Causal communication between gut microbiota dysbiosis and neuroinflammation in Alzheimer’s disease and therapeutic intervention by oligomannate

Abstract Background Recently, increasing evidence has demonstrated the dynamic interaction between gut microbiota dysbiosis and Alzheimer’s disease (AD) progression, yet major knowledge on how gut microbiota pathogenic attacks AD remains obscure. Method We provide a multi‐dimensional profiling of gut microbiota, metabolomics and peripheral and central immune patterns in AD transgenic mice, to decipher the pathogenic outcomes of gut microbiota dysbiosis and its potential mechanistic linkage to neuroinflammation in AD progression. Result We discovered that, during AD progression, the dynamic alteration of gut microbiota composition and associated metabolites profoundly affected the peripheral immune pattern of the gut and that of the brain. Furthermore, the brain‐infiltrated peripheral immune cells crossed with the microglia activation, contributing to AD‐associated neuroinflammation and then neuronal injury. Importantly, similar alteration in microbiota‐derived metabolites and immune cell subtypes in the blood were also observed in the cohorts of patients with mild cognitive impairment (MCI) due to AD and AD. Interestingly, sodium oligomannate that has demonstrated a consistent cognition improvement in a phase 3 clinical trial in China and approved for the treatment of mild‐to‐moderate AD, was found to suppress gut microbiota dysbiosis and the associated abnormal metabolites, which harnessed peripheral inflammation and neuroinflammation and reversed the cognition impairment in AD transgenic mice. Conclusion Our findings highlight the role of gut microbiota dysbiosis‐promoted neuroinflammation and neurodegeneration in AD progression, and further suggest a novel strategy for AD therapy by targeting gut‐brain axis.