YSM Issue 90.1

medicine
NEWS
THE FLU SEASON CRAVINGS PARADOX
The connection between metabolism and disease outcome
►BY MARY CHUKWU
www.yalescientific.org
PHOTOGRAPHY BY CHUNYANG DING
►Yale researchers in Professor Ruslan Medzhitov’s lab found
connections between metabolism and infection that may lead to
new approaches to nutrition for the critically ill.
As winter settles in, perhaps the only seasonal “foods” more iconic
than hot chocolate and s’mores are cough drops and tea. Why do
some people want to weather colds holding steaming bowls of comforting
soup, while others suffer queasy stomachs and leave dinner
plates untouched? The seemingly paradoxical appetite changes associated
with sickness are a well-recognized and evolutionarily ancient
trait, but up until now scientists could only speculate about
their cause and purpose.
Yale researchers led by Ruslan Medzhitov, professor of immunobiology
at the Yale School of Medicine, have found that the answer
to this puzzle lies with the causes of infection. The key insight of
their research is that not all sicknesses are created the same. Fighting
viral versus bacterial infections requires completely opposite
nutritional needs. The findings of their research hold the potential
to transform how healthcare approaches nutrition in illness.
The researchers began by tracing out how anorexia, or loss of appetite,
affects disease outcome in bacterial infections. Researchers
infected mice with Listeria monocytogenes, a common cause of
food poisoning. Mice that were fed during infection died; those
who did not eat lived.
Similarly, the researchers infected mice with influenza virus, the
cause of the flu, and again varied caloric intake. Now the fortunes
were reversed: fed mice survived viral infection while those that did
not eat mostly died. These trends held true not only for infection
but also when the experiments were repeated for bacterial and viral
inflammation—whole body immune activation.
The real story linking nutrition and disease, however, emerged in
the search for the nutrient causing the outcomes. Between protein,
fat, and glucose, only glucose was required to induce the complete
effects of caloric intake. Moreover, blocking glucose utilization rescued
bacteria-infected mice while killing virus-infected mice.
Interestingly, glucose does not change the number of pathogens
or the strength of the immune response. Instead, glucose
shapes the role of metabolism in the body’s tolerance of the immune
response. Metabolism refers to all the chemical reactions
needed to sustain life; use of the immune system comes at a price.
“Depending on the type of inflammation or infection, there
are different metabolic processes that are necessary to survive the
critical illness condition,” Medzhitov explained. Specifically, bacterial
and viral infections generate different kinds of tissue damage
depending on the presence of glucose.
While glucose dominates metabolism in the fed state, during
a fasting state the body begins breaking down fat stores to utilize
molecules called ketone bodies for energy. Bacterial infections
cause an immune response that releases reactive oxygen species
(ROS), or “free radicals,” which kill pathogens as well as damage
host cells. Glucose exacerbates this negative side effect while ketone
bodies from starvation are protective. A parallel exists for
viral infection.
In response to the cellular damage caused by viral infection,
the unfolded protein response (UPR) targets and eliminates cells
producing abnormal proteins. This process is regulated by glucose—without
glucose, this stress-induced response leads to excessive
cell damage.
“We discovered that by blocking glucose utilization in viral infections
we prevented a normal response against viruses and instead
caused a response that ended up being destructive for the
host,” said Andrew Wang, first author and clinical fellow in medicine.
Shockingly enough, the battleground where glucose decided
life and death was not in the heart or the lungs, as may be expected
for a pulmonary illness like the flu, but rather in the brain.
PET scans and tissue studies revealed damage at critical sites in
the brain following bacterial and viral infection. Absence of glucose
increased neuronal damage in viral infections while for bacteria
the opposite was true. The damage was once again linked to
either overactivity of the UPR or overproduction of ROS.
Medzhitov and his team hope that these new findings can
improve nutrition for the acutely ill. Currently, all ICU patients
are fed intravenous liquid food that is 30 to 60 percent carbohydrates,
but Medzhitov’s study suggests that these formulations
need to be adjusted based on the cause of illness. The Yale
team is currently preparing clinical trials that test that premise.
Future studies by the team will continue using mouse models
to study different types of infections, including parasitic and
fungal. Their work will contribute to new holistic models of
healthcare treatment.
“The general implication is that there is a certain wisdom
to the body’s reactions and our preferences during illness, and
many of these are protective,” Medzhitov said. In sickness at
least, we can all benefit from listening to our bodies.
December 2016
Yale Scientific Magazine
11