期刊
LIVER INTERNATIONAL
卷 28, 期 7, 页码 1026-1033出版社
WILEY-BLACKWELL
DOI: 10.1111/j.1478-3231.2008.01723.x
关键词
aspirin-induced gut leakiness; endotoxin; gut leakiness; leaky gut; NASH; non-alcoholic steatohepatitis; steatohepatitis; steatosis; susceptibility to gut leakiness
资金
- NCCIH NIH HHS [R01 AT007143] Funding Source: Medline
- NIAAA NIH HHS [RC2 AA019405, R01 AA013745] Funding Source: Medline
Introduction: 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. Methods: 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. Results: 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. Discussion: 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.
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