Exploring the microbiota-Alzheimer’s disease linkage using short-term antibiotic treatment followed by fecal microbiota transplantation

Gut microbiota is proven to be involved in the development of beta amyloid (Aβ) pathology in Alzheimer’s disease (AD). Since there are difficulties in translating microbiota findings based on germ-free mice into clinical practice, here, we used short-term antibiotic cocktail treatment to develop a novel model with a near-germ-free status and without impacting Aβ pathology. Three months old APPSWE/PS1ΔE9 mice were fed with antibiotic cocktails for two weeks by gavage to obtain a near “germ-free” status, and then received the donor fecal matter from the 16 months old APPSWE/PS1ΔE9 mice for 7 consecutive days. Fecal pellets were collected prior to antibiotics treatment, following antibiotic exposure, prior to and following fecal microbiota transplantation for gut microbiota analysis. Also, Aβ pathology, astrocyte and microglia morphology were further explored. Pre-antibiotic-treated mice successfully allowed engraftment of gut microbiota following 7 consecutive days gavage with aged APPSWE/PS1ΔE9 mice microbiota. Microbiota reconstitution by transplantation was largely attributable to the donor source (e.g. g_Coriobacteriaceae and g_Clostridium) and led to a significant increase in Aβ plaques. Surprisingly, astrocyte activation around Aβ plaques was suppressed rather than microglia, the well-recognized plaque phagocytic cell type in Aβ clearance, following microbiota engraftment. Our findings provide a novel framework for understanding the mechanisms of AD through the gut-brain axis and the translation of gut microbiota manipulation from bench to clinical practice.