Molecular docking-guided caffeic acid phenethyl ester/hydroxypropyl-β-cyclodextrin host-guest complexes: Alleviating of colonic inflammation and insights into their synergistic mechanism

Caffeic acid phenethyl ester (CAPE), a prominent polyphenolic compound in propolis, faces limited nutritional application due to its hydrophobicity and low bioavailability. By molecular docking, CAPE/hydroxypropyl-β-cyclodextrin (HP-β-CD) host-guest complexes exhibiting the lowest binding energy were identified and synthesized using saturated aqueous solution-freeze-drying methods, achieving an inclusion efficiency of 96.13% and enhanced storage stability. In vivo studies demonstrated that CAPE/HP-β-CD complexes effectively alleviated colonic inflammation by suppressing NF-κB pathway, restoring mucosal integrity and levels of short-chain fatty acids (SCFAs). Imaging flow cytometry revealed that HP-β-CD enhances cellular uptake of CAPE through an endocytosis-mediated mechanism, surpassing passive diffusion, thereby increasing intracellular CAPE accumulation in Caco-2 cells from 4.63 mg/g to 44.54 mg/g. Bioinformatic analyses further indicated that these complexes exhibited superior efficacy compared to CAPE in ameliorating gut microbial dysbiosis and promoting the proliferation of several bacterial genera within the Lachnospiraceae family, which contribute to maintaining intestinal homeostasis and producing SCFAs. Additionally, the majority of microbiota exhibited negative correlations with key inflammatory markers, including the beneficial genus Bifidobacterium , which is associated with butyric acid production. This study highlights the utility of molecular docking in the rational high-throughput screening of cyclodextrin-based carriers and elucidates the multifaceted mechanisms by which CAPE/HP-β-CD complexation enhances the efficacy of nutritional interventions against colonic inflammation. • Molecular docking enables efficient screening of CD-based host-guest complexes with excellent loading and storage capabilities. • HP-β-CD boosts cellular uptake via endocytosis, enhancing CAPE absorption. • CAPE/HP-β-CD complexes demonstrate superior efficacy over free CAPE in alleviating gut microbial dysbiosis. • The complexes enhance Lachnospiraceae genus proliferation, supporting intestinal homeostasis and SCFA production.