Coevolution of the Human Brain and Microbiome: Roles of Accelerated Regions and Maternal Microbiota in Neurodevelopment

The coevolution of the human brain and microbiome has emerged as a critical area of research, shedding light on the profound interactions that have shaped human development. Human Accelerated Regions (HARs), the genomic sequences evolved rapidly in humans, play a pivotal role in brain development, influencing cognitive functions and susceptibility to neurological disorders. Our analysis shows that HARs have ~47-fold more gut microbiota–associated genetic factors than expected, supporting an evolutionary interplay between human evolution and microbial symbiosis. Vertical transmission of metabolites from maternal microbiome is crucial for fetal neurodevelopment. Through integrative analysis of metabolomics data and pathway enrichment, we demonstrate how microbial metabolites, including short-chain fatty acids, tryptophan derivatives, and critical amino acids like L-glutamic acid, L-phenylalanine, and L-tryptophan, modulate neurodevelopmental pathways by crossing the placental barrier. These metabolites act through specific signaling pathways including JAK-STAT, prolactin, and retinol metabolism to influence neuronal proliferation, migration, and synaptogenesis, thereby contributing to normal brain function. Our network analyses identify specific transcription factors, miRNAs, and regulatory motifs that potentially mediate HAR-microbiome interactions across brain regions, providing molecular mechanisms through which microbial communities influence brain development and function. The manuscript also explores how evolutionary theories, including the "Expensive Tissue Hypothesis" and "Hologenome Theory," contextualize these host-microbe interactions. This interdisciplinary synthesis integrates insights from neuroscience, evolutionary biology, and microbiology to highlight the coevolutionary dynamics between the human brain and microbiome. The findings have significant implications for developing therapeutic strategies aimed at mitigating neurodevelopmental disorders and enhancing brain health through microbiome modulation.