Akkermansia muciniphila alleviates diabetic cognitive impairment by inhibiting NLRP3 inflammasome activation and ameliorating hippocampal synaptic defects

Abstract

Emerging evidence suggests that nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation contributes to diabetic cognitive impairment (DCI), making its inhibition a potential therapeutic strategy for DCI. Akkermansia muciniphila (A. muciniphila) has shown benefits in metabolic diseases, neurodegenerative disorders, and neuroinflammation. However, its effect on NLRP3 inflammasome activation in the hippocampus of DCI mice remains unclear. This study aims to explore the effects and underlying mechanisms of A. muciniphila treatment in DCI mice. Herein, we demonstrated that the relative abundance of A. muciniphila was significantly decreased in patients with type 2 diabetes mellitus with normal cognition and in DCI patients compared to healthy participants. Oral administration of either live or pasteurized A. muciniphila significantly ameliorated the symptoms of cognitive impairment induced by a high-fat diet, as evidenced by reduced impairments in learning and memory, decreased neuronal loss, ameliorated impairments in synaptic plasticity, and increased expression of postsynaptic density protein-95 and synaptophysin proteins. Furthermore, A. muciniphila alleviated gut microbiota dysbiosis and neuroinflammation in DCI mice and simultaneously inhibited the activation of the NLRP3 inflammasome. However, the beneficial effects were abolished when A. muciniphila intervention was applied to NLRP3 knockout mice. These results emphasize the potent efficacy of A. muciniphila in alleviating DCI by inhibiting the activation of the NLRP3 inflammasome and ameliorating hippocampal synaptic defects. This study provides insights into the underlying mechanisms and presents a novel avenue for probiotic-based treatment of DCI.