Akkermansia muciniphila reduces neuroinflammation and Aβ deposition via tryptophan metabolism in the APP/PS1 mouse model of Alzheimer’s disease

Akkermansia muciniphila (A. muciniphila), a beneficial gut bacterium, has increasingly attracted interests in Alzheimer's disease (AD) research, its specific role in the microbiota-gut-brain axis still remains unclear. In this study, we demonstrated that A. muciniphila administration improve cognitive deficits and reduce amyloid-beta (Aβ) deposition in APP/PS1 mice, a transgenic model of AD. Subsequently, it is revealed that A. muciniphila administration significantly alters gut microbiota diversity and composition. Mechanically, our metabolomics analysis of cecal contents indicates A. muciniphila administration increases short-chain fatty acids (SCFAs) derived from the intestinal microbiota, including butyric acid and acetic acid. Significantly, in APP/PS1 mice with the A. muciniphila administration, targeted metabolomics identify that the production of 62 metabolites are increased such as indole-3-acetic acid (IAA), tryptophan, acetic acid and cinnamic acid, as well as aconitic acid and threonine, et al.; the production of 28 metabolites are decreased such as isoleucine and N-acetylneuraminic acid (NANA) as well as ornithine and docosapentaenoic acid (DPA), et al. It is also identified by cytokine analysis of plasma that A. muciniphila administration reduces peripheral pro-inflammatory cytokines interleukin-6 (IL-6), IL-1β, IL-17 and tumor necrosis factor-alpha (TNF-α), et al., whereas it increases anti-inflammatory cytokines, such as IL-4, IL-10 and IL-22, et al. There is no any change of other cytokines, such as interferon-gamma (IFN-g), IL-2 and granulocyte-macrophage colony-stimulating factor (GM-CSF), et al. Interestingly, a significant positive correlation is observed between the increased IAA, tryptophan as well as acetic acid and cognitive function indicators. At the same time, A. muciniphila administration improves cognitive deficits, alleviates neuroinflammation and Aβ deposition via AhR/NF-κB/NLRP3 signaling pathway in APP/PS1 mice. In summary, our findings suggest A. muciniphila is a promising approach for preventing AD progression by microbiota-gut-brain axis.