Researchers at the University of California, San Francisco announced on March 25 that they have identified a molecular pathway connecting the gut immune system to the brain during parasitic infections, explaining why people often experience a lingering loss of appetite after stomach bugs.
This discovery could help explain not only the effects of parasitic worm infections, which affect millions worldwide, but also provide insight into conditions involving gut discomfort such as food intolerances and irritable bowel syndrome.
The study, published in Nature, focused on two rare cell types in the gut. Tuft cells detect parasites and trigger immune responses, while enterochromaffin (EC) cells release signals that activate nerve fibers leading to the brain. Previously, it was unclear whether these two cell types communicated with each other. "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 Richard Locksley, MD, co-senior author and UCSF immunologist.
Koki Tohara, PhD—a postdoctoral researcher at UCSF—used genetically engineered sensor cells placed next to tuft cells under a microscope. When exposed to succinate (a molecule produced by worms), tuft cells released acetylcholine—a chemical messenger usually used by neurons—which then caused EC cells in lab-grown tissue to release serotonin and activate vagal nerve fibers signaling 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."
The research showed that tuft cells release acetylcholine in two phases: an initial brief burst followed by a slower sustained phase as infection progresses. This timing may explain why appetite loss typically develops days into an illness rather than immediately. "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." Tests in mice confirmed this molecular chain drives reduced food intake during infection.
Locksley said controlling outputs from tuft cells could help manage physiological responses associated with parasite infections and might have broader implications for treating disorders like irritable bowel syndrome or chronic visceral pain due to similar pathways being present throughout various body tissues.
