title: Susceptibility to gut leakiness: a possible mechanism for endotoxaemia in non-alcoholic steatohepatitis.
abstract: 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.
authors.affiliation: Department of Medicine, Division of Digestive Diseases and Nutrition, Rush University, Chicago, IL 60612, USA. ashkan_farhadi@rush.edu
authors.forename: Ashkan
authors.initials: A
authors.lastname: Farhadi
authors.forename: Sushama
authors.initials: S
authors.lastname: Gundlapalli
authors.forename: Maliha
authors.initials: M
authors.lastname: Shaikh
authors.forename: Constantine
authors.initials: C
authors.lastname: Frantzides
authors.forename: Laura
authors.initials: L
authors.lastname: Harrell
authors.forename: Mary M
authors.initials: MM
authors.lastname: Kwasny
authors.forename: Ali
authors.initials: A
authors.lastname: Keshavarzian
mesh_terms: 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
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D008353:Mannitol; D007792:Lactulose; D013395:Sucrose; C026285:trichlorosucrose; D001241:Aspirin