PROJECT SUMMARY
Lead (Pb) is an everyday contaminant with low level exposure rates of one in every three children worldwide. A
major source of exposure to this heavy metal is via drinking water delivered through Pb lines. Children are
particularly vulnerable, with an exposure rate of up to 800 million globally, as they absorb Pb differently than
adults. Even children exposed to very low levels of Pb often go on to experience intellectual deficits with
associative macroscopic changes in the brain. While many of these poor neurological outcomes are ascribed to
the ability of Pb to cross the blood brain barrier (BBB), how the affects of Pb on other compartments of the body
contribute to an underdeveloped brain remains largely unknown. The gut brain-axis has recently been brought
into clinical and preclinical spotlights as accumulating evidence confer bidirectional communication between the
two organs. As a collective, the microorganisms/microbiota colonizing the vertebrate gut play a commensal role
in training the immune system and promoting healthy brain development. This is particularly evident in cases of
gut dysbiosis associated with an array of neurological diseases/disorders of developmental origins. Upon Pb
contaminated water consumption, the gut microbiota is amongst the first exposed and are readily altered in
species composition which has been reported in a limited number of preclinical animal studies. However, how
Pb-induced gut dysbiosis impacts the enteric and central nervous system independent of Pb entry systemically
remains elusive. Building on a novel germ-free piglet paradigm developed by our group, we will test the central
hypothesis that low level Pb exposure impairs brain development by altering the gut microbiome which in turn
negatively impacts distinct central and enteric nervous system cell types. We will employ a multipronged
approach to test the following three independent yet complementary Aims. In Aim 1, we will determine the effects
of a Pb-altered microbiome on key neurodevelopmental trajectories by recolonizing germ-free piglets with donor
gut microbiota exposed to low doses of Pb orally. This will enable us to rule out any direct effects of Pb on the
brain via entry through the blood brain barrier. In Aim 2, we will identify and characterize alterations that occur
in the gut microbiome after Pb exposure. Using multiomics and several other in vivo and in vitro techniques, we
will evaluate changes in microbial diversity, metabolites, and host physiology. Aim 3 will include assessments of
both compartments to interrogate direct and indirect Pb-induced alterations in distinct central and enteric nervous
system cell types. Completion of these studies will provide mechanistic insights on the cellular, microbial, and
systems level and illuminate new aspects of Pb exposure that may lead to novel strategies for targeted
therapeutic interventions to improve neurological outcomes in children exposed to Pb.