Scientists Just Found Why You Suddenly Lose Your Appetite When Sick

Scientists finally cracked the mystery of why infections kill your appetite—and it all starts with hidden gut cells talking to your brain.

Anyone who has gone through a severe stomach illness knows the experience. Your appetite disappears and often stays low even after the worst symptoms pass. For millions of people worldwide living with chronic parasitic worm infections, this same pattern occurs. Until now, scientists have not fully understood why.

Researchers at UC San Francisco have now mapped the biological pathway that links the gut’s immune response to the brain during a parasitic infection. Their findings explain how the immune system can actively suppress appetite.

“The question we wanted to answer was not just 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 recipient of the 2021 Nobel Prize in Physiology or Medicine. “It turns out there’s a very elegant molecular logic to how that happens.”

Published in Nature today (March 25), the study reveals a previously unknown form of communication between two specialized cell types. The discovery may also help explain a variety of gut-related conditions, including food intolerances and irritable bowel syndrome.

Gut Cells Link Immune Response to Brain Signals

The research centered on two rare types of cells found in the gut. Tuft cells act as sensors that detect parasites and trigger immune defenses. Enterochromaffin (EC) cells, on the other hand, release chemical signals that stimulate nerve fibers connected to the brain. These EC cells are known to produce sensations such as nausea, pain, and general gut discomfort. However, it was unclear whether they interact directly with tuft cells.

“My lab has long been interested in how tuft cells, after they initially respond to a parasitic infection, release signals to other cell types,” said co-senior author Richard Locksley, MD, a UCSF immunologist.

First author Koki Tohara, PhD, a postdoctoral researcher at UCSF, designed an experiment to observe this interaction. He placed specially engineered sensor cells next to tuft cells under a microscope. When the tuft cells were exposed to succinate, a chemical produced by parasitic worms, the sensor cells lit up. This showed that tuft cells were releasing acetylcholine, a signaling molecule typically associated with nerve cells.

When acetylcholine was introduced to lab-grown gut tissue containing EC cells, those cells responded by releasing serotonin. This, in turn, activated vagal nerve fibers that transmit signals from the gut to the brain.

“What we found is that tuft cells are doing something neurons do, but by a completely different mechanism,” Tohara said. “They’re using acetylcholine to communicate, but without any of the usual cellular machinery that neurons rely on to release it.”

A Two-Stage Signal That Explains Delayed Appetite Loss

The researchers also found that tuft cells release acetylcholine in two stages. This helps explain why appetite loss often does not happen immediately after infection.

In the early stage, tuft cells release a short burst of acetylcholine. Later, once the immune system is fully activated, the number of tuft cells increases. At that point, they produce a steady and prolonged release of acetylcholine, which is strong enough to activate EC cells and send signals to the brain.

“This explains why you feel fine at first but then start to feel sick as the infection becomes established,” Julius said. “The gut is essentially waiting to confirm that the threat is real and persistent before it tells the brain to change your behavior.”

Beyond Parasites: Potential Impact on Gut Disorders

To see whether this pathway affects real-world behavior, the team studied mice infected with parasitic worms. Mice with normal tuft cell function ate less as the infection progressed. In contrast, mice engineered so that their tuft cells could not produce acetylcholine continued eating normally. This confirmed that the signaling pathway directly influences appetite.

The findings may open the door to new ways of treating symptoms linked to parasitic infections.

“Controlling the outputs of tuft cells could be a way to control some of the physiologic responses associated with these infections,” Locksley said, noting that the implications may extend further.

Tuft cells are not limited to the gut. They are also present in the airways, gallbladder, and reproductive system. Disruptions in this newly identified signaling pathway could play a role in conditions such as irritable bowel syndrome, food intolerances, and chronic visceral pain.

Reference: “Parasites trigger epithelial cell crosstalk to drive gut–brain signalling” by Kouki K. Touhara, Jinhao Xu, Joel Castro, Hong-Erh Liang, Guochuan Li, Mariana Brizuela, Andrea M. Harrington, Sonia Garcia-Caraballo, Tracey O’Donnell, Daniel Neumann, Nathan D. Rossen, Fei Deng, Gudrun Schober, Yulong Li, Richard M. Locksley, Stuart M. Brierley and David Julius, 25 March 2026, Nature.
DOI: 10.1038/s41586-026-10281-5

The research was conducted in collaboration with Stuart Brierly, PhD, and his team at the University of Adelaide in Australia.

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