Transplantaion of Parabacteroides distasonis mitigated Aβ-associated changes in APP/PS1 mice via gut-brain interactions by attenuating neuroinflammation

Abstract Background: Alzheimer's Disease (AD) is a neuropathological condition marked by cognitive deterioration and chronic neuroinflammation. Previous investigations have unveiled a strong correlation between the gut microbiota and the progression of AD. In this study, our objective is to probe the effects of Parabacteroides distasonis (P.distasonis), previously found to be conspicuously diminished in AD patients, on the APP/PS1 mice model. Methods: To assess the impact of orally administered P.distasonis on gut microbiota and metabolites, we utilized 16s rDNA sequencing and GC-MS to analyze gut composition and short-chain fatty acids in APP/PS1 mice after one month of P.distasonis gavage. To investigate the effects of P.distasonis administration over a six-month period on APP/PS1 mice, we evaluated cognitive function using novel object recognition and Y-maze tests, assessed intestinal barrier integrity and AD-related pathological features with immunofluorescence, and analyzed immune cell subpopulations in intestine, blood, spleen, and brain tissues via flow cytometry. The Luminex assay was employed to detect inflammatory cytokine secretion in the same regions. Results: One-month oral administration of P.distasonis modulated the gut microbiota, elevated butyrate levels. Six-month oral administration of P.distasonis improved cognitive function in APP/PS1 mice, reducing Aβ deposition and inhibiting glial cell proliferation. It also amplified Treg cells within the gut, concomitant with the decreased Th1 proliferation and intestinal inflammation. Additionally, we observed the migration of peripheral CD4+ T cells to the brain through chemotaxis, accompanied by an increase in Treg cells and higher levels of anti-inflammatory factors such as IL-10 and TGF-β in the brain. Collectively, these multifaceted effects contributed to the alleviation of neuroinflammation. Conclusion: These findings underscore the potential of transplanting P.distasonis in alleviating AD-related pathology, suggesting a role for gut microbiota in neuroinflammation attenuation.