope of potential applications extends beyond IBS to conditions involving visceral hypersensitivity more broadly.
The timing is also worth noting: this is basic science published in March 2026. Even in the most optimistic pharma scenario, a target like Chrm3 in enterochromaffin cells is years from an IND filing, let alone a Phase 2 result that would actually tell you whether the mechanism holds in human IBS patients. The biology is real. The translation is not yet.
