Propagation and Characterization of Phage Related to Human Growth

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Project Description Bacteriophage (phage) are viruses that infect prokaryotes. Bacteriophage can destroy the bacterial cell they infect (bacteriolysis), and thereby mold bacterial populations. Our incomplete knowledge of phage biology, in particular phage-bacterial pairing, the range of bacterial hosts for a given phage, and the effect of an introduced phage on phage-bacteria community dynamics limits our ability to understand how phage impact gut health. The human gut contains a highly complex community of bacteria and phage. Alterations in bacteriophage communities are associated with disorders such as inflammatory bowel disease, diabetes, hypertension, and colorectal cancer. Stunting (poor linear growth) adversely affects one-third of the half-billion preschool children in low and middle-income countries and is associated with ~20% of all-cause deaths before age five. Stunting is believed to be a consequence of environmental enteric dysfunction (EED). We recently defined the comprehensive gut virome and the bacterial gut microbiome in a longitudinal cohort of rural Malawian children with EED. We found 13 bacteriophage that were differentially associated with linear growth. Twelve of the 13 bacteriophage were associated with subsequent poor growth velocity. Intriguingly, we found an inverse relationship between bacteria and bacteriophage richness in children with subsequent poor linear growth (bacteriophage richness diminishes as bacterial richness increases in children with poor growth). Our data suggest that disruption of the equilibrium between bacteria and bacteriophage communities might impair childhood linear growth. This observation that changes in the phage community are associated with subsequent linear growth is intriguing as there is currently no way to treat or prevent EED and stunting. Additionally, the pathophysiology underlying EED is not well understood, and there currently is not a reliable marker of disease. Therefore, further understanding of these bacteriophage as either drivers or markers of disease would be a significant advance for the field. We suggest that further characterization, and potentially future manipulation, of these microbial signatures may reveal novel avenues for prevention, diagnosis, or treatment of EED and stunting. Here we aim to advance understanding of phage biology, global gut health, and child health and development. We will identify and grow bacterial host(s) of the phages of interest, culture phages, and further characterize them. While we propose to apply our methods to study phage in the context of EED, execution of this approach will also provide a much-needed roadmap for future studies of phage in other disorders.