Anyone who has survived a bad stomach illness knows that feeling. Loss of appetite begins and lingers even after the initial illness. The same is true for millions of people around the world who are chronically infected with parasites. But scientists have long been puzzled as to exactly why.
Now, researchers at the University of California, San Francisco have traced the molecular pathways that connect the gut immune system to the brain during parasitic infections to explain how the immune system triggers anorexia.
The question we wanted to answer was not only how the immune system fights parasites, but also how to recruit the nervous system to change behavior. It turns out there’s a very sophisticated molecular logic to how that happens. ”
Dr. David Julius, co-senior author, UCSF Professor and Professor of Physiology, and 2021 Nobel Prize Laureate in Physiology or Medicine
The survey results are nature A March 25 study reveals an unexpected communication system between two types of cells that may shed light on a wide range of conditions associated with intestinal discomfort, from food intolerances to irritable bowel syndrome.
two cells communicating
A new study focused on two rare cell types in the intestine. Tuft cells detect parasites and trigger immune defenses, while enterochromaffin (EC) cells release signals that activate nerve fibers leading to the brain. EC cells are known to cause sensations such as nausea, pain, and intestinal discomfort, but it was unclear whether EC cells communicate with tuft cells.
“My lab has long been interested in how tuft cells release signals to other cell types after their initial response to parasitic infection,” said co-senior author Richard Locksley, M.D., Ph.D., an immunologist at UCSF.
Lead author Dr. Koki Higashihara, a postdoctoral fellow at UCSF, found the answer by placing genetically engineered sensor cells right next to tuft cells under a microscope. When the tuft cells were exposed to succinate, a molecule produced by the parasite, the sensor cells lit up, revealing that the tuft cells were releasing acetylcholine, a chemical messenger primarily used by neurons.
When acetylcholine was added to laboratory-grown intestinal tissue containing EC cells, serotonin was released. This activated the vagus nerve fibers that carry signals from the gut to the brain.
“What we discovered is that tuft cells do the same thing as neurons, but the mechanism is completely different,” Professor Higashihara said. “They use acetylcholine to communicate, but they don’t use any of the normal cellular machinery that neurons rely on to release acetylcholine.”
The researchers also discovered that tuft cells release acetylcholine in two distinct stages. This explains why appetite often does not decrease until several days after infection. In the first stage, acetylcholine is released for a short time. Then, after the immune system mounts a full response, tuft cells proliferate and slowly and sustainably release enough acetylcholine to activate EC cells.
“This explains why people may feel well at first, but then start to feel unwell once the infection takes hold,” Julius says. “The gut is essentially waiting for confirmation that the threat is real and persistent before telling the brain to change behavior.”
Impact beyond parasites
To test whether this pathway was important outside the lab, the researchers infected mice with the parasite and tracked their food intake. Mice with normal tuft cell function ate less once the infection took hold. Mice engineered to lack the acetylcholine-producing machinery in their tuft cells continued to eat normally, confirming that the molecular chain drives behavioral responses. This new discovery may have implications for treating symptoms of parasitic infections.
“Controlling the output of tuft cells could be a way to control some of the physiological responses associated with these infections,” Professor Locksley said, adding that the study could also have broader implications.
Tuft cells are present throughout the body, not only in the intestines, but also in the respiratory tract, gallbladder, and reproductive tract, and disruption of the newly identified pathway could lead to symptoms such as irritable bowel syndrome, food intolerance, and chronic visceral pain.
The study was conducted in collaboration with Dr. Stuart Brierley and his research group at the University of Adelaide in Australia.
sauce:
University of California, San Francisco
Reference magazines:
KK Higashihara others. (2026). Parasites cause epithelial cell crosstalk and promote gut-brain signaling. nature. DOI: 10.1038/s41586-026-10281-5. https://www.nature.com/articles/s41586-026-10281-5
