Hibernating squirrels stay strong thanks to urea-salvaging gut microbes

The gut microbes of hibernating ground squirrels recycle urea to replenish crucial amino acids, allowing the mammals to survive long periods of inactivity and fasting, according to a new study. The results, which reveal an important role of the gut microbiome in hibernation, suggest that similar processes could help maintain protein balance and mitigate muscle wasting in other species, including humans. Hibernation evolved among mammals to help them survive challenging seasonal periods, such as winter. Hibernating animals become dormant, entering a state of decreased physiological activity. For many mammals, prolonged inactivity and starvation causes the body to break down muscle proteins in a process that yields ammonium, which is further concentrated into urea. Toxic at high concentrations, urea is usually excreted as urine, and due to this process, the body will continue to lose nitrogen – essential for core biological functions. Despite dietary nitrogen deficiency and prolonged inactivity, some hibernators, like the thirteen-lined ground squirrel (Ictidomys tridecemlineatus) – which can fast for nearly 6-months out of the year – lose remarkably little muscle mass and function during long winters. It’s thought that these hibernators may accomplish this by leveraging the capacities of gut microbes to recycle urea nitrogen back into their protein pools through a process termed urea nitrogen salvage. Matthew Regan and colleagues used stable isotope labeling to track nitrogen flow in hibernating squirrels. These experiments revealed that urea, in addition being excreted in urine, is transported to the squirrels’ gut lumen. Regan et al. analyzed the gut microbiome activity in hibernating ground squirrels and found that ureolytic gut microbes incorporated nitrogen from urea into metabolites that were reabsorbed into the host, allowing the hosts to maintain a functional protein balance. As a result of this process, nitrogen loss was compensated, which counteracted muscle wasting. “Muscle wasting is prevalent in those suffering from age-related sarcopenia, protein malnutrition or prolonged inactivity such as during space travel or hospitalizations related to severe diseases,” write Felix Sommer and Fredrik Bäckhed in a related Perspective. “Because mechanisms for nitrogen salvaging from urea seem to be functional in humans, microbiota-directed interventions for urea recycling could be a potential therapy for treating such conditions.”