Maternal Microbiota-Derived Metabolites Shaping the Neonatal Immune System Are Transferred to the Offspring Ante- and Postnatally

Metabolic capacity of the host and immune system development are dependent on colonization with commensal microbiota. There is evidence that signals originating from commensals during early life or from maternal microbiota before birth are required to shape the neonatal immune system. Our system of reversible colonization of germ-free mice with the auxotrophic E. coli strain, HA107, allows us to expose pregnant mice to microbiota without subsequently colonizing their offspring. We use this system to detect maternal microbiota-derived metabolites that are transferred to the offspring and to assess their influence on neonatal immunity. After colonization of pregnant germ-free mice with ¹⁴C-labeled HA107, microbiota-derived products were present in placenta and fetus as well as in the maternal milk as detected by liquid scintillation. Likewise, using ¹³C-labeled HA107 and mass spectrometry, we identified ¹³C-labeled products in the maternal milk and the offspring, indicating that maternal microbiota-derived products can reach the offspring. Exposing pregnant mice to HA107 increased the number of intestinal NKp46⁺ type 3 innate lymphoid cells (ILC3s) and F4/80⁺ CD11c⁺mononuclear cells (MNCs) in the offspring and altered the offspring’s sensitivity to LPS challenge. Cross-fostering between reversibly colonized and germ-free mothers revealed that both ante- and postnatal transfer of maternal microbiota-derived metabolites are required to fully shape the neonatal immune system.

*S.C.G. and M.G.A. contributed equally to this work; K.D.M. and A.J.M. are co-last author.