The association of gut microbiota and gut function with health and disease in Bangladeshi children [electronic resource]

Overview: 555 million preschool children live in developing countries where malnutrition (undernutrition) is a significant problem. The factors that contribute to this issue are multiple, with two important factors being gut microbiota and gut function. To begin to understand gut microbiota and gut function in a developing country, we performed two parallel studies: in the first study, we characterized the baseline gut microbiota of healthy Bangladeshi children, and in the second study, we investigated the association between household environmental conditions and gut function in Bangladeshi children. The gut microbiota affect nutrient metabolism, immune function, and pathogen resistance. Loss of gut function as occurs in environmental enteropathy (a multifaceted, subclinical intestinal disorder likely derived from repeated episodes of infectious gastroenteritis and chronic inflammation) contributes to malnutrition and growth faltering. It is possible that these processes are interrelated with the gut microbiota serving a critical role in environmental enteropathy. Gut microbiota: Previous studies have focused on the gut microbiota of infants and adults from developed countries, but few have characterized the gut microbiota of people living in developing countries. Furthermore, little is known about the gut microbiota and its variation over time in primary-school-age children and adolescents in either developed or developing countries. In this study, we compared the monthly variation in fecal microbiota composition of healthy children (ages 8--14 years) living in an urban slum in Bangladesh with that of age-matched children from affluent suburban communities in the United States. We analyzed 8,000 near full-length sequences of the small-subunit ribosomal RNA gene (16S rDNA) and over 845,000 pyrosequencing reads spanning the V1-V3 variable region of the 16S rDNA. The distal gut of Bangladeshi children harbored significantly higher microbial diversity than U.S. children, a result validated by the discovery of several novel lineages from various bacterial phyla in the full-length Bangladeshi dataset. Bangladeshi and U.S. children displayed distinct gut microbiota architectures. Moreover, significantly lower month-to-month temporal stability was observed in Bangladeshi children compared to U.S. children. Together, these results suggest that different environmental or genetic variables may affect the microbiota of healthy children in the two countries. Further studies are necessary to investigate the underlying mechanisms of these differences and to incorporate these insights into prevention or treatment of diseases. Gut function: Although poor water quality, sanitation, and hygiene are putative risk factors for environmental enteropathy, there are no studies investigating the relationship of household environmental conditions to environmental enteropathy. We compared levels of environmental enteropathy markers to growth patterns and measured the prevalence of parasitic infections in children living in different levels of environmental cleanliness based on indictors of water, sanitation, and hygiene in their households. We conducted a follow-up study of 119 children (< 4 years old) from an existing cohort, living in rural Bangladesh and divided into two types of households: a 'mitigated household' had good water quality, improved sanitation, and a handwashing station stocked with water and soap, and a 'contaminated household' had poor water quality, and inadequate sanitation and handwashing facilities. We measured anthropometry, intestinal parasitic infection, and the following markers to assess gut function: Lactulose:Mannitol (L:M) ratio, immunoglobulin G endotoxin core antibody (IgG EndoCAb), and total IgG. After adjustment for potential confounding, children from mitigated households had higher height-for-age Z-scores (HAZ), lower L:M ratios, and lower IgG EndoCAb titers than children from contaminated households. The L:M ratio was also strongly associated with HAZ in the cohort. Children living in environmentally mitigated households had lower levels of parasitic infection, improved measures of gut function, and improved growth compared to children living in contaminated environments. These results support the hypothesis that environmental contamination mediated through environmental enteropathy could be a cause of growth faltering in low-income countries. Interpretation: By characterizing the baseline gut microbiota of healthy children living in a developing country and correlating their gut function with household environmental conditions, our work provides a foundation to address the role of the gut microbiota and environmental enteropathy in child health.

Keywords: Microbiology and Immunology
Advisor: Singh Upinder (Physician)
Parsonnet Julie
Relman David A. advisor. Thesis advisor
Schoolnik Gary K. advisor. Thesis advisor
Sonnenburg Justin