Junhua Xie, Xi‐jian Dai, Qiqiong Li, Wei Zhang, Xinke Nie, Haihua Ji, Xinyang Chen, Yue Wang, Jing Feng, Zhipeng Li, Qiong Liu, Jianxin Ye, G Zhang, Shaoping Nie
Gut microbiota dysbiosis is a driving factor in Alzheimer's disease (AD), yet the mechanisms behind remain elusive. Emerging evidence highlights that outer membrane vesicles (OMVs) are critical mediators of microbiota-host communication. Here, we observed a reduction in a gut probiotic Escherichia coli Nissle 1917 (EcN)-like strain in AD patients, and its levels are positively associated with cognitive ability. The EcN OMVs containing outer membrane protein A (OmpA) translocate to the brain, reshaping the dysregulated immune network. Specifically, EcN OMVs are internalized by glia and neurons, suppressing glial hyperactivation and restoring synaptic function, thereby reducing Aβ deposition and cognitive deficits. The results further show that OmpA plays an important role in vesicle trafficking and inflammatory pathways and may be the key regulator of inflammatory mediators in EcN OMVs, modulating astrocyte-microglia-neuron interactions and functionality. This work discloses the substantial therapeutic potential of the probiotic and its secreted OMVs in intervention and treatment of neurological disorders.