Farhadi Ashkan, Gundlapalli Sushama, Shaikh Maliha, Frantzides Constantine, Harrell Laura, Kwasny Mary M, Keshavarzian Ali
Department of Medicine, Division of Digestive Diseases and Nutrition, Rush University, Chicago, IL 60612, USA.
Liver Int. 2008 Aug;28(7):1026-33. doi: 10.1111/j.1478-3231.2008.01723.x. Epub 2008 Apr 7.
One of the proposed second hit mechanisms in the pathophysiology of non-alcoholic steatohepatitis (NASH) is hepatic oxidative stress triggered by elevated levels of endotoxin. We investigated one possible mechanism for the endotoxaemia--disruption of intestinal barrier integrity.
We enrolled 16 subjects with fatty liver (10 NASH; 6 steatosis) and 12 healthy subjects. Steatosis and NASH were diagnosed by liver biopsy using the Brunt criteria. Gastrointestinal permeability was measured using urinary excretion of 5-h lactulose/mannitol (L/M) ratio and 24-h sucralose. Permeability testing was repeated after aspirin challenge.
Groups had similar baseline urinary 0-5 h L/M ratio (small bowel permeability) and 0-24 h sucralose (whole-gut permeability). Aspirin increased 0-5 h urinary L/M in most subjects. In contrast, aspirin significantly increased whole-gut permeability only in NASH subjects. In fact, the major increase in the urinary sucralose occurred in the 6-24 h samples, which points towards the colon as the major site responsible for aspirin-induced leakiness in NASH patients. Serum endotoxin levels were significantly higher in NASH subjects.
Our findings suggest that aspirin acts on the colon to unmask a susceptibility to gut leakiness in patients with NASH. This effect may be the underlying mechanism for increased serum endotoxin, which is the second hit (after altered lipid metabolism) that is required to initiate a necroinflammatory cascade in hepatocytes which are already primed with obesity-induced abnormal lipid homoeostasis.
非酒精性脂肪性肝炎（NASH）病理生理学中提出的二次打击机制之一是内毒素水平升高引发的肝脏氧化应激。我们研究了内毒素血症的一种可能机制——肠道屏障完整性的破坏。
我们招募了16名脂肪肝患者（10名NASH患者；6名脂肪变性患者）和12名健康受试者。使用布伦特标准通过肝活检诊断脂肪变性和NASH。通过5小时乳果糖/甘露醇（L/M）比值的尿排泄量和24小时三氯蔗糖测量胃肠道通透性。阿司匹林激发后重复进行通透性测试。
各组的基线0-5小时尿L/M比值（小肠通透性）和0-24小时三氯蔗糖（全肠道通透性）相似。大多数受试者中，阿司匹林增加了0-5小时尿L/M。相比之下，阿司匹林仅在NASH受试者中显著增加了全肠道通透性。事实上，尿三氯蔗糖的主要增加发生在6-24小时的样本中，这表明结肠是NASH患者中阿司匹林诱导渗漏的主要部位。NASH受试者的血清内毒素水平显著更高。
我们的研究结果表明，阿司匹林作用于结肠，揭示了NASH患者对肠道渗漏的易感性。这种效应可能是血清内毒素增加的潜在机制，血清内毒素是引发肝细胞坏死性炎症级联反应所需的二次打击（在脂质代谢改变之后），而这些肝细胞已经因肥胖诱导的异常脂质稳态而处于致敏状态。
