Liver-brain epigenetic axis: The frontier for depression and its treatment using Western or Traditional Chinese Medicine

Major Depressive Disorder (MDD) is a common mental illness, for which current Western pharmacotherapies often suffer from limited targets, delayed onset of action, and high relapse rates. Traditional Chinese Medicine (TCM) have potentials in multi-target regulation for improving the treatment outcome. A great number of classic TCM herbal formulas such as Yueju Pill and Chaihu Shugan San, as well as their active ingredients, can alleviate depressive symptoms via mechanisms such as neuroplasticity, inflammatory response, and tryptophan metabolism. The TCM "liver" organ is more functional and integrative, with "dispersing and discharging" characteristic. It is proposed that stagnation due to liver's dispersing and discharging dysfunction may lead to depression, and thus “soothing the liver and relieving stagnation” is critical for the treatment. Previous studies have shown the involvement of liver regulation of metabolism of tryptophan or bile acid, immunity in depression. An increasing number of evidence indicates the important role of epigenetics in depression, which is contingent on the metabolic products by liver. Here the research progress on liver-brain epigenetic axis and its connection with immune system for the development and treatment of depression is reviewed. Epigenetic mechanisms include DNA/RNA methylation, histone modification, and non-coding RNA regulation. The metabolic products by liver, including factors such as S-adenosylmethionine (SAM), provide the doner for epigenetic modification. Immune system is profoundly involved for the liver-brain epigenetic axis. Emerging studies of TCM treatment of depression start to investigate the mechanism. Further exploration of the liver-brain epigenetic axis and its interaction to immune systems in regulation of depression are discussed.