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

Abstract

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.

Fig. 1

Histological characteristic of representative samples of steatosis (a) and non-alcoholic steatohepatitis (NASH) (b). There is clear cytoplasmic fat accumulation in the liver cells in both conditions. However, lobular lymphocytic aggregates (arrows) are only seen in NASH subjects.

Fig. 2

Aspirin increased the 5-h urinary lactulose mannitol (L/M) ratio in most subjects (a). However, aspirin-induced increase in the L/M ratio was only statistically significant in healthy controls (*P = 0.03). (b) represents a magnified portion of (a) that shows healthy control subjects. NASH, non-alcoholic steatohepatitis; NL, healthy control.

Fig. 3

Aspirin challenge significantly increased the whole-gut permeability (24 h urinary sucralose excretion) only in the subjects with NASH (*, P < 0.05). NASH, non-alcoholic steatohepatitis; NL, healthy control.

Fig. 4

6–24 h urinary sucralose excretion as a marker of distal gut (colon) permeability was significantly increased by aspirin challenge only in patients with NASH (*, P < 0.05). NASH, non-alcoholic steatohepatitis; NL, healthy control.

Fig. 5

The plasma endotoxin level was significantly higher in subjects with NASH compared with healthy controls. (*, P < 0.05) NASH, non-alcoholic steatohepatitis; NL, healthy control.