Mulberry Leaf Extract Attenuates High‐Fat Diet‐Induced Obesity Through Modulation of Gut Microbiota, Intestinal Mechanical Barrier, and Inflammation

Intestinal barrier dysfunction is a key driver of obesity pathogenesis. This study aimed to elucidate the anti-obesity mechanism of mulberry leaf extract (MLE) by investigating its effects on the intestinal barrier, including the mechanical, immune, and microbial barriers. A high-fat diet (HFD)-induced obese mouse model was employed and treated with MLE. We systematically assessed obesity phenotypes, glucolipid metabolic parameters, systemic and intestinal inflammation, intestinal tight junction proteins and mucus secretion, and gut microbiota composition. The results showed that MLE significantly reduced body weight by over 5%, and ameliorated dyslipidemia, hepatic steatosis, and glucose intolerance. Concurrently, MLE activated PPARα/CPT-1 fatty acid β-oxidation and PI3K/AKT signaling while suppressing SREBP-1c lipogenesis. Mechanistically, MLE enhanced intestinal mechanical barriers, as evidenced by the upregulation of tight junction proteins, increased mucus secretion, and reduced serum levels of intestinal permeability markers (diamine oxidase and endotoxin). Furthermore, MLE suppressed systemic and intestinal inflammation (TNF-α, IL-1β, and IL-6). Furthermore, MLE improved gut microbiota dysbiosis, reducing the Firmicutes/Bacteroidota ratio by 61.39%, enriching beneficial Alloprevotella and Muribaculaceae_norank, and depleting Faecalibaculum and Lachnoclostridium. Correlation analysis revealed significant associations between MLE-modulated microbiota and improved metabolic and barrier parameters. Collectively, MLE alleviated obesity by synergistically modulating glucolipid metabolism, gut microbiota, intestinal mechanical barrier and inflammation.