Eating is not only about getting enough calories. Animals also need to choose the right nutrients. When the body lacks protein, it must seek essential amino acids — the protein building blocks that cannot be made internally and must come from food.
A research team led by Director SUH Seong-Bae of the Center for Microbiome–Body–Brain Physiology within the Institute for Basic Science (IBS), in collaboration with researchers at Seoul National University and Ewha Womans University, has uncovered how the gut detects protein deficiency and directs the brain to seek out essential nutrients. The study reveals a previously unknown gut-brain signaling system that rapidly alters feeding behavior through coordinated neuronal and hormonal pathways.
Proteins are indispensable nutrients because they contain essential amino acids that animals cannot synthesize on their own. Although animals are known to develop cravings for protein-rich foods when deprived of protein, the biological mechanisms linking nutrient deficiency to selective feeding behavior have remained poorly understood.
The IBS team found that the gut responds to protein deficiency through two coordinated pathways — a fast neural circuit rapidly informs the brain that essential amino acids are lacking, while a slower hormonal signal sustains protein-seeking behavior over time.
The researchers first studied fruit flies, a powerful model for identifying neural circuits that control feeding. Using neural imaging, behavioral experiments, and genetic tools in fruit flies, the team identified the neural circuitry underlying this process.
When flies were deprived of dietary protein, specialized intestinal cells in the gut produced a peptide hormone called CNMa. This signal first activates gut-associated enteric neurons, which rapidly relay information about amino acid deficiency to the brain through a direct gut-brain neural circuit. At the same time, CNMa enters circulation as a hormone and reaches the brain more slowly, reinforcing and sustaining the appetite for essential amino acids over time.
“Our study shows that the gut is not simply a digestive organ, but an active sensory system that continuously monitors nutritional state and directly guides behavioral decisions,” said Director SUH Seong-Bae.
The researchers further found that the system did not simply increase appetite overall. Instead, it selectively changed dietary priorities: animals became more attracted to protein-related nutrients while losing interest in sugar. CNMa signaling inhibited activity in sugar-sensing neurons known as DH44 neurons, effectively shifting feeding preference away from carbohydrates and toward protein-related nutrients.
The study additionally revealed that gut microbiota influence this circuit. Flies lacking commensal gut bacteria showed stronger activation of amino acid-seeking brain neurons, linking microbial regulation of nutrient availability to feeding behavior.
The researchers also showed that the mechanism is evolutionarily conserved in mammals. Similar experiments using mice revealed that protein-deprived animals similarly developed a strong preference for essential amino acids.
Surprisingly, the response remained intact even in mice lacking FGF21 — a hormone long believed to play a central role in protein appetite. The finding suggests that animals possess additional, previously unknown nutrient-sensing systems.
These findings demonstrate that animals do not simply eat more when nutrients are lacking. Instead, the brain selectively adjusts feeding priorities to favor the nutrients that are specifically deficient.
The researchers say the findings provide important insight into how the body maintains nutritional balance and may open new avenues for obesity, metabolic disease, and eating disorder research.
“Most current obesity and appetite-control drugs rely on gut hormone signaling, yet we still know relatively little about how naturally produced gut signals influence the brain and behavior,” said Director SUH Seong-Bae. “This study reveals fundamental principles of nutrient selection by the gut-brain axis and provides a foundation for future therapeutic strategies targeting metabolic and feeding disorders.”
The findings were published in the journal Science on May 21.