ABSTRACT
BACKGROUND: Childhood undernutrition is a major global health challenge with devastating lifelong consequences. Linear growth stunting due to undernutrition has been linked to poor health outcomes, and mothers who experience growth stunting in childhood are more likely to give birth to stunted children later in life. Based on these findings, we hypothesized that intergenerational colonization of mice with microbiota from human donors with undernutrition may recapitulate certain immune and growth changes observed in this disorder. RESULTS: To test this hypothesis, we developed a gnotobiotic murine model of undernutrition using microbiota from human infants with healthy or stunted growth trajectories. Intergenerational colonization with microbiota derived from children with growth stunting lead to less linear growth and the development of immune features of undernutrition and enteropathy, including intestinal villus blunting, lower liver IGF-1 and accumulation of intraepithelial lymphocytes and plasma cells in the small intestine. In contrast, colonization after weaning lead to fewer host phenotypic changes between these distinct microbial communities. CONCLUSIONS: These results are broadly consistent with previous findings demonstrating that exposure of the immune system to microbial products during the weaning phase is a critical determinant of later life immune function. Overall, our results suggest intergenerational colonization with human microbiota samples is a useful approach with which to investigate microbiota-dependent changes in growth and immunity in early life. Murine models that capture the intergenerational and multifactorial nature of undernutrition are critical to understanding the underlying biology of this disorder. Video Abstract.
Subject(s)
Gastrointestinal Microbiome , Malnutrition , Microbiota , Animals , Humans , Infant , Mice , Growth Disorders , Intestine, SmallABSTRACT
Childhood undernutrition is a major global health challenge with devastating lifelong consequences. Linear growth stunting due to undernutrition has been linked to poor outcomes, and mothers who experience stunting are more likely to give birth to stunted children. Murine models that capture the intergenerational and multifactorial nature of undernutrition are critical to understanding the underlying biology of this disorder. Here we report a gnotobiotic mouse model of undernutrition using microbiota from human infants with healthy or stunted growth trajectories. Intergenerational transmission of microbiota from parents to offspring leads to the development of growth and immune features of undernutrition and enteropathy, including reduced linear growth, intestinal villus blunting and accumulation of intraepithelial lymphocytes. In contrast, colonization after weaning reduces sensitivity to detect changes driven by distinct microbial communities. Overall, these results suggest intergenerational colonization is a useful approach with which to investigate microbiota-dependent growth and immunity in early life.
