Propolis Modulates the Gut Microbiota–Gut Hormone–Liver AMPK Axis to Ameliorate High-Fat Diet-Induced Metabolic Disorders in Rats

<b>Objectives</b>: Emerging evidence suggests that propolis possesses significant anti-obesity properties. While gut hormones and microbiota are known to play crucial roles in obesity development, the specific mechanisms through which propolis exerts its effects via the gut hormone axis remain poorly characterized. <b>Methods</b>: A high-fat diet (HFD) rat model was established to investigate the regulatory effects of propolis. After 10 weeks of intervention, blood serum, liver, colon tissues, and luminal contents were analyzed for metabolic parameters, gene expression of gut hormones and AMPK pathway markers, microbial community structure, and short-chain fatty acid production. <b>Results</b>: Propolis effectively mitigated HFD-induced metabolic disturbances, including excessive weight gain, adipose tissue accumulation, hyperlipidemia, and hepatic dysfunction. These improvements were associated with significant upregulation of the AMPK pathway. Importantly, propolis enhanced intestinal barrier integrity and differentially modulated gut hormone expression by increasing the mRNA levels of <i>Cck</i>, <i>Gip</i>, and <i>Ghrl</i>, and decreasing <i>Lep</i> and <i>Gcg</i> levels. 16S rRNA sequencing analysis revealed that propolis administration selectively enriched butyrate- and propionate-producing bacterial species. Correlation analysis further identified the <i>Eubacterium brachy</i> group as a pivotal microbial mediator in the propolis-modulated gut microbiota-gut hormone-liver AMPK axis. <b>Conclusions</b>: Our findings establish that propolis ameliorates obesity-related metabolic disorders by orchestrating crosstalk among gut microbiota, enteroendocrine hormones, and hepatic AMPK signaling. These results elucidate a novel mechanistic pathway in rodents; however, their direct translatability to humans requires further clinical investigation. This tripartite axis offers a mechanistic foundation for developing microbiota-targeted anti-obesity therapies.