The role of secondary genomes in neurodevelopment and co-evolutionary dynamics.

This chapter examines how human biology and microbial "secondary genomes" have co-evolved to shape neurodevelopment through the gut-brain axis. Microbial communities generate metabolites that cross blood-brain and placental barriers, influencing synaptogenesis, immune responses, and neural circuit formation. Simultaneously, Human Accelerated Regions (HARs) and Endogenous Retroviruses (ERVs) modulate gene expression and immune pathways, determining which microbes thrive in the gut and impacting brain maturation. These factors converge to form a dynamic host-microbe dialogue with significant consequences for neurodevelopmental disorders (NDD), including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia. Building on evolutionary perspectives, the chapter elucidates how genetic and immune mechanisms orchestrate beneficial and pathological host-microbe interactions in early brain development. It then explores therapeutic strategies, such as probiotics, prebiotics, fecal microbiota transplantation, and CRISPR-driven microbial engineering, targeting gut dysbiosis to mitigate or prevent neurodevelopmental dysfunctions. Furthermore, innovative organ-on-chip models reveal mechanistic insights under physiologically relevant conditions, offering a translational bridge between in vitro experiments and clinical applications. As the field continues to evolve, this work underscores the translational potential of manipulating the microbiome to optimize neurological outcomes. It enriches our understanding of the intricate evolutionary interplay between host genomes and the microbial world.