Researchers Discover Gut-Brain Link in Post-Illness Protein Appetite

Researchers at the Yale School of Medicine have uncovered a significant gut-brain signaling pathway that restricts protein intake during recovery from acute illnesses. Their findings, published on November 4 in the journal Cell, highlight how the body regulates appetite, particularly for protein, when recovering from conditions such as flu or pneumonia.

The study’s lead author, Nikolai Jaschke, MD, Ph.D., conducted the research while completing a postdoctoral fellowship under the supervision of Andrew Wang, MD, Ph.D., an associate professor of internal medicine. Jaschke observed that many patients experience a prolonged period of diminished well-being even after the major symptoms of their illness have subsided. He emphasized the lack of therapeutic options available to support individuals during this recovery phase.

The research team focused on mice that had entered a catabolic state, known for reduced appetite and increased breakdown of muscle and protein for energy. Mice were provided with diets that contained equal calories and micronutrients but varied in macronutrient composition—protein, carbohydrates, or fat. Notably, those on a protein-rich diet consumed significantly less food than those on carbohydrate or fat-rich diets.

The team identified a strong aversion to protein-rich foods in recovering mice. To delve deeper, they tested 20 different amino acids to determine which ones influenced appetite. They found that only three amino acids—glutamine, lysine, and threonine—led to reduced food intake. Interestingly, when these amino acids were not included in their diet, the mice consumed food without any reduction in appetite.

Jaschke noted a peculiar observation while monitoring the mice. Upon extending the duration of their high-protein diet, the mice gradually began to consume more protein. However, he discovered that their bedding was excessively wet due to increased urination. This led to the realization that the breakdown of protein generates ammonia, which must be detoxified by the liver. The process requires additional water, explaining the increased urination observed.

The research team hypothesized that the reduced intake of protein-rich foods was linked to the need to manage ammonia levels. Further investigations showed that glutamine, lysine, and threonine produced higher ammonia levels compared to other amino acids. When the mice’s ability to detoxify ammonia was enhanced, they were able to consume more protein.

As the study progressed, the team identified the specific location in the small intestine where ammonia production was sensed—the duodenum. They found that a particular receptor on specialized cells in this area mediated the aversion to protein. Mice lacking this receptor showed no aversion to protein-rich diets, while activating the receptor significantly suppressed their appetite for protein.

In exploring how the gut communicates with the brain, the researchers pinpointed two regions in the brainstem—the area postrema and the nucleus tractus solitarius—where activation correlated with protein intake and ammonia production. This suggests that the gut-to-brain signaling pathway plays a critical role in regulating protein appetite during recovery.

The implications of this study extend beyond dietary recommendations for recovering patients. Joseph Luchsinger, MD, Ph.D., a co-first author and resident in the Neuroscience Research Training Program at Yale, expressed interest in how these findings could relate to psychiatric conditions like anorexia, where appetite regulation is significantly altered.

The research indicates a need for further studies to determine how these findings might translate to human physiology. Notably, two recent clinical trials revealed that increasing protein intake during recovery from critical illnesses did not yield improved outcomes, highlighting the importance of understanding the underlying mechanisms of appetite regulation.

As researchers continue to explore this gut-brain signaling axis, they aim to evaluate how adjusting diets, particularly concerning these three specific amino acids, could promote recovery from illnesses. The potential applications are far-reaching, including implications for individuals with urea cycle disorders, those experiencing appetite suppression, and conditions like cancer cachexia.

This foundational research opens new avenues for developing therapeutic strategies to support recovery from illness, emphasizing the intricate connections between gut health and overall well-being. Further studies are essential to fully understand the complex interactions at play and to enhance recovery protocols for patients worldwide.