Is NASH Triggered by a Leaky Gut?

Abstract

Purpose: The pathophysiology of non-alcoholic steatohepatitis(NASH) has not been clearly delineated, but there appears to be a “two hit” mechanism. Based on animal studies, one of the proposed second hit mechanisms is oxidative stress triggered by endotoxin. Increased intestinal permeability has been shown to be a source of endotoxemia and oxidative stress in alcoholics. We aim to determine whether patients with NASH have intestinal hyperpermeability and whether leaky gut can differentiate simple steatosis from NASH in obese patients. Methods: Patients were recruited from the Bariatric surgery center or Nutrition clinic at Rush. Steatosis and NASH were diagnosed by liver biopsy using Brunt criteria. Intestinal permeability was measured using urinary excretion of poorly absorbed sugars (lactulose, sucrose, mannitol and sucralose). To determine whether patients had increased susceptibility to leakiness, the permeability test was repeated after aspirin challenge (1300mg ASA). Urinary sugars were measured by gas chromatography. Small bowel permeability was defined by the Lactulose/Mannitol (L/M) ratio and whole gut permeability was defined by sucralose excretion. Median values for sugar excretion were compared between all groups using Kruskal-Wallis and between each group using Mann-Whitney tests. Results: There was no statistically significant difference between patients with steatosis (n = 6) and NASH (n = 10) in regards to demographics, BMI, AST, AP, bilirubin, or cholesterol. ALT levels were significantly higher in patients with NASH (98) vs. steatosis (55). (p = 0.021). Small bowel permeability (median L/M ratio) was similar between groups pre and post aspirin. Whole gut permeability (sucralose excretion) was similar between groups at baseline, control 0.0245, steatosis 0.0323 and NASH 0.0328. (p = 0.873). However, patients with NASH had a significant increase in whole gut permeability with aspirin challenge, 0.0613, compared to both controls, 0.0283 (p = 0.006) and steatosis 0.0405 (p = 0.023). In contrast, patients with steatosis had no increased susceptibility to leakiness with aspirin compared to controls. Conclusions: Our data indicate that patients with NASH are susceptible to colonic leakiness as they have an exaggerated response to aspirin challenge. This susceptibility should result in increased endotoxemia and oxidative stress in these patients. Therefore, avoidance of factors that may deleteriously affect intestinal permeability, such as NSAIDs, is strongly suggested in those at risk for NASH.