Background: The pathoetiology and pathophysiology of migraine are widely accepted as unknown.
Methods: The current article reviews the wide array of data associated with the biological underpinnings of migraine
and provides a framework that integrates previously disparate bodies of data.
Results: The importance of alterations in stress- and pro-inflammatory cytokine- induced gut dysbiosis, especially
butyrate production, are highlighted. This is linked to a decrease in the availability of melatonin, and a relative
increase in the N-acetylserotonin/melatonin ratio, which has consequences for the heightened glutamatergic excitatory
transmission in migraine. It is proposed that suboptimal mitochondria functioning and metabolic regulation
drive alterations in astrocytes and satellite glial cells that underpin the vasoregulatory and nociceptive changes in
Conclusion: This provides a framework not only for classical migraine associated factors, such as calcitonin-gene
related peptide and serotonin, but also for wider factors in the developmental pathoetiology of migraine. A number
of future research and treatment implications arise, including the clinical utilization of sodium butyrate and
melatonin in the management of migraine.