Maternal undernutrition exacerbates microbiota-driven growth stunting through pre and postnatal effects

Stunting, a chronic condition characterized by reduced linear growth, affects approximately 20% of children under five years of age globally and is a significant barrier to human development. It has far-reaching consequences that continue into adulthood, including increased susceptibility to infection, reduced cognitive development, and higher risk for metabolic diseases. Current nutritional interventions are largely ineffective in rescuing stunted growth. An emergent hypothesis suggests that a significant proportion of stunting originates in utero, contributing to the ineffectiveness of nutritional interventions later in childhood. However, the mechanisms by which maternal undernutrition drives growth stunting remain poorly characterized. Understanding when and how reduced linear growth develops is critical to more effectively target nutritional therapies. To address this knowledge gap, we employed a gnotobiotic murine model of intergenerational undernutrition in which offspring are exposed to distinct microbial communities both in utero and after birth. We first tested whether maternal undernutrition influenced offspring growth in different microbiota contexts, finding that maternal undernutrition exacerbated offspring growth deficits in the presence of microbiota from an undernourished infant. Maternal undernutrition also altered offspring microbiota, increasing abundance of specific taxa including Enterococcus species and Escherichia coli in pups with growth stunting. We then used cross-fostering approaches to demonstrate critical roles for the microbiota in growth both during gestation and in early life. These findings highlight the interplay between maternal undernutrition, microbiota, and offspring growth, emphasizing the need to consider transmission of the microbiota across generations in the design of nutritional therapies for undernutrition.