Towards a mechanistic understanding of the role of gut microbiota in postnatal growth impairment

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PROJECT SUMMARY Precision engineering of the gut microbiota requires a mechanistic understanding of how microbes interact with host physiological pathways in order to produce desired health outcomes. In stunted children, commensal gut microbes have been correlated with aberrant host inflammation and growth impairment, but mechanisms underlying these associations are poorly understood. Mouse models have suggested causality, but they fail to recapitulate the dynamics of the mucosal immune system in humans and the complexity of the human gut microbiota. This project will interrogate these questions in vivo in a cohort of >1500 children from rural Bangladesh at risk for stunting, for which biological specimens were collected longitudinally from 0-3 years of age. Preliminary analysis of 16S rRNA gene sequences from >3700 fecal samples collected from these children has identified a Bifidobacterium sequence variant that is highly correlated with intestinal inflammation and subsequent growth faltering. In Aim 1, I will identify strain-specific microbial genes that might mediate these observed associations. In Aim 2, I will interrogate the mechanistic underpinnings by evaluating microbial small- molecule metabolites in feces and blood associated with high levels of Bifidobacterium and concurrent gut and/or systemic inflammation in children 14 months old. In Aim 3, I will use advanced latent variable statistical modeling to determine the importance of associated groups of microbial (taxonomic, metagenomic, and metabolic) and host (gut and systemic inflammation) features on future growth faltering. I will also estimate the maximum achievable improvement in child growth from a theoretical, 100% efficacious microbiota-manipulation intervention, providing an expected effect size for comparison with other intervention alternatives. This work will increase our mechanistic understanding of the associations between early life gut microbiota and aberrant intestinal/systemic inflammation as well as future growth faltering, producing new options for predictably manipulating the gut microbiota to mitigate adverse health outcomes. The proposed project will provide a rigorous training experience in the fields of gut microbiota, microbial metabolites, multivariate statistics, and pediatric gastroenterology under the mentorship of a group of scientific experts, and will equip me with the skills necessary to become an independent researcher.