Anyone who has had a severe stomach illness will recognize this pattern. Even after the worst symptoms have subsided, people often lose their appetite, and recovery may take time. This same effect is experienced by millions of people around the world living with long-term parasitic infections. Despite how common it is, scientists have a hard time pinpointing the exact cause of this loss of appetite.
Researchers at the University of California, San Francisco have identified a biological pathway that links the gut’s immune response to the brain during parasitic infections. Their research shows how signals from the immune system can actively suppress appetite.
“The question we wanted to answer was not only how the immune system fights parasites, but also how do we recruit the nervous system to change behavior,” said co-senior author David Julius, Ph.D., UCSF professor and professor of physiology and 2021 Nobel Prize in Physiology or Medicine winner. “It turns out there’s a very sophisticated molecular logic to how that happens.”
This study nature On March 25, researchers discovered an unexpected way in which two types of cells communicate. This discovery may also help explain a variety of digestive problems, such as food intolerances and irritable bowel syndrome.
How do intestinal cells communicate with the brain?
The study focused on two unusual cell types found in the intestine. Tuft cells act as detectors that sense parasites and mount immune defenses. Enterochromaffin (EC) cells release chemical signals that stimulate neural pathways connected to the brain. These EC cells are known to cause sensations such as nausea, pain, and general intestinal discomfort, but it was unclear whether they directly interact 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.
For the study, lead author Dr. Koki Higashihara, a UCSF postdoctoral fellow, 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 the parasite, nearby sensor cells lit up. This revealed that the tuft cells release acetylcholine, a signaling molecule normally associated with nerve cells.
When acetylcholine was introduced into laboratory-grown intestinal tissue containing EC cells, these cells responded by releasing serotonin. 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.”
Delayed signals that explain loss of appetite
The researchers also discovered that tuft cells release acetylcholine in two separate stages. This helps explain why loss of appetite often appears later rather than immediately after infection.
First, the tuft cells release acetylcholine for a short period of time. As the immune response increases and the number of tuft cells increases, they begin to release the same signals more slowly and in a sustained manner. This prolonged release is powerful enough to activate EC cells and send signals to the brain.
“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.”
Widespread effects on intestinal diseases
To find out whether this pathway affected behavior outside the lab, the researchers studied mice infected with the parasite. Mice with normal tuft cell function ate less as the infection progressed. In contrast, mice lacking the ability to produce acetylcholine in their tuft cells continued to eat normally. This confirmed that the signaling pathway directly causes changes in appetite.
These findings could ultimately guide new treatments for conditions associated with parasitic infections.
“Controlling the output of tuft cells could be a way to control some of the physiological responses associated with these infections,” Locksley said, noting that the effects could extend beyond the parasite.
Tuft cells are found in several parts of the body, including the intestines as well as the respiratory tract, gallbladder, and reproductive system. Disturbances in this newly identified signaling pathway may be involved in conditions such as irritable bowel syndrome, food intolerance, and chronic visceral pain.
The study was conducted in collaboration with Dr. Stuart Brierley and his research team at the University of Adelaide in Australia.
