Alam Naqash, Ding Xinhua, Fu Yu, Jia Linying, Ali Sadiq, Liu Enqi
Laboratory of Animal Center, School of Basic Medical Sciences, Health Science Center, Xi'an Jiaotong University, Xi'an, People's Republic of China.
Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Health Science Center, Xi'an Jiaotong University, Xi'an, People's Republic of China.
Am J Physiol Gastrointest Liver Physiol. 2025 May 1;328(5):G578-G593. doi: 10.1152/ajpgi.00190.2024. Epub 2025 Apr 17.
Metabolic dysfunction-associated steatohepatitis (MASH) has emerged as a major global health concern that affects about a quarter of the global population. Recently, host-gut microbiota metabolic interactions have emerged as key mechanistic pathways in MASH development. Oryzanol (ORY), a rice bran bioactive compound, exhibits antioxidant, anti-inflammatory, hypolipidemic, and hypoglycemic properties. Here, we investigated the potential of ORY in alleviating MASH and its association with gut microbiota and MASH progression. Male C57BL/6J mice were fed normal chow diet or methionine-choline-deficient diet and received ORY supplementation at 300 mg/kg/day via gavage for 4 wk. Liver injury, inflammation, lipid accumulation, and TLR4/NF-κB signaling protein levels were assessed. In addition, changes in gut microbiota diversity and abundance across groups were evaluated using 16S rDNA sequencing. Our results demonstrated that ORY significantly reduced lipid accumulation and liver enzymes, ameliorated liver and ileum damage, and restored intestinal barrier function in MASH mice. Furthermore, ORY decreased plasma lipopolysaccharide levels, and inflammatory cytokines and downregulated TLR4, MyD88, and NF-κB protein levels in the liver. ORY enhanced tight junction protein level (ZO-1, occludin) in the gut. Microbial analysis revealed that ORY positively impacted Firmicutes and Bacteroidetes abundance, promoted beneficial bacteria like and , and inhibited harmful bacteria such as , , and . Notably, ORY increased abundance, potentially modulating metabolic and inflammatory pathways. ORY exerted restorative and reversible effects on the pathophysiological damage within the gut-liver axis in MASH mice. The therapeutic mechanism may be related to the modulation of the gut microbiota and TLR4/NF-κB signaling pathway. This study demonstrates that oryzanol (ORY), a bioactive rice bran compound, alleviates metabolic dysfunction-associated steatohepatitis (MASH) in mice by reducing lipid accumulation and inflammation. ORY beneficial effects are associated to the modulation of gut microbiota, enhancing gut barrier integrity, and lowering endotoxemia and TLR4/NF-κB signaling pathway. These findings suggest ORY potential in MASH prevention and treatment, highlighting its influence on gut-liver axis dynamics.
代谢功能障碍相关脂肪性肝炎（MASH）已成为一个主要的全球健康问题，影响着约四分之一的全球人口。最近，宿主-肠道微生物群代谢相互作用已成为MASH发展中的关键机制途径。谷维素（ORY）是一种米糠生物活性化合物，具有抗氧化、抗炎、降血脂和降血糖特性。在此，我们研究了ORY在减轻MASH方面的潜力及其与肠道微生物群和MASH进展的关联。雄性C57BL/6J小鼠喂食正常饲料或蛋氨酸-胆碱缺乏饲料，并通过灌胃以300 mg/kg/天的剂量补充ORY，持续4周。评估肝脏损伤、炎症、脂质积累和TLR4/NF-κB信号蛋白水平。此外，使用16S rDNA测序评估各组肠道微生物群多样性和丰度的变化。我们的结果表明，ORY显著减少了脂质积累和肝酶，改善了肝脏和回肠损伤，并恢复了MASH小鼠的肠道屏障功能。此外，ORY降低了血浆脂多糖水平、炎性细胞因子，并下调了肝脏中TLR4、MyD88和NF-κB蛋白水平。ORY提高了肠道紧密连接蛋白水平（ZO-1、闭合蛋白）。微生物分析显示，ORY对厚壁菌门和拟杆菌门的丰度产生了积极影响，促进了如 和 等有益细菌的生长，并抑制了如 、 和 等有害细菌。值得注意的是，ORY增加了 的丰度，可能调节代谢和炎症途径。ORY对MASH小鼠肠-肝轴内的病理生理损伤具有恢复性和可逆性作用。其治疗机制可能与肠道微生物群和TLR4/NF-κB信号通路的调节有关。本研究表明，生物活性米糠化合物谷维素（ORY）通过减少脂质积累和炎症来减轻小鼠的代谢功能障碍相关脂肪性肝炎（MASH）。ORY的有益作用与调节肠道微生物群、增强肠道屏障完整性以及降低内毒素血症和TLR4/NF-κB信号通路有关。这些发现表明ORY在MASH预防和治疗方面的潜力，突出了其对肠-肝轴动态的影响。
