Kurzfassung

Objectives:
Microglia-driven neuroinflammation is a key characteristic of Alzheimer's disease (AD). Dietary omega-3 polyunsaturated fatty acids (PUFAs) have been shown to exert anti-inflammatory effects and to improve microglial function in the diseased brain. Further, omega-3 PUFAs have the potential to shape the gut microbiota and thereby influence microglial cells via the gut-brain axis. In a short-term pilot experiment, we aimed to decipher whether the omega-3 PUFA eicosapentaenoic acid (EPA) modulates the gut microbiome and thereby microglia and AD pathology.
Methods:
APP-PS1 mice (RRID: MMRRC_034829-JAX) (TG) and non-transgenic littermates (WT), 13-14 months old, were fed a diet supplemented with 0.3% EPA or control chow for 3 weeks. The hippocampus and blood plasma was used for quantification of eicosanoids. Platelets were isolated to assess platelet activation. Primary microglia were isolated of one hemisphere to perform a phagocytosis assay. Brain and retinal tissue were used for immunohistochemistry. Fecal pellets were analyzed for gut microbiota composition.
Results:
Microbiome analysis revealed elevated abundance of Bacteroidetes in the TG mice, indicating genotype specific gut microbiota dysbiosis. EPA supplementation decreased the percentage of Bacteroidetes and increased bacteria of the phyla Firmicutes in APP-PS1 and WT mice. The ratio of Firmicutes to Bacteroidetes, which was shown to decline in ageing and AD, was significantly increased by EPA-diet. However, other AD characteristics such as increased platelet activation, higher hippocampal levels of pro-inflammatory eicosanoids (5-HETE, PGD2, TXB2), microgliosis in the cortex, astrogliosis in the cortex and retina, and increased microglial phagocytosis of amyloid peptide ex vivo, were not affected by the short-term EPA supplementation.
Conclusions:
Short-term EPA supplementation counteracted gut microbiota dysbiosis in APP-PS1 mice; future experiments will determine whether long-term EPA treatment could also influence AD pathology in the brain of APP-PS1 mice.