RESUMEN
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, including depression, anxiety, and Alzheimer's Disease (AD) and the use of probiotics as therapy for these 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 functional outcomes were assessed via behavioral testing and electrophysiology. Mechanisms relevant to AD pathogenesis including dendritic spine morphology and turnover, Amyloid Precursor Protein (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 correlate 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-induced LTPs, indicative of functional and electrophysiological effects. Moreover, we observed attenuated AD pathogenesis, including reduced Amyloid Beta (Aß) burden, as well as more mature dendritic 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 neuroinflammation. 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.
