Researchers at UC San Francisco have now identified the biological pathway that links the gut’s immune response to the brain during a parasitic infection. Their work shows how signals from the immune system can actively reduce the desire to eat.

“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.”

The study, published in Nature on March 25, uncovered an unexpected way that two types of cells communicate. This discovery may also help explain a range of digestive issues, including food intolerances and irritable bowel syndrome.

How Gut Cells Communicate With the Brain

The research focused on two uncommon cell types found in the gut. Tuft cells act as detectors that sense parasites and initiate immune defenses. Enterochromaffin (EC) cells release chemical signals that stimulate nerve pathways connected to the brain. These EC cells are known to produce sensations such as nausea, pain, and general gut discomfort, but it was unclear whether they directly interact 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.

To investigate, first author Koki Tohara, PhD, a postdoctoral researcher at UCSF, used genetically engineered sensor cells placed next to tuft cells under a microscope. When the tuft cells were exposed to succinate, a compound released by parasitic worms, the nearby sensor cells lit up. This revealed 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 then activated vagal nerve fibers, which carry 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 Delayed Signal That Explains Appetite Loss

The researchers also found that tuft cells release acetylcholine in two separate phases. This helps explain why appetite loss often appears later rather than immediately after infection.

At first, tuft cells release a short burst of acetylcholine. As the immune response builds and tuft cells increase in number, they begin producing a slower, sustained release of the same signal. This prolonged release 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.”

Broader Implications for Gut Disorders

To test whether this pathway affects behavior outside the lab, the team studied mice infected with parasitic worms. Mice with normal tuft cell function ate less as the infection progressed. In contrast, mice that lacked the ability to produce acetylcholine in their tuft cells continued eating normally. This confirmed that the signaling pathway directly drives appetite changes.

These findings could eventually help guide new treatments for 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 beyond parasites.

Tuft cells are found in several parts of the body, including the airways, gallbladder, and reproductive system, not just the gut. Disruptions in this newly identified signaling pathway may play a role in conditions such as irritable bowel syndrome, food intolerances, and chronic visceral pain.

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