Premature infants are often lacking normal microbial community, or microbiota, in their
intestines that naturally should have come from mothers. Infants are also exposed to unnatural
microbiota in the hospital environment that results in abnormal intestinal colonization. Premature
infants are often at risk of perinatal hypoxic-ischemic brain injury, considered as one of the
major factors leading to motor, sensory and cognitive deficits.
Gut microbiota affects the body in numerous ways and one of the most pronounced effects
is on the infant’s immune system. Therefore we hypothesize that neonatal gut microbiota can
regulate immune reaction of the neonatal brain to hypoxic brain injury. We propose to examine
the effect of gut microbiota on hypoxia-induced neonatal brain injury utilizing a mouse model.
Neonatal mouse pups without microbiota in guts (germ free) or with conventional microbiota will
be exposed to periods of low oxygen in air (intermittent hypoxia), mimicking episodes of apnea
in premature infants. Intermittent hypoxias results in neuroinflammation and diffuse white matter
brain injury that can be quantified by state-of-the-art MRI methodology and tissue analysis.
In the Specific Aim 1 we will first determine the effect of abnormal gut microbial colonization
on hypoxia-induced brain injury by using advanced MRI techniques (aim 1a) and motor and
cognitive deficits using behavioral tests (aim 1b). In addition, we will evaluate the effect of
microbiota on neuroinflammatory factors (aim 1c), and correlate with the alterations on brain
imaging and behavioral tests. The second specific aim will expand the results in a clinically
relevant scenario in which gut microbiota will be modified in a controlled manner. Specifically,
germ free mouse pups will be exposed to known pathogenic or beneficial bacteria strains and
studied for resistance to hypoxia.
Understanding the protective or deleterious role of gut microbiota on neurologic responses
to perinatal hypoxia-ischemia may lead to novel therapeutic strategies since manipulation of
intestinal microbiota is easily achievable through targeted probiotic supplementation and other