Honokiol attenuates diabetes by enriching Akkermansia muciniphila andregulating tryptophan metabolism in mice.

Honokiol improved glucose tolerance and lipid metabolism in a gut microbiota-dependent manner.

• Intervention duration was 8 weeks.
• Gut microbiota dependence was demonstrated through fecal microbiota transplantation (FMT) and antibiotic treatment experiments.
• Antibiotic treatment abolished or reduced HON's beneficial effects, confirming microbiota dependency.
• FMT from HON-treated mice transferred metabolic improvements to recipient mice.

Honokiol administration significantly increased the abundance of Akkermansia muciniphila (AKK) in diabetic mice.

• AKK abundance was measured using 16S rRNA gene sequencing.
• The increase in AKK was identified as a key mediator of HON's antidiabetic effects.
• AKK enrichment was associated with modulation of tryptophan metabolism.

Honokiol modulated tryptophan metabolism, as evidenced by untargeted and targeted metabolomics analysis.

• Both untargeted and targeted metabolomics analyses were used to characterize changes in tryptophan metabolites.
• HON treatment altered the profile of tryptophan-derived metabolites in DM mice.
• Tryptamine (TA) was identified as a key tryptophan metabolite relevant to HON's mechanism of action.

Akkermansia muciniphila metabolized tryptophan into tryptamine and other metabolites in vitro.

• In vitro experiments demonstrated that AKK can directly convert tryptophan to tryptamine.
• This finding establishes AKK as a microbial producer of tryptamine in the context of HON treatment.
• Other unspecified tryptophan metabolites were also produced by AKK in vitro.

Both Akkermansia muciniphila and tryptamine activated the aryl hydrocarbon receptor (AHR) pathway and increased circulating GLP-1 levels.

• AKK and TA activated the AHR pathway in DM mice.
• AHR pathway activation led to increased circulating glucagon-like peptide-1 (GLP-1) levels.
• Both AKK supplementation and TA treatment ameliorated diabetes-related symptoms in DM mice.
• The AHR-GLP-1 axis was identified as the downstream mechanism linking gut microbiota changes to antidiabetic effects.

Honokiol has low oral bioavailability yet demonstrates antidiabetic potential through gut microbiota-mediated mechanisms.

• HON is derived from Magnolia officinalis bark.
• Low oral bioavailability of HON suggests its effects may be mediated indirectly through the gut microbiome rather than systemic absorption.
• The gut microbiota-dependent mechanism may explain HON's efficacy despite limited systemic exposure.