Akkermansia muciniphila: A potential novel mechanism of nuciferine to improve hyperlipidemia.

Abstract Background Intestinal microbiota is a novel drug target of metabolic diseases, especially for those with poor oral bioavailability. Nuciferine, with poor bioavailability, has an anti-hyperlipidemic effect at low dosages. Purpose In the present study, we aimed to explore the role of intestinal microbiota in the anti-hyperlipidemic function of nuciferine and identify the key bacterial targets that might confer the therapeutic actions. Methods The contribution of gut microbes in the anti-hyperlipidemic effect of nuciferine was evaluated by conventional and antibiotic-established pseudo-sterile mice. Whole-metagenome shotgun sequencing was used to characterize the changes in microbial communities by various agents. Results Nuciferine exhibited potent anti-hyperlipidemic and liver steatosis-alleviating effects at the doses of 7.5-30 mg/kg. The beneficial effects of nuciferine were substantially abolished when combined with antibiotics. Metagenomic analysis showed that nuciferine significantly shifted the microbial structure, and the enrichment of Akkermansia muciniphila was closely related to the therapeutic effect of nuciferine. Conclusions Our results revealed that gut microbiota played an essential role in the anti-hyperlipidemic effect of nuciferine, and enrichment of Akkermansia muciniphila represented a key mechanism through which nuciferine exerted its therapeutic effects.