Susceptibility to gut leakiness: A possible mechanism for endotoxaemia in non-alcoholic steatohepatitis

Ashkan Farhadi, Sushama Gundlapalli, Maliha Shaikh, Constantine Frantzides, Laura Harrell, Mary M. Kwasny, Ali Keshavarzian

Research output: Contribution to journalArticlepeer-review

148 Scopus citations


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 0-5h L/M ratio (small bowel permeability) and 0-24h 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.

Original languageEnglish (US)
Pages (from-to)1026-1033
Number of pages8
JournalLiver International
Issue number7
StatePublished - Aug 2008


  • Aspirin-induced gut leakiness
  • Endotoxin
  • Gut leakiness
  • Leaky gut
  • NASH
  • Non-alcoholic steatohepatitis
  • Steatohepatitis
  • Steatosis
  • Susceptibility to gut leakiness

ASJC Scopus subject areas

  • Hepatology


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