The impact of early-life exposures on growth and adult gut microbiome composition is dependent on genetic strain and parent- of- origin

Authors: HUDA, NAZMUL - University Of California, Davis; KELLY, EMER - University College Dublin; BARRON, KERRI - University Of North Carolina; XUE, JING - University Of North Carolina; VALDAR, WILLIAM - University Of North Carolina; TARANTINO, LISA - University Of North Carolina; SCHOENROCK, SARAH - University Of North Carolina; IDERAABDULLAH, FOLAMI - University Of North Carolina; Bennett, Brian

Submitted to: Microbiome
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/30/2025
Publication Date: 6/16/2025
Citation: Huda, N.M., Kelly, E., Barron, K., Xue, J., Valdar, W., Tarantino, L.M., Schoenrock, S., Ideraabdullah, F.Y., Bennett, B.J. 2025. The impact of early-life exposures on growth and adult gut microbiome composition is dependent on genetic strain and parent- of- origin. Microbiome. 13.Article 143. https://doi.org/10.1186/s40168-025-02130-w.
DOI: https://doi.org/10.1186/s40168-025-02130-w

Interpretive Summary: Environmental insults such as dietary deficiencies or drugs (e.g., antibiotics) during early infancy is harmful and has long lasting effect on health. Dietary protein and vitamin D deficiency among pregnant and lactating mothers are widespread. Deficiencies during the developmental period play a significant role in offspring’s health during adulthood and although many mechanisms are responsible, the role of changes to the offspring’s gut microbiota are implicated but poorly understood. Moreover, genetics and parent-of-origin (PO) may modulate the effect of these environmental factors on health. However, our understanding of how developmental environment, genetics, and PO interact to modulate offspring’s gut microbiota and health is still limited. This study aimed to investigate the effect of early exposure of known or putative insults to the microbiome (antibiotics exposure, protein deficiency, and vitamin D deficiency). Mothers were maintained on antibiotic-containing (AC), low protein (LP), low vitamin D (LVD), or mouse control diets from 5 weeks prior to the pregnancy to the end of the lactation. Our study revealed that early developmental exposure to antibiotics, protein deficiency, and vitamin D deficiency have a long-lasting effect on offspring’s growth, and gut microbial diversity and composition depending on the genetics architecture. We also observed a significant PO effect on offspring’s gut microbiota. Our results suggest that antibiotic use, and protein deficiency, during the developmental period have long-lasting effects on gut microbiota and growth at adulthood depending on genetic architecture and PO, which demonstrated the importance of preventing maternal deficiency and reducing antibiotics use during pregnancy and lactating period for better offspring’s growth and gut health.

Technical Abstract: Early life exposure to environmental insults such as dietary deficiencies or drugs (e.g., antibiotics) is a major concern for public health. Dietary protein and vitamin D deficiency among pregnant and lactating mothers are widespread. Deficiencies during the developmental period play a significant role in offspring’s health during adulthood and although many mechanisms are responsible, the role of changes to the offspring’s gut microbiota are implicated but poorly understood. Moreover, genetics and parent-of-origin (PO) effects may interact with environmental factors such as diet to modulate gut microbiota, thus health. However, our understanding of how developmental environment, genetics, and PO interact to modulate offspring’s gut microbiota and health is still limited. This study aimed to investigate the effect of early exposure of known or putative insults to the microbiome (antibiotics exposure, protein deficiency, and vitamin D deficiency). Mothers were maintained on antibiotic-containing (AC), low protein (LP), low vitamin D (LVD), or mouse control diets from 5 weeks prior to the pregnancy to the end of the lactation. Parent of origin effects was determined using F1 offspring from reciprocal crosses of genetically advanced Collaborative Cross (CC) mice generated using reciprocal crossbreeding pairs of CC001xCC011 (Female X Male) and CC011xCC001, CC004xCC017 and CC017xCC004, and CC041xCC051 and CC051xCC041. Therefore, all F1 offspring within a reciprocal pair were genetically identical except for the PO, X-, Y-chromosomes, mitochondrial genome, and any epigenetic imprinting. We assayed offspring’s gut microbiota and bodyweight at their 8 weeks of age using the 16S sequencing method. Our study revealed that early developmental exposure to antibiotics, protein deficiency, and vitamin D deficiency have a long-lasting effect on offspring’s growth, and gut microbial diversity and composition depending on the genetics architecture. We also observed a significant PO effect on offspring’s gut microbiota. For instance, offspring of the CC011xCC001 mice had higher diversity indices compared to corresponding reciprocal cross CC001xCC011. Our results suggest that antibiotic use, and protein deficiency, during the developmental period have long-lasting effects on gut microbiota and growth at adulthood depending on genetic architecture and PO, which demonstrated the importance of preventing maternal deficiency and reducing antibiotics use during pregnancy and lactating period for better offspring’s growth and gut health.