Gut microbial metabolite indole-3-acetic acid inhibits microglia-mediated synaptic loss in Alzheimer's disease by targeting CCR4.

Gut microbial metabolites abnormity links to Alzheimer's disease (AD) progression, yet the mechanism remains unknown. Here, we observed a markedly decreased level of indole-3-acetic acid (IAA) in AD patients, and the IAA level was negatively correlated with cognitive impairment. IAA supplementation improved cognitive dysfunction and synaptic damage, and suppressed microglial activation and synaptic phagocytosis in AD mouse and cell models. RNA sequencing revealed an increase in phagocytosis-associated pathway activity and gene expression, and C-C chemokine receptor 4 (CCR4) was identified as a key regulator of this process. IAA could inhibit the expression level of CCR4, and siRNAs CCR4 markedly inhibited microglia-mediated phagocytosis of synapse. We further demonstrated that microglial CCR4 interacts with aryl hydrocarbon receptor (AHR), a key receptor of IAA, and proposed the hypothesis that AHR binds to the CCR4 promoter, thereby inhibiting its transcriptional activity. Moreover, we further revealed that bacteria producing IAA supplementation inhibited microglia-mediated synaptic loss by down-regulating CCR4, thus delaying Alzheimer's progression. These findings elucidate the mechanisms underlying microbial metabolite IAA's impact on AD, highlighting that targeting CCR4 inhibition in microglia-mediated synaptic phagocytosis represents a promising therapeutic strategy for AD.