INSIGHTS
PERSPECTIVES
By Felix Sommer^1 and Fredrik Bäckhed2,3,4F
or mammals, prolonged inactivity and
starvation, such as during hiberna-
tion, prompt the body to break down
muscle proteins to create a source of
energy. Known as muscle wasting,
this process yields ammonium, which
is further converted to urea. Because high
concentrations of urea are toxic to neurons
in mammals, it is normally excreted with
urine. As a result, the body is constantly los-
ing nitrogen in the form of ammonium and
needs to replenish it through dietary up-
take, because nitrogen is essential for pro-
tein and nucleotide synthesis. With the lack
of regular food intake, it has been enigmatic
how mammals maintain their physiologicalfunctions during hibernation. On page 460
of this issue, Regan et al. ( 1 ) describe the
molecular processes underlying the urea
nitrogen salvage mechanism in hibernat-
ing squirrels and reveal a functional role of
intestinal microorganisms in this adaptive
physiological process.
Hibernating animals do not eat or drink
over a long period of time, often months,
when they are inactive and spend most of
their time sleeping. During this torpid state,
hibernators can drastically reduce their
metabolic rates, allowing them to reduce
their energy demands. Despite this combi-
nation of fasting and inactivity, hibernat-
ing animals keep their lean mass relatively
stable, with some even gaining muscle mass
by the end of hibernation ( 2 ).To elucidate how squirrels maintain their
physiological functions during hibernation,
Regan et al. used stable isotope labeling
to track the flow of nitrogen and carbon in
squirrels during the active phase and hi-
bernation. These experiments revealed that
urea, which is produced by the host during
protein catabolism, is transported from the
blood to the gut lumen in addition to being
excreted in the urine.
All animals live in close association with a
vast diversity of microorganisms—the micro-
biota—that contributes to various aspects of
host physiology ( 3 ). Previous research iden-
tified that hibernation alters the gut micro-
biota ( 4 , 5 ). In bears, the microbiota assists in
extracting energy from the diet to facilitate
prehibernation fattening ( 4 ). In hibernatingMICROBIOTAStaying strong during hibernation
The microbiota of hibernating squirrels salvages urea to replenish amino acids
science.org SCIENCEPHOTO: INGO ARNDT/MINDEN PICTURES376 28 JANUARY 2022 • VOL 375 ISSUE 6579