When the body runs short of protein, the gut directly instructs the brain that "protein must be eaten first," rather than simply sending a generic hunger signal, according to a new study.
The Institute for Basic Science (IBS) said Tuesday that a research team led by Seo Sung-bae, director of the Center for Microbiome-Body-Brain Physiology, has identified the mechanism of the "gut-brain axis" that operates under protein deficiency. The study was conducted jointly with researchers at Seoul National University and Ewha Womans University, the Ministry of Science and ICT said.
The gut-brain axis is a network through which the gut and brain exchange neural, hormonal and immune signals. The gut is not merely a digestive organ but also senses the body's nutritional status, gut microbiota and food components, earning it the nickname "the second brain."
Until now, it remained unclear how nutritional deficiency signals originating in the gut were transmitted to the brain and translated into behavioral changes that drive cravings for specific foods.
Fast Neural Signals, Slow Hormones: The Body Switches to "Protein-First Mode"
Through experiments on fruit flies, the researchers found that under protein-deficient conditions, gut epithelial cells secrete a peptide hormone called "CNMa."
CNMa is a signaling molecule that regulates the intake of essential amino acids—nutrients the body cannot produce on its own and must obtain through food.
The key finding of the study is that the gut-brain axis uses two pathways simultaneously.
First, the gut transmits signals to the brain rapidly through neurons. Gut neurons use the neurotransmitter acetylcholine to activate specific brain neurons (R3m neurons), prompting the brain to direct behavior toward consuming essential amino acids.
A slower hormonal pathway then kicks in. The CNMa hormone released from the gut travels through the bloodstream to the brain, sustaining the preference for protein for a longer period.
In simpler terms, the body does not merely command "eat more"—it recalibrates appetite itself toward "protein is needed before carbohydrates right now."
The researchers also confirmed that CNMa signaling not only boosts protein intake but simultaneously suppresses the activity of "DH44 neurons," which are linked to carbohydrate consumption.
Mice Show the Same Response—Could It Offer Clues for Obesity Treatment?
The study is notable in that similar responses were observed not only in fruit flies but also in mice.
Mice with protein deficiency likewise showed a stronger preference for essential amino acids. Notably, the same phenomenon appeared even in mice lacking FGF21, a hormone previously known as a key mediator of the protein-deficiency response.
This suggests that appetite changes caused by protein shortage may operate not only through the previously known pathway but also through another regulatory system—the gut-brain axis.
In a commentary published in the same issue, Stephen Simpson and David Raubenheimer, professors at the University of Sydney in Australia, said "the gut serves as a central control hub for protein appetite regulation," adding that the findings "could provide important clues for understanding human obesity."
The study, however, is at the basic research stage, conducted on fruit flies and mice. No therapeutic agent applicable to humans has yet emerged.
"Most current obesity and appetite-control drugs make use of gut hormone signals, but how naturally secreted gut hormones affect the brain and behavior has not been sufficiently studied," IBS director Seo said. "This study illustrates how the gut-brain system alters behavior to select specific nutrients."
He added, "It could serve as an important foundation for future research into treatments for obesity, metabolic disorders and eating behavior disorders."
The findings were published in the international journal Science on Friday local time.
