Humans have co-evolved with a complex mutualistic microbiota, organized into distinct communities in a range of body habitats, upon which we rely for our health. Periodic exposure of these microbial communities to potent antibiotics has become common in both the developed and developing world, a situation that is unprecedented in our evolutionary history. Such exposures lead to immediate, profound changes in the composition of the human microbiota. Despite the apparent overall robustness of these communities, some antibiotic-induced changes in composition appear to be stable. Functional changes in the community may also occur, but have scarcely been examined. These changes are worrisome, because many beneficial interactions between microbes and the human host are specific to particular strains;related strains that fill the same ecological niche within the community may not have the same beneficial interactions with the host. An understanding of the effects of antibiotics on human-microbe interactions remains fragmentary in part because effective, high-throughput tools for addressing the composition, functional potential and interactions within such complex communities have only recently become available, and data addressing the routine temporal variation in the composition and function of the gut microbiota in the absence of disturbance are scarce. The broad, long-term objectives of the proposed work are to understand the routine temporal variability in composition and function of the human gut microbiota, to discover factors contributing to the stability and resilience (or lack thereof) of these communities after disturbance by a course of antibiotics, and to characterize inter-individual differences in the compositional and functional dynamics, and in the relationship between composition and function over time.
Specific Aim 1. Characterize the temporal dynamics of the taxonomic composition of the gut microbiota in healthy human adults over 36 weeks in the absence of deliberate disturbance, based on deep sequencing of 16S rRNA genes in weekly fecal samples in 10 subjects, and multivariate and time series analyses.
Specific Aim 2. Characterize the temporal dynamics of the functional gene content and of the chemical milieu of the gut microbiota in healthy human adults over 36 weeks in the absence of deliberate disturbance, based on shotgun DNA sequencing and metabolomic analysis of a subset of the weekly fecal samples from Aim 1, and multivariate coinertia-based tools.
Specific Aim 3. Characterize the impact of a short course of an antibiotic on the taxonomic composition, functional gene content, and chemical milieu of the gut microbiota in healthy human adults, based on deep sequencing of 16S rRNA genes, shotgun DNA sequencing and metabolomic analysis of weekly fecal samples from 20 healthy subjects collected over 25 weeks (with a course of ciprofloxacin during week 13).

Public Health Relevance

Humans rely on the microbial communities that colonize the gut for a wide variety of critical functions, including nutrition, immune system maturation, protection against infection by disease-causing microbes, and detoxification of environmental chemicals. Antibiotics, although sometimes necessary for disease treatment, have detrimental, but poorly understood effects on the health-associated human microbial communities. We propose to characterize these effects, with the long-term goal of being able to predict and avoid the damaging impact of antibiotics on human health.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZGM1-GDB-2 (MC))
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Sledjeski, Darren D
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Palo Alto Institute for Research & Edu, Inc.
Palo Alto
United States
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