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


CONCLUSIONS
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.
Farhadi
Ashkan
A
Department of Medicine, Division of Digestive Diseases and Nutrition, Rush University, Chicago, IL 60612, USA. ashkan_farhadi@rush.edu
Gundlapalli
Sushama
S
Shaikh
Maliha
M
Frantzides
Constantine
C
Harrell
Laura
L
Kwasny
Mary M
MM
Keshavarzian
Ali
A
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001241:Aspirin; D019446:Endotoxemia / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D005234:Fatty Liver / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000503:physiopathology*; D007792:Lactulose / Q000652:urine; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008353:Mannitol / Q000652:urine; D008875:Middle Aged; D018384:Oxidative Stress; D010539:Permeability / Q000187:drug effects; D013395:Sucrose / Q000031:analogs & derivatives / Q000652:urine
D000894:Anti-Inflammatory Agents, Non-Steroidal; D008353:Mannitol; D007792:Lactulose; D013395:Sucrose; C026285:trichlorosucrose; D001241:Aspirin