Fetal development generally takes place within a microbe-free environment. During delivery and rapidly thereafter, microbes from a variety of sources colonize the infant skin, mouth, and gastrointestinal tract until dense, complex communities are established. Successional changes in the structure and function of these communities are marked in early development and have important consequences for infant nutrition, pathogen resistance, gut maturation, and immune system programming. During this time, deviations from the normal development of the indigenous microbiota may affect child health. Antibiotic disruption of the native microbiota is implicated in a wide range of human disease, including Clostridium difficile colitis and other acute and chronic forms of diarrhea. Longer-term consequences, such as childhood asthma, obesity, and inflammatory bowel disease have also been linked to antibiotic use early in life. Surprisingly, we lack a clear understanding of the direct effects of antibiotics on the developing microbiota of infants. In part this is because until recently, methods capable of detecting the signature of disturbance within complex, dynamic microbial communities were unavailable. Albeit an integral and universal part of human development, the postnatal assembly of the indigenous microbiota, including its variability over time, sources of colonists, responses to disturbance, and the key factors affecting such patterns remains poorly understood. Our objective is to track microbiome assembly from birth until two years of age in a cohort of 20 healthy infants, by following baseline developmental patterns and responses to antibiotic perturbation using time series analysis of high-throughput phylogenetic marker gene and metagenomic sequencing surveys. We will also track the postpartum microbiomes of their mothers, and assess the evidence for direct transmission from mother to child. We hypothesize that the developing microbiomes of infants exhibit resilience in the wake of antibiotic therapy. Having examined this question, we will go on to test the specific hypothesis that the response of the developing microbiome to antibiotic exposure depends, in part, on the infant's mode of delivery. We will study this question in a larger cohort of amoxicillin-treated infants. The long-term goal of this research is to understand the ecological basis of microbiome resilience (or collapse) in the context of early childhood development. It will lay important groundwork for predictive models of antibiotic (or other) perturbation responses that will aid in the promotion of healthy microbiome transmission and assembly.

Public Health Relevance

Humans live in close association with complex microbial communities that aid in our nutrition, protect us from infection, and stimulate our immune system, with every birth renewing this intimate web of connections. Antibiotics, while often necessary for disease treatment, have detrimental, yet poorly understood effects on the microbial communities of infants, which are not yet fully developed. We propose to study these effects in detail, with the long-term goal of being able to predict and promote healthy colonization in infants and children.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Career Transition Award (K99)
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Developmental Biology Subcommittee (CHHD)
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Grave, Gilman D
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Stanford University
Schools of Medicine
United States
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