The influence of the microbiome on growth and immune development in early-life undernutrition

Linear growth stunting due to undernutrition affects 20% of children under the age of five with far-reaching consequences, including increased susceptibility to infection and altered cognitive development. Current nutritional interventions are largely ineffective in rescuing linear growth. A significant proportion of stunting originates in utero; however, the mechanisms by which maternal undernutrition is transmitted between generations remain poorly characterized. In this thesis, we utilized multiple gnotobiotic murine models of intergenerational undernutrition to investigate the contributions of (1) intergenerational microbial transmission, (2) maternal nutritional status, and (3) pre- and postnatal factors in the development of stunting. Offspring exposed to microbiota derived from children with growth stunting exhibited impaired linear growth and developed immune features characteristic of undernutrition and enteropathy, including intestinal villus blunting, reduced liver Insulin-like Growth Factor 1 (IGF-1), and increased accumulation of intraepithelial lymphocytes and plasma cells in the small intestine. In contrast, colonization after weaning mitigated host phenotypic changes driven by distinct microbial communities. Maternal undernutrition exacerbated offspring growth deficits in a microbiota-dependent manner, altering the offspring microbiota by increasing the abundance of Enterococcus species and Escherichia coli.
Our cross-fostering studies demonstrated that postnatal exposure to the stunted donor (SD) microbiota was sufficient to induce growth deficits, mirroring those observed in animals born to colonized dams. Furthermore, the ability of the SD microbiota to displace healthy donor (HD) microbes suggests that both pre- and postnatal interventions may be necessary to effectively restore growth in undernourished populations. Additionally, we identified distinct microbial taxa targeted by Immunoglobulin A (IgA), a key regulator of gut homeostasis. These findings suggest that specific microbes may contribute to growth deficits, and future research will determine whether targeted microbial species independently drive stunting. This thesis findings highlight the critical role of the microbiota in shaping linear growth during gestation and early life, emphasizing the necessity of addressing both maternal and infant microbiota in the development of therapeutic interventions for undernutrition.