Impact of Parabacteroides presence, timing and function on preterm infant health

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PROJECT SUMMARY Our overarching goal is to understand the role of the microbiome in preterm infant development, and to identify means of optimizing the microbiome to improve preterm infant health. Studies of the preterm infant microbiome to date have primarily been correlation studies of microbiome diversity and taxonomy patterns with specific clinical factors. Microbiome function and the mechanisms by which the microbiome impacts preterm infant development remains a significant gap in knowledge. Production of metabolites that can influence the growth of other organisms or directly impact the host is a key mechanism of microbiome function. Our studies from both a preterm infant cohort and mouse models transfaunated with preterm infant microbial communities have identified Parabacteroides distasonis (Pd) as a critical organism associated with preterm infant health (decreased inflammation, improved growth, enhanced intestinal development). We now have an important tool to decipher what microbiome functions and outputs are key for preterm infant health. With this proposal, we will investigate the effect of Pd isolated from a preterm infant on microbial community function, specifically metabonomics output, and test the hypothesis that Pd can be used to understand microbiome functions critical to preterm infant health and development. We will use cultivation and bioreactor models to study microbe/microbe interactions and identify what metabolites are produced by the addition of Pd. We will also use mouse models transfaunated with preterm infant microbial communities with or without Pd for investigation of microbiome/host informed metabolites and interactions at the cellular level that are not possible in human infant patients. Responses to Pd will be compared to responses to Lactobacillus acidophilus and Bifidobacterium infantis (La/Bi), as an example of a combination of probiotics already used in preterm infant clinical trials for neonatal necrotizing enterocolitis, to determine if there are functions specific to Pd versus other probiotics. We will then use the functional information obtained from these models to interrogate our existing biorepository of longitudinally collected fecal samples from preterm infants with known clinical outcomes to confirm which metabolites, produced by microbes and associated with specific molecular effects, are associated with health outcomes in actual infants, and during which window of time. Microbial community alteration, functional outcomes (inflammation, growth, intestinal development) and metabonomic profiles will all be examined. This study will begin to reveal which microbiome-based functions are most critical for preterm infant health and which windows of time are most important for microbiome optimization. This knowledge is necessary for the development of rational microbiome-based therapeutic options for this vulnerable patient population.