Ávila-Gálvez María Ángeles, Romo-Vaquero María, Mazarío-Gárgoles Carmen, Tomé-Carneiro Joao, López de Las Hazas María-Carmen, Dávalos Alberto, Selma María Victoria, González-Sarrías Antonio, Espín Juan Carlos
Laboratory of Food & Health; Research Group on Quality, Safety, and Bioactivity of Plant Foods, CEBAS-CSIC, Campus de Espinardo, Murcia, Spain.
Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies (IMDEA)-Food, CEI UAM + CSIC, Madrid, Spain.
Mol Nutr Food Res. 2025 Aug;69(15):e70104. doi: 10.1002/mnfr.70104. Epub 2025 May 12.
Milk exosomes (EXOs) enhance polyphenols' bioavailability, but their potential for oral administration remains underexplored. Ellagic acid (EA) is poorly bioavailable. We investigate whether EA encapsulated in EXOs (EXO-EA) consumed orally improves EA bioavailability and (or) modulates gut microbiota. For 2 weeks, BALB/c mice received EXO, non-encapsulated EA (NEA), or EXO-EA (0.27 mg EA/kg bw) orally. Targeted and untargeted metabolomics (UPLC-qTOF-MS), fecal SCFAs (GC-MS), and gut microbiota (PacBio 16S-sequencing) were performed. Additionally, EA plasma and brain kinetics were evaluated in rats following intravenous administration of EXO-EA and NEA. Unlike NEA, EXO-EA quadrupled EA plasma levels in Sprague-Dawley rats and enabled brain detection. However, oral EXO-EA in mice failed to deliver EA systemically due to gastrointestinal instability, confirmed by in vitro digestion. Sex-dependent EXO-EA metabolomic effects were observed. Also, in males only, EXO-EA increased fecal urolithin A and SCFAs and enriched the microbiota with Christensenellaceae R7, Ruminococcus species, and Clostridium fusiformis, among others. In females, both EXO-EA and NEA enriched the microbiota with bifidobacteria, including Bifidobacterium pseudolongum. Oral EXO-EA impacted plasma metabolome, modulated gut microbiota, and increased urolithin A and SCFA production sex-dependently. However, gastrointestinal instability, limited EA encapsulation, and low dose administered prevented systemic delivery.
牛奶外泌体（EXOs）可提高多酚的生物利用度，但其口服潜力仍未得到充分探索。鞣花酸（EA）的生物利用度较差。我们研究口服包裹在EXOs中的EA（EXO-EA）是否能提高EA的生物利用度和（或）调节肠道微生物群。连续2周，BALB/c小鼠口服EXO、未包裹的EA（NEA）或EXO-EA（0.27毫克EA/千克体重）。进行了靶向和非靶向代谢组学（超高效液相色谱-四极杆飞行时间质谱）、粪便短链脂肪酸（气相色谱-质谱）和肠道微生物群（PacBio 16S测序）分析。此外，在大鼠静脉注射EXO-EA和NEA后，评估了EA在血浆和大脑中的动力学。与NEA不同，EXO-EA使Sprague-Dawley大鼠的EA血浆水平提高了四倍，并能够在大脑中检测到。然而，体外消化证实，由于胃肠道不稳定，小鼠口服EXO-EA未能实现EA的全身递送。观察到EXO-EA存在性别依赖性的代谢组学效应。此外，仅在雄性小鼠中，EXO-EA增加了粪便中尿石素A和短链脂肪酸的含量，并使微生物群中富集了克里斯滕森菌科R7、瘤胃球菌属和梭形梭菌等。在雌性小鼠中，EXO-EA和NEA均使双歧杆菌属，包括假长双歧杆菌在微生物群中富集。口服EXO-EA会影响血浆代谢组，调节肠道微生物群，并性别依赖性地增加尿石素A和短链脂肪酸的产生。然而，胃肠道不稳定、EA包裹有限和给药剂量低阻碍了全身递送。
