Background: The brain-gut-microbiome axis has emerged as an important pathway through which perturbations in the gut and/or microbial microenvironment can impact neurological function. Such alterations have been implicated in a variety of neuropsychiatric disorders, includ- ing depression, anxiety, and Alzheimer’s Disease (AD) and the use of probiotics as therapy for th- ese diseases remains promising. However, the mechanisms underlying the gut microenvironment’s influence on disease pathogenesis and therapy remain unclear. Objective: The objective of this study is to investigate the effect of a novel probiotic formula, BIOCG, on cognitive function and pathobiological mechanisms, including amyloid processing and dendritic spine dynamics, in a mouse model of AD. Methods: BIOCG was administered for 3 months to 3xTg or 3xTg; Thy1-YFP AD mice and func- tional outcomes were assessed via behavioral testing and electrophysiology. Mechanisms relevant to AD pathogenesis including dendritic spine morphology and turnover, Amyloid Precursor Pro- tein (APP) processing and microglial phenotype were also evaluated. Finally, we sequenced fecal samples following probiotic treatment to assess the impact on gut microbial composition and corre- late the changes with the above described measures. Results: Mice treated with BIOCG demonstrated preserved cognitive abilities and stronger Long- Term Potentiation (LTP), spontaneous Excitatory Postsynaptic Currents (sEPSC), and glutamate-in- duced LTPs, indicative of functional and electrophysiological effects. Moreover, we observed atten- uated AD pathogenesis, including reduced Amyloid Beta (Aβ) burden, as well as more mature den- dritic spines in the BIOCG-treated. Our finding of changes in microglial number and phenotype in the treatment group suggests that this formulation may mediate its effects via attenuation of neu- roinflammation. Sequencing data confirmed that the gut microbiome in treated mice was more varied and harbored a greater proportion of “beneficial” bacteria. Conclusion: Overall, our results indicate that treatment with BIOCG enhances microbial diversity and, through gut-brain axis interactions, attenuates neuroinflammation to produce histologic and functional improvement in AD pathogenesis.
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