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 emerging technologies.
The proposal explores previously not described mechanisms of increased susceptibility of a premature infant brain to intermittent hypoxia injury by gut microbial community. 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 emerging technologies.
