Circadian Phytonutrition Using Polyphenol-Rich Botanical Extracts to Remodel Immunometabolism in Autoimmune Thyroid Disorders: A Mechanistic Review and Research Roadmap

Abstract

Imbalances between proinflammatory T helper 17 (Th17) cells and immunosuppressive regulatory T (Treg) cells have been shown to play a key role in the pathogenesis of autoimmune thyroid diseases (AITD), such as Hashimoto's thyroiditis and Graves' disease. In particular, Th17/Treg cell ratio is associated with levels of autoantibodies and the severity of AITD. Furthermore, different metabolic pathways underlie the generation of Th17 cells (glucose-dependent anabolic metabolism) and Tregs (oxidative mitochondrial metabolism). The association between these Th17/Treg immune cells, their respective metabolic pathways and the autoimmune disease has led to the hypothesis that AITD is partly an immunometabolic disease. Moreover, it has been demonstrated independently that molecular clocks of thyroid cells are altered in autoimmune thyroiditis, with decreased expression of circadian rhythm proteins BMAL1 and PER2, which correlate with the level of inflammation and that disruption of circadian rhythm (light-shift) exacerbates the disease severity in the animal model. Third line of research, not linked to either of the above, has revealed the ability of various dietary polyphenols — such as green tea catechins (EGCG), curcumin, resveratrol, citrus polymethoxyflavones — to modulate transcription of the core clock-genes and directly inhibit Th17 development while enhancing Treg induction. This review integrates these three bodies of literature and offers, in the form of an explicit but untested hypothesis, that timing of polyphenol administration from botanical sources in alignment with, rather than disregard of, the physiological rhythms of the intrinsic immune and thyroid clocks will be capable of reprogramming Th17/Treg metabolism in early AITD more effectively than conventional polyphenol ingestion. It refer to this strategy as circadian phytonutrition. The review concludes with a series of in vitro, animal and human studies in translation, designed as a step-wise process. No original data are offered here; all proposed mechanisms are hypotheses derived from indirect evidence.