Using flavonoids as a therapeutic intervention against rheumatoid arthritis: The known and unknown

Rheumatoid arthritis (RA) is an intricate autoimmune disease involved in numerous factors. Aberrant immune responses at joint sites are considered primary in the pathogenesis of RA. The complex interactions may occur between distinct immune cells, aiming at amplifying and accelerating inflammatory responses in inflamed joints. At present, gut-joint axis hypothesis holds the idea that RA originates in the gut as a result of coactions between the intestinal immune cells and dysbiotic microbiota. Dysbiosis causes intestinal inflammation and alterations in intestinal permeability, which provides a pathological basis for the transfer of activated intestinal immune cells and their products to the joints through systemic circulation or other ways. Some therapeutic options widely utilized for the treatment of RA are associated with gut-joint axis, suggesting modulation of gut-joint axis may be a promising strategy in preventing and treating RA. Flavonoids are a type of polyphenol widely existed in herbs and foods showing anti-RA potentials. However, the mechanisms by which flavonoids mitigate RA have not been well organized. In this review, we outline and discuss current understanding of the underlying mechanisms of anti-RA flavonoids through immunoregulation, gut-joint axis, and inflammatory responses, providing a reference for developing novel strategies for the treatment and prevention of RA.