Growth velocity in children with environmental enteric dysfunction is associated with specific bacterial and viral taxa of the gastrointestinal tract in Malawian children

Authors: DESAI, CHANDNI - Washington University; HANDLEY, SCOTT - Washington University; RODGERS, RACHEL - Washington University; RODRIGUEZ, CYNTHIA - Washington University; ORDIZ, MARIA - Washington University; MANARY, MARK - Children'S Nutrition Research Center (CNRC); HOLTZ, LORI - Washington University

Submitted to: PLOS Neglected Tropical Diseases
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/13/2020
Publication Date: 6/23/2020
Citation: Desai, C., Handley, S., Rodgers, R., Rodriguez, C., Ordiz, M.I., Manary, M.J., Holtz, L.R. 2020. Growth velocity in children with environmental enteric dysfunction is associated with specific bacterial and viral taxa of the gastrointestinal tract in Malawian children. PLOS Neglected Tropical Diseases. 14(6):e0008387. https://doi.org/10.1371/journal.pntd.0008387.
DOI: https://doi.org/10.1371/journal.pntd.0008387

Interpretive Summary: Stunting (poor linear growth) is a major global problem. Stunting 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). EED is a gut inflammatory process that is endemic in children living in low and middle-income countries. EED and, by extension, stunting are thought to have microbial origins. However, attempts to find specific pathogens that drive (or protect from) EED have not been fruitful. Here, we define the comprehensive gut virome, which includes viruses that infect humans and animals and viruses that infect bacteria (bacteriophage) and the bacterial gut microbiome in rural Malawian children. These participants are very well characterized (with careful growth measurements and intestinal permeability testing), enabling us to more precisely correlate the populations of viruses and bacteria in their stool with how well, or how poorly, the children are growing. We found thirty bacterial species and three bacteriophage that were differentially associated with linear growth in the three months after sampling. We found a positive correlation between bacteria and bacteriophage richness in children with subsequent adequate and moderate linear growth which children with subsequent poor growth lacked. Our data suggest that disrupting the bacteria-bacteriophage equilibrium between bacteria and bacteriophage communities might impair childhood linear growth.

Technical Abstract: Environmental enteric dysfunction (EED) is characterized by diffuse villous atrophy of the small bowel. EED is strongly associated with stunting, a major public health problem linked to increased childhood morbidity and mortality. EED and subsequent stunting of linear growth are surmised to have microbial origins. To interrogate this relationship, we defined the comprehensive virome (eukaryotic virus and bacteriophage) and bacterial microbiome of a longitudinal cohort of rural Malawian children with extensive metadata and intestinal permeability testing at each time point. We found thirty bacterial taxa differentially associated with linear growth. We detected many eukaryotic viruses. Neither the total number of eukaryotic families nor a specific viral family was statistically associated with improved linear growth. We identified 3 differentially abundant bacteriophage among growth velocities. Interestingly, there was a positive correlation between bacteria and bacteriophage richness in children with subsequent adequate/moderate growth which children with subsequent poor growth lacked. This suggests that a disruption in the equilibrium between bacteria and bacteriophage communities might be associated with subsequent poor growth. Future studies of EED and stunting should include the evaluation of viral communities in addition to bacterial microbiota to understand the complete microbial ecology of these poorly understood entities.