Honokiol attenuates diabetes by enriching Akkermansia muciniphila and regulating tryptophan metabolism in mice

Diabetes mellitus (DM) is a chronic disease influenced by gut microbiome disturbances. Honokiol (HON), a low oral bioavailability compound from Magnolia officinalis bark, has been proposed as a treatment for DM. This work aims to elucidate the impacts of HON on gut microbiota and host metabolism, thereby further clarifying the overall mechanism of HON on DM. HON could improve glucose tolerance and lipids metabolism in a gut microbiota-dependent manner after intervention for 8 weeks by fecal microbiota transplantation or antibiotic treatment. Specifically, HON treatment led to a remarkable increase in Akkermansia muciniphila (AKK) abundance and exerted regulatory effects on tryptophan metabolism based on 16S rRNA gene sequencing and untargeted/targeted metabolomics analysis. Interestingly, we discovered that AKK could metabolize tryptophan into tryptamine (TA) and other metabolites in vitro. Both AKK and TA were found to activate the aryl hydrocarbon receptor (AHR) pathway, resulting in elevated circulating GLP-1 levels and thus alleviating diabetes-related symptoms in DM mice. Our findings demonstrated that the hypoglycemic effect of HON is primarily attributed to the activation of AHR-GLP-1 pathways through targeting modulation of AKK and microbial tryptophan metabolites TA, which may enhance the clinical applicability of HON.