Study Gut Dysbiosis in Anemic Preterm Infants Using a Multiomics Approach

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Project Summary/Abstract This proposal details a longitudinal prospective study to define the changes in stool microbiota and host responses as severe anemia develops in preterm infants. The specific goals are to determine the hematocrit (Hct) threshold associated with gut dysbiosis and how anemia development influences the microbiota and host interactions using a multiomics approach. This translational study will provide clinical-relevant information that can potentially change the clinical management of anemia, a common condition in preterm infants. All preterm infants are at risk for anemia and this risk increases with lower birth weight and gestational age. Greater than 50% of very low birth weight (VLBW, <1500 g) infants require a blood transfusion to treat anemia but there is a lack of research evidence to guide clinicians when to transfuse to achieve optimal health outcomes. Anemia in preterm infants has been associated with inflammation, gut dysbiosis, and gut injury with high morbidity and mortality such as necrotizing enterocolitis. The severity of anemia also determined the severity of the outcomes. Recently, anemia has been linked to intestinal dysbiosis characterized by increased proportion of gram-negative Proteobacteria and lower bacterial diversity in preterm infants and this relationship warrants further investigation. Our preliminary data showed that Proteobacterial abundance correlated with total bacterial virulence factors and higher virulence factor abundance was found in anemic group compared to control group. It is a challenge to subject vulnerable preterm infants to invasive procedures or biospecimen collection for research purposes. Stool holds abundance information on gut bacteria, bacterial and human metabolic products that can provide critical insights into the changes in the gut microbiota and the interaction between microbiota and host. A multiomics approach using metagenomics, metaproteomics, and metabolomics data altogether will reveal the potential mechanisms of gut inflammation and injury associated with severe anemia. To achieve our goals, we will perform the following aims: 1) conducting a longitudinal study of VLBW infants who develop severe anemia (had Hct ൑ 25%) to define the microbiome pattern and predictors of anemia associated dysbiosis and 2) compare stool multiomics profiles (metagenomics, metaproteomics, metabolomics, and biomarkers) between anemic (had Hct ൑ 25%) and non-anemic infants (Hct >30%) to identify the changes in gut microbiota composition and function, and host response. We leverage a large cohort of 370+ VLBW infants from an ongoing enrollment to provide the required sample size for this proposal. 16S rRNA V4 region will be used to compute bacterial microbiome composition and comparative biostatistical analyses and survival analysis models of clinical, and microbiome will be performed for aim 1. Stool metagenomics, metaproteomics, metabolomics, and biomarkers will be used in lasso penalized mixed-effects logistic regression and network analysis to identify the interactions and compare between anemic and control groups for aim 2.