Study Reveals How the Gut Communicates Appetite Loss to the Brain

Anyone who has endured a severe stomach illness knows the lingering loss of appetite that often follows. For millions of people chronically infected with parasitic worms, that same symptom can persist—but until now, the cause was unclear. Scientists at UC San Francisco have identified the molecular pathway linking the gut’s immune system to the brain during parasitic infection, showing how the immune system triggers decreased 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. “It turns out there’s a very elegant molecular logic to how that happens.” The findings, published in Nature, uncover a communication system between immune‑sensing and nerve‑interacting cells and may offer insights into digestive conditions such as food intolerances and irritable bowel syndrome. 

The research examined two rare cell types in the gut: tuft cells, which detect parasites and activate immune defenses, and enterochromaffin (EC) cells, which release signals that stimulate nerves connected to the brain. EC cells are central to sensations like nausea or gut discomfort, but whether they interacted with tuft cells had not been known. “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.

First author Koki Tohara resolved this connection by placing engineered sensor cells beside tuft cells under a microscope. When tuft cells encountered succinate—a molecule produced by worms—they released acetylcholine, a chemical typically used by neurons to transmit signals. Further experiments showed that acetylcholine prompts EC cells to release serotonin, which triggers vagal nerve fibers sending messages 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. The team also found that tuft cells release acetylcholine in two phases: a short burst followed by a sustained release days later, explaining why appetite loss develops gradually. “The gut is essentially waiting to confirm that the threat is real and persistent before it tells the brain to change your behavior,” Julius said. 

Experiments in mice confirmed that animals lacking acetylcholine‑producing tuft cells maintained normal eating, while typical mice lost appetite as infection progressed. Locksley noted that modulating tuft cell outputs could one day help reduce symptoms of parasitic and other gut‑related disorders.