Credit: Cell (2025). DOI: 10.1016/j.cell.2025.10.005

When we get sick, with the flu, say, or pneumonia, there can be a period where the major symptoms of our illness have resolved but we still just don’t feel great.

“While this is common, there’s no real way to quantify what’s going on,” says Nikolai Jaschke, MD, Ph.D., who recently completed a postdoctoral fellowship at Yale School of Medicine (YSM) in the lab of Andrew Wang, MD, Ph.D., associate professor of internal medicine (rheumatology). “And unfortunately, we lack therapeutic tools to support people in this state.”

Jaschke noticed this while taking care of patients recovering from acute illnesses and, when he joined Wang’s lab, he began studying what was happening in the body during recovery. Through this work, Jaschke, Wang, and their colleagues uncovered a gut-to-brain signaling pathway in mice that restricts appetite—specifically for protein—during recovery. They published their findings on Nov. 4 in Cell.

“The hope is that down the line we’re able to develop therapeutic approaches to support the recovery process,” says Jaschke, co-first author of the study and now a principal investigator and physician at the Hamburg Center for Translational Immunology and University Medical Center Hamburg-Eppendorf in Germany.

Reduced protein appetite is linked to ammonia

Many people experience appetite loss when they’re sick, and with less food intake, their bodies begin breaking down molecules like protein for energy. This is known as a catabolic state and it’s where the researchers started their work.

They offered mice that were in a catabolic state one of three diets that each had the same amounts of calories and micronutrients but different macronutrients: protein, carbohydrates, or fat. The mice given the high-carbohydrate and high-fat diets ate expected amounts, but those given the protein-rich diet ate much less than mice not in a catabolic state.

Through various experimental approaches, Jaschke and colleagues found that mice recovering from catabolic states displayed an exceptionally strong aversion to protein-rich food.

Proteins are made up of amino acids, so the researchers tested the 20 different amino acids to see if any (or all of them) would lead to the same reduction in food intake. They found only three did: glutamine, lysine, and threonine. When given food without those three amino acids, catabolic mice ate just fine.

That left the researchers wondering what was special about these three amino acids, and it was around this time that Jaschke discovered something that helped answer that question.

“I was giving mice the high-protein diet for a longer period of time to see if their appetites for it would change over time, and they did. The mice slowly increased how much of it they ate,” says Jaschke. “But then I noticed their cage bedding was very wet and figured that their water bottles were leaking. It turned out to be urine and the mice were urinating more than 10 times the amount they typically do.”

When protein, whether stored in tissue or consumed in the diet, is broken down, ammonia is generated, which must be detoxified by the liver and excreted by the kidneys. This process requires water and, therefore, increases urination. Together, these observations led to the idea that mice were adjusting their intake of amino acids based on their capacity to detoxify ammonia.

The researchers then examined whether glutamine, lysine, and threonine produce more ammonia than other amino acids. Ammonia is toxic, so if these three amino acids produce more of it, it could explain why the mice avoid them.

The researchers found that indeed, the three amino acids led to higher ammonia levels than other amino acids. Further, when their capacity to detoxify ammonia increased, mice were able to eat more protein-rich food.

“It’s still not clear why they’re more ammoniogenic, but our findings collectively suggest that this generation of ammonia is necessary and sufficient for the protein aversion we observed in the catabolic mice,” says Jaschke.

A better diet for recovery

Because people often eat less while they’re sick, they’ll typically receive high-protein meals if they’re recovering in a hospital to help replace the protein they lost. But two recent clinical trials found that extra protein during critical illness recovery actually didn’t help patient outcomes but rather made things worse.

The new study was done in mice and, the scientists note, more research needs to be done to see if these observations translate to humans. But the trial findings converge with those of this study to suggest additional research might identify a more effective recovery diet.

Joseph Luchsinger, MD, Ph.D., co-first author of the study and a resident in YSM’s Neuroscience Research Training Program, was interested in this work because of the applications he saw to his field.

“How and why we choose to eat is really poorly understood,” says Luchsinger. “And it’s significantly altered in psychiatric illness, from depression and anxiety to anorexia, but we don’t yet know why that is.”

Luchsinger was interested in how Jaschke’s findings might relate to psychiatric illnesses, and particularly to those, such as anorexia, for which we currently lack medications. Together, the team uncovered a gut-to-brain signaling axis that regulates this post-illness lack of protein appetite.

The gut and brain communicate to suppress protein appetite

First, the researchers identified where ammonia production was being sensed in the body—a part of the small intestine called the duodenum—and that it was being sensed by one particular receptor on one type of cell. When they developed mice without the receptor, the animals had no aversion to food rich in glutamine, lysine, and threonine. On the other hand, activating the receptor strongly suppressed food intake.

“With this being a behavior, it has to be controlled in some way by the brain, so we started looking for which brain areas might be involved,” says Luchsinger.

They found two regions in the brainstem where activation aligned with protein intake and ammonia production—the area postrema and the nucleus tractus solitarius. While these areas are known to be involved in satiety and nausea and are already targeted pharmacologically by drugs like semaglutide (Ozempic) for appetite suppression, the question remained how ammonia detection in the small intestine was being transmitted to the brain.

The neurons that innervate the duodenum sit within part of the vagus nerve, a bundle of sensory fibers that delivers information from organs, including the intestine, to the brainstem.

When the researchers silenced the neurons innervating the duodenum, mice ate more protein. The findings indicate that during illness recovery, this gut-to-brain signaling is able to detect harmful ammonia before it begins to circulate in the blood and suppress protein appetite.

There’s still more to uncover, the researchers say. For instance, when they counteracted the various parts of this system, mice never over-ate protein, suggesting there are additional layers of regulation to identify. But the findings are intriguing in a number of ways.

“The next step is to compare different diets across different physiological and disease states to see whether reducing the amount of these three amino acids might promote illness recovery,” says Jaschke. “And this would be relevant for people with urea cycle disorders, for suppressing overactive appetite, and for stimulating appetite when it’s pathologically suppressed, such as with anorexia or cancer cachexia.”

More information: Nikolai P. Jaschke et al, Gut-to-brain signaling restricts dietary protein intake during recovery from catabolic states, Cell (2025). DOI: 10.1016/j.cell.2025.10.005

Journal information: Cell

Citation: Gut-to-brain signaling restricts post-illness protein appetite, researchers discover (2025, November 7) retrieved 7 November 2025 from https://medicalxpress.com/news/2025-11-gut-brain-restricts-illness-protein.html

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