PR003017 (Project)

Description:Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disease primarily driven by Th17 and Th1 cells, and the gut microbiota is associated with MS onset and progression. Kurarinone (KU), a key component of the traditional Chinese medicine Radix Sophora Flavesvara, exhibits anti-inflammatory and immune-regulatory effects and can modulate the gut microbiota. However, it is unclear whether KU affects MS via a gut microbiota-mediated mechanism. Herein, we demonstrated that KU significantly alleviated experimental autoimmune encephalomyelitis (EAE), an animal model of MS, by modulating the gut microbiota, particularly by enriching Akkermansia muciniphila. The disease-alleviating effect of KU was achieved in a manner dependent on A. muciniphila. Meanwhile, KU significantly upregulated the tryptophan metabolite indole-3-acetaldehyde (IAAld). The IAAld content was positively correlated with the relative abundance of A. muciniphila and negatively with the severity of EAE in mice. In vitro, A. muciniphila alone could also facilitate the tryptophan metabolism to produce IAAld. Oral IAAld suppresses Th17 and Th1 differentiation to ameliorate EAE. In vitro, IAAld activates AhR and inhibits STAT3/STAT4 phosphorylation, thereby reducing Th17/Th1 differentiation. Collectively, this study identifies a novel mechanism by which KU ameliorates EAE via the gut microbiota-indole-3-acetaldehyde-AhR axis and unveils the potential therapeutic targets for MS.