Colonization during a key developmental window reveals microbiota-dependent shifts in growth and immunity during undernutrition

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.