Parental microbiome programming of early-life neurodevelopment: multi-niche contributions through the microbiome-gut-brain axis

Abstract

The microbiota-gut-brain axis (MGBA) is a central pathway through which gut microbial communities influence neurodevelopment via immune, metabolic, and neural signalling. Early life, spanning preconception through infancy, represents a particularly sensitive window during which parental microbiomes exert disproportionate influence on offspring gut colonization, immune education, and neurodevelopmental programming. This review synthesizes current evidence on how maternal and paternal microbiomes shape pediatric neurodevelopment through coordinated microbial, metabolic, immune, and epigenetic pathways. We examine pregnancy-associated remodeling of maternal microbiomes across gut, vaginal, oral, skin, and milk niches, highlighting how hormonal, metabolic, and immune adaptations drive site-specific microbial shifts with downstream consequences for fetal and infant brain development. Core microbial mechanisms are discussed, including short-chain fatty acids (SCFAs), tryptophan-derived metabolites, bile-acid signaling, and immune mediators that link microbial metabolism with immune and neurodevelopmental processes. These mechanisms are integrated with key transmission routes, including placental metabolite transfer, mode-of-delivery-dependent microbial seeding, breast milk-mediated signaling, and early environmental exposures that further shape the developing MGBA. We also incorporate emerging evidence on paternal microbiome contributions via preconception programming, sperm epigenetic remodeling, and germline-microbiome interactions, expanding the traditional maternal-centric view of intergenerational microbial inheritance. Finally, we evaluate modifiable factors, including diet, metabolic status, stress, antibiotic exposure, and microbiome-targeted interventions, and discuss their translational relevance. While associations between the microbiome and neurodevelopment are increasingly supported by human studies, many mechanistic insights remain derived from animal models, and causal relationships are not yet fully established. By integrating mechanistic, clinical, and systems-level perspectives, this review positions the MGBA as a promising but still evolving framework for understanding and potentially modulating early-life brain development.