Microbial communities associated with the human body, in particular the gastrointestinal tract, play crucial roles in health and disease. The objective of this proposal is to understand how specific patterns in gut microbial succession are related to health and disease, and specifically to neonatal necrotizing enterocolitis (NEC). Although available evidence suggests that intestinal microbes contribute to the pathogenesis of NEC, the details of this relationship remain poorly understood. At present, relatively little is known about the gut colonization process in premature newborns, and about differences between this process in premature infants with and without NEC. We propose complementary high-throughput phylogenetic and metagenomic analyses to study microbial colonization of the premature infant gut during the first three weeks after birth. Our proposed work will elucidate, at high resolution, the population structure of microbial communities that develop during colonization of the premature infant gut and examine the roles of early colonists, gastrointestinal tract-mediated selection, immigration, the effects of mobile elements on genomic variation and microbial survival, and examine how these processes relate to onset of NEC. We will use """"""""next-generation"""""""" sequencing to resolve species- and population-level community succession patterns during the critical initial period of gut colonization in babies that do and do not go on to develop NEC. We will profile community development using high-throughput 16S rRNA tag sequencing of stool samples collected daily during the first three weeks after birth. We will then carry out deep metagenomic sequencing of microbial DNA from half of these fecal time series samples to reconstruct genomes for coexisting bacterial, archaeal, phage, and plasmid populations. This will allow us to track species membership, community structure, metabolic potential, and population-level genetic heterogeneity. We will use these data to test the extent to which initial consortia predict succeeding community diversity [Aim 1], the importance of in situ diversification mediated by phage, insertion elements, and plasmids vs. immigration in determining population structure and metabolic potential [Aim 2], and to define ecological trajectories that correlate with health and disease [Aim 3]. Our preliminary metagenomic data conclusively demonstrate that the proposed approach can be used to reconstruct near-complete genomes of coexisting organisms from premature infant gut fecal samples with sufficient population depth to analyze population heterogeneity and dynamics. Improved understanding of the colonization process in the premature infant gut could translate to improved outcomes for premature babies by suggesting more effective strategies for disease prevention and treatment. More broadly, this research will uncover aspects of ecosystem colonization dynamics that have implications for other aspects of human health and the environment. !
Gut colonization is critical in establishing a functioning digestive system and is intimately connected to overall infant development. Perturbation of normal gut colonization may trigger onset of diseases such as necrotizing enterocolitis (NEC), the most common gastrointestinal emergency of premature babies. Using a metagenomic approach with resolution at the level of bacterial strains, we will examine features of normal gut colonization and test whether virus-host interactions might play a role in the development of disease. !
|Brown, Christopher T; Xiong, Weili; Olm, Matthew R et al. (2018) Hospitalized Premature Infants Are Colonized by Related Bacterial Strains with Distinct Proteomic Profiles. MBio 9:|
|Rahman, Sumayah F; Olm, Matthew R; Morowitz, Michael J et al. (2018) Machine Learning Leveraging Genomes from Metagenomes Identifies Influential Antibiotic Resistance Genes in the Infant Gut Microbiome. mSystems 3:|
|Brooks, Brandon; Olm, Matthew R; Firek, Brian A et al. (2018) The developing premature infant gut microbiome is a major factor shaping the microbiome of neonatal intensive care unit rooms. Microbiome 6:112|
|Brooks, Brandon; Olm, Matthew R; Firek, Brian A et al. (2017) Strain-resolved analysis of hospital rooms and infants reveals overlap between the human and room microbiome. Nat Commun 8:1814|
|Olm, Matthew R; Brown, Christopher T; Brooks, Brandon et al. (2017) dRep: a tool for fast and accurate genomic comparisons that enables improved genome recovery from metagenomes through de-replication. ISME J 11:2864-2868|
|Olm, Matthew R; Brown, Christopher T; Brooks, Brandon et al. (2017) Identical bacterial populations colonize premature infant gut, skin, and oral microbiomes and exhibit different in situ growth rates. Genome Res 27:601-612|
|Costello, Elizabeth K; Sun, Christine L; Carlisle, Erica M et al. (2017) Candidatus Mycoplasma girerdii replicates, diversifies, and co-occurs with Trichomonas vaginalis in the oral cavity of a premature infant. Sci Rep 7:3764|
|Raveh-Sadka, Tali; Firek, Brian; Sharon, Itai et al. (2016) Evidence for persistent and shared bacterial strains against a background of largely unique gut colonization in hospitalized premature infants. ISME J 10:2817-2830|
|Brown, Christopher T; Olm, Matthew R; Thomas, Brian C et al. (2016) Measurement of bacterial replication rates in microbial communities. Nat Biotechnol 34:1256-1263|
|Raveh-Sadka, Tali; Thomas, Brian C; Singh, Andrea et al. (2015) Gut bacteria are rarely shared by co-hospitalized premature infants, regardless of necrotizing enterocolitis development. Elife 4:|
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