Pasteurized Akkermansia muciniphila ameliorates preeclampsia via inhibiting mitochondrial dysfunction-mediated placental apoptosis in vivo and in vitro

Preeclampsia (PE) is a severe metabolic disorder that occurs during pregnancy and is linked to dysbiosis of the gut microbiota, characterised by a decrease in Akkermansia muciniphila (AKK). Emerging evidence suggests that pasteurized Akkermansia muciniphila (pAKK) is a promising candidate for preventing or treating obesity-related metabolic disorders. However, the modulatory function and the underlying mechanisms of pAKK supplementation in PE remain to be fully elucidated. In this study, we examined the impact of pAKK oral administration on PE and its underlying mechanisms. Our findings demonstrate that pAKK significantly improved PE-like symptoms in mice induced by nitro-L-arginine methylester (L-NAME) in a dose-dependent manner. Of note, pAKK inhibited L-NAME-induced placental apoptosis, countered apoptosis-related biochemical alterations like the increase in the Bax/Bcl-2 ratio, and the activation of cleaved-Caspase-3, alongside mitigating L-NAME-induced placental mitochondrial dysfunction. Hypoxia-reoxygenation (H/R)-induced HTR8/SVneo cells have been established as an in vitro model to mimic the condition of PE. Interestingly, similar results were also obtained in vitro; mitochondrial dysfunction-mediated apoptosis induced by H/R in HTR-8/SVneo cells was prevented by pAKK. Importantly, the PI3K inhibitor (LY-294002) significantly negated the protective effects of pAKK on mitochondrial dysfunction and apoptosis. Furthermore, we observed that pAKK treatment improved the composition of gut microbiota communities in PE mice. Our findings indicate that pAKK improved PE-like symptoms both in vivo and in vitro by activating the PI3K/Akt signalling pathway, highlighting the potential for developing a probiotic therapeutic agent based on AKK for PE.