The hologenome in brain health and disease

Genetic variants altering brain function have been considered the primary cause of many neurological disorders. Therefore, current therapeutics target the brain directly. However, an often-overlooked source of genetic variation comes from microbes inhabiting our bodies, which can profoundly modulate host brain function via metabolic and immune pathways. As a result of the dynamic interplay and co-evolution between the host and microbes, the concept of the hologenome-the collective genomes of host and microbes-has emerged. Intriguingly, recent studies suggest a paradigm shift in our understanding of disease etiology-neurological symptoms in some genetic diseases may have distinct hologenomic origins and may even originate outside the brain, potentially evading brain-targeting therapies. This perspective will summarize recent findings on the hologenome's role in neurological disorders and recommend a roadmap for future research. The proposed approach aims to provide new insights into human/animal biology, enhancing the rigor and reproducibility of both preclinical and clinical research.