UCSF Researchers Uncover How Gut Immune Signals Suppress Appetite During Infection

At UCSF's Mission Bay campus, the patients who most confound clinicians often are not the most acutely ill. They are the chemotherapy patients, long COVID survivors, the people weeks into treatment for a stubborn infection who simply cannot eat, not from nausea, but because something has switched hunger off. A study published March 25 in Nature now maps the molecular mechanism behind that switch, tracing it from two rare cell types in the gut wall to the hunger-regulating circuits of the brain.

The research was co-led by David Julius, PhD, professor and chair of Physiology at UCSF and recipient of the 2021 Nobel Prize in Physiology or Medicine, and immunologist Richard Locksley, MD. The signaling chain begins with tuft cells, gut sentinels that detect parasites and initiate immune defenses. Their output reaches enterochromaffin, or EC, cells, which activate nerve fibers running to the brainstem and hypothalamus. Scientists knew both cell types existed; what connected them was unknown.

First author Koki Tohara, PhD, a postdoctoral researcher in the Julius lab, found the link by placing genetically engineered sensor cells directly beside tuft cells under a microscope. When the tuft cells encountered succinate, a molecule secreted by parasitic worms, the sensors lit up, revealing that tuft cells were releasing acetylcholine, the same chemical messenger neurons use to communicate, but without any of the standard neuronal release machinery.

"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."

The release unfolds in two stages, which explains a pattern clinicians have long observed: patients feel relatively normal early in an infection, then progressively stop eating. Tuft cells first emit a short acetylcholine burst. As the immune response escalates and tuft cell numbers multiply, a slower sustained release follows, strong enough to activate EC cells and fire signals toward the brain's appetite centers.

"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," Julius said. "It turns out there's a very elegant molecular logic to how that happens."

The clinical stakes are significant. Studies consistently find that 30 to 50 percent of hospitalized cancer patients show signs of malnutrition, and involuntary appetite loss is linked to longer inpatient stays and reduced tolerance for chemotherapy. For the roughly 1.5 billion people worldwide living with chronic parasitic worm infections, sustained appetite suppression compounds the wasting that deepens their vulnerability.

Locksley noted that tuft cells are not confined to the intestine; they also appear in the airways, gallbladder, and reproductive system, suggesting the same signaling axis could underlie appetite disruption in a broader range of conditions, from irritable bowel syndrome to food intolerances. "Controlling the outputs of tuft cells could be a way to control some of the physiologic responses associated with these infections," he said.

The UCSF team, which collaborated with Stuart Brierley, PhD, at the University of Adelaide, plans follow-up experiments to determine whether blocking the tuft-cell-to-EC-cell pathway can safely restore appetite without impairing immune defenses, a critical distinction given that some appetite suppression during infection may itself serve a protective purpose. If those experiments hold, the molecular circuit mapped at Mission Bay could eventually change how clinicians feed the patients who most need it.