Flavonoids bridging the gut and the brain: Intestinal metabolic fate, and direct or indirect effects of natural supporters against neuroinflammation and neurodegeneration

In recent years, experimental evidence suggested a possible role of the gut microbiota in the onset and devel-opment of several neurodegenerative disorders, such as AD and PD, MS and pain. Flavonoids, including an-thocyanins, EGCG, the flavonol quercetin, and isoflavones, are plant polyphenolic secondary metabolites that have shown therapeutic potential for the treatment of various pathological conditions, including neurodegen-erative diseases. This is due to their antioxidant and anti-inflammatory properties, despite their low bioavail-ability which often limits their use in clinical practice. In more recent years it has been demonstrated that flavonoids are metabolized by specific bacterial strains in the gut to produce their active metabolites. On the other way round, both naturally-occurring flavonoids and their metabolites promote or limit the proliferation of specific bacterial strains, thus profoundly affecting the composition of the gut microbiota which in turn modifies its ability to further metabolize flavonoids. Thus, understanding the best way of acting on this virtuous circle is of utmost importance to develop innovative approaches to many brain disorders. In this review, we summarize some of the most recent advances in preclinical and clinical research on the neuroinflammatory andneuroprotective effects of flavonoids on AD, PD, MS and pain, with a specific focus on their mechanisms of action including possible interactions with the gut microbiota, to emphasize the potential exploitation of dietary fla-vonoids as adjuvants in the treatment of these pathological conditions.