After an illness like the flu, symptoms may go away while a person still feels lousy. Researchers wanted to learn more about this state, and how people who are recovering from illnesses can be supported. Using a mouse model, the investigators determined that during a recovery from an illness, there is signaling from the gut to the brain that suppresses appetite, particularly the appetite for protein. The findings, which could help scientists develop treatments to help people recover faster, were reported in Cell.
Appetite loss is typical during an illness. When people are sick and stop eating, their metabolism switches to a catabolic state, in which proteins and other molecules are broken down to fuel the body with energy.
In this study, the researchers began with mice that were in a catabolic state, and gave them one of three diets that had the same caloric and nutritional content, but were rich in either carbohydrates, fats, or proteins. Mice that were given diets high in carbohydrates or fats ate the expected amounts of food, while mice given a diet high in proteins consumed much less food compared to mice that were not in a catabolic state.
Additional work confirmed that mice that were in recovery from a catabolic state were not interested in eating protein-rich food.
Since proteins are made up of amino acids, the researchers determined which of the twenty amino acids caused this aversion to high-protein food in animals recovering from catabolic states. There were three amino acids that led mice to consume less food: glutamine, lysine, and threonine. If catabolic mice were offered protein-rich foods that did not contain these amino acids, they began to eat the expected amounts again.
The researchers also found that the mice on diets high in glutamine, lysine, and threonine for a long period of time also began to slowly increase the amount of food that they consumed, and they were also urinating far more than usual. The scientists determined that those three amino acids were causing the body to produce more ammonia as protein is broken down. This normal byproduct is usually excreted by the kidneys, and the whole process requires water.
This ammonia production is also detected by the body, in the region of the small intestine known as the duodenum. One receptor on a particular cell type identifies the ammonia.
When the researchers engineered mice to lack this receptor, their aversion to glutamine, lysine, and threonine was eliminated. If the same receptor was stimulated, the mice no longer had an appetite.
There are neurons in the duodenum that are also part of the vagus nerve. Further work showed that the vagus nerve sends signals directly from the gut to the brain. When neuronal signals in the duodenum were halted in a mouse model, the mice began other consume more protein again. This gut-brain connection was found to be part of the ammonia detection process, which can halt the consumption of more protein so that ammonia levels will not get dangerously high.
"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," said co-first study author Nikolai Jaschke, MD, Ph.D., a principal investigator and physician at the Hamburg Center for Translational Immunology and University Medical Center Hamburg-Eppendorf in Germany. "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."
Sources: Yale University, Cell