The gut microbiota of the infant, acquired by exposure to the mother and the early rearing environment, plays a critical role in establishing a functional gastrointestinal tract and promoting health via stimulating the maturation of the immune, endocrine, and enteric nervous systems. Our project uses a nonhuman primate model to specifically determine the mechanistic pathways through which the infant's gut microbiome affects brain development, as well as emotional and behavioral responsiveness during the first year of life. The mother's microbiome will be experimentally controlled during the pregnancy and nursing periods, enabling us to generate infants with two distinctive microbiome profiles. Microbial community analyses will be run on Illumina MiSeq to acquire high quality 16S rRNA data in order to track the development of the infant's microbiota while it is with the mother, and subsequently after weaning when the gut bacterial community is reorganized, due to the consumption of solid foods and exposure to peers. Based on preliminary results, we focus on two sets of signaling mediators: 1) the production of neurochemicals by gut bacteria, including monoamine neurotransmitters and GABA, and 2) inflammatory cytokine activity in the blood and intrathecal compartments. At one year of age, state-of-the-art neuroimaging will be used for structural analyses of cortical brain regions (gray and white matter volumes), and for quantifying the pace of myelination with diffusion tensor imaging. During the initial R21 phase, we will verify that 20 infant monkeys with distinct microbiome profiles can be reliably generated, and that population differences persist, allowing us to create peer social groups comprised of infants with comparable microbiota. During the R33 phase, a larger cohort of 40 infants will be generated, enabling us to also use fecal transplant methods to systematically change the composition of the gut microbiota and to test the hypothesis that behavioral and neural trajectories will shift to that of the donor animal. This project takes advantage of the unique resources of a major primate breeding facility, permitting us to evaluate a large number of infant monkeys under controlled environmental conditions, and the multi-disciplinary expertise and resources of the collaborating research team at 4 institutions. Innovative methods are employed, including the biopsy collection of gut tissue specimens to validate sequencing and neurochemical conclusions from directed metabolomic panels derived from the more routinely collected rectal swabs. Our project directly addresses a central tenet of the RFA, which is to investigate the influence of the maternal and infant microbiome on behavioral and brain maturation, and to determine if a dysregulated microbiome is associated with atypical development. Multi-tiered, molecular biology and developmental neuroscience approaches are employed. This research has a clear translational relevance for child health, contributing to extant findings that indicate an abnormal microbiome is evident in several pediatric disorders. We are poised to validate new biomarkers for tracking the influence of the gut microbiota on systemic physiology and to make novel discoveries on how the gut and enteric nervous system interface with the microbiome to influence the normal functioning and development of the central nervous system.

Public Health Relevance

Human health and wellbeing are intimately associated with the commensal bacteria present in our gastrointestinal tract. This symbiotic relationship has special significance for the young infant because the gut microbiota serve many protective and regulatory functions, prime immune responses, and can influence somatic, brain, and behavioral development. Several pediatric conditions have now been associated with either an atypical composition or abnormal levels of gut bacteria. Our project investigates how the maternal microbiota are transferred and established in the young infant, and the pathways through which gut bacteria and the enteric nervous system affect the developing central nervous system. State-of-the-art techniques will be employed to characterize the abundance, diversity and phylogeny of the gut microbiome community, and neuroimaging will be used to examine the normalcy of brain structure and myelination in the young infant.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZMH1)
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Vicentic, Aleksandra
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University of Wisconsin Madison
Schools of Arts and Sciences
United States
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Amaral, Wellington Z; Lubach, Gabriele R; Proctor, Alexandra et al. (2017) Social Influences on Prevotella and the Gut Microbiome of Young Monkeys. Psychosom Med 79:888-897
Amaral, Wellington Z; Lubach, Gabriele R; Kapoor, Amita et al. (2017) Low Lactobacilli abundance and polymicrobial diversity in the lower reproductive tract of female rhesus monkeys do not compromise their reproductive success. Am J Primatol 79:
Rendina, Danielle N; Lubach, Gabriele R; Coe, Christopher L (2016) Gestational Timing of Prenatal Disturbance and Fetal Sex Determine the Developmental Outcomes. Neonatology 109:314-20