Unveiling functional heterogeneity in pasteurized Akkermansia muciniphila identifies AKK2645 as a superior postbiotic for metabolic syndrome.

Metabolic syndrome (MetS) represents an escalating global health burden, underscoring an urgent need for innovative microbiome-targeted therapeutics. This investigation involved a systematic functional evaluation of 42 pasteurized Akkermansia muciniphila strains, providing the first direct evidence of significant differences among strains in their ability to alleviate MetS. Through systematic screening using cell and mouse models, we identified strain Akkermansia muciniphila YGMCC2645 (AKK2645) emerged as the lead candidate. Furthermore, it demonstrated superior and reproducible efficacy in attenuating diet-induced obesity, restoring glucose homeostasis, and ameliorating hepatic steatosis. AKK2645 uniquely modulated host immunity, decreasing pro-inflammatory cytokines (IL-6, IL-1β) and increasing anti-inflammatory markers (Il4, Il10, and Foxp3) in both adipose and hepatic tissues. It also favorably altered gut microbiota (increasing Akkermansia, Lactobacillus,and Bifidobacterium) and activated intestinal GLP-1 signaling. Collectively, these findings establish strain-specific functional heterogeneity as a fundamental principle governing postbiotic efficacy and identify AKK2645 as a high-potency, precision postbiotic for MetS intervention.