Murine maternal microbiome modifies adverse effects of protein undernutrition on offspring neurobehavior

Protein undernutrition results in impaired growth and neurobehavioral development in children. However, the impact of timing, environmental factors, and maternal versus neonatal influences are unclear. Here, using a mouse model of fetal growth restriction where maternal protein intake is limited during pregnancy, we show that adult offspring exhibit cognitive and anxiety-like behavioral abnormalities. Cross-fostering newborn mice to dams previously exposed to either low protein or standard diet reveals that behavioral impairments in adult offspring require diet-induced conditioning of both fetal development and maternal peripartum physiology. Maternal gut microbiome diversity is reduced, maternal immune, milk, and serum metabolomic profiles are altered, and widespread changes in fetal brain transcriptomic and metabolomic profiles are observed, including subsets of microbiome-dependent metabolites. Finally, we show that dams treated with a cocktail of ten diet- and microbiome-dependent metabolites results in differential effects on fetal development and postnatal behavior. Our study highlights the impact of prenatal maternal protein undernutrition on offspring neurobehavioral trajectories and the role of the maternal microbiome.