Gut Microbiota‐Derived Indole‐3‐Acetaldehyde Contributes to the Disease‐Alleviating Effects of Kurarinone in Experimental Autoimmune Encephalomyelitis

Multiple sclerosis (MS) is a central nervous system autoimmune disease primarily driven by Th1 and Th17 cells, whose onset and progression are closely associated with gut microbiota. Kurarinone (KU), an active component from Radix Sophora Flavescens, exhibits anti-inflammatory, immunoregulatory and gut microbiota-modulating properties. However, whether KU alleviates MS severity via a gut microbiota-mediated mechanism remains unclear. Here, we demonstrate that KU ameliorates experimental autoimmune encephalomyelitis (EAE)-an animal model of MS-by modulating the gut microbiota, particularly via enriching Akkermansia muciniphila, and A. muciniphila is essential for the protective effects of KU in EAE. Furthermore, KU elevates levels of the tryptophan metabolite indole-3-acetaldehyde (IAAld). IAAld levels are positively correlated with the relative abundance of A. muciniphila and negatively correlated with EAE severity. In vitro, A. muciniphila alone is sufficient to facilitate tryptophan metabolism to produce IAAld. IAAld treatment ameliorates EAE and reduces the frequencies of pathogenic Th1 and Th17 cells in mice. Mechanistically, IAAld activates the aryl hydrocarbon receptor (AhR) and suppresses JAK/STAT signaling, thereby dampening Th1 and Th17 differentiation; these effects are abolished following AhR blockade. Collectively, this study identifies a novel mechanism by which KU mitigates EAE via the gut metabolite IAAld-AhR-immune axis and unveils potential therapeutic targets for MS.