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

Authors

  • Ashkan Farhadi,

    1. Department of Medicine, Division of Digestive Diseases and Nutrition, Rush University, Chicago, IL, USA
    2. Department of Molecular Biophysics and Physiology, Rush University, Chicago, IL, USA
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  • Sushama Gundlapalli,

    1. Department of Medicine, Division of Digestive Diseases and Nutrition, Rush University, Chicago, IL, USA
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  • Maliha Shaikh,

    1. Department of Medicine, Division of Digestive Diseases and Nutrition, Rush University, Chicago, IL, USA
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  • Constantine Frantzides,

    1. Department of Surgery, Rush University, Chicago, IL, USA
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    • *Present address:
      Prof. Constantine Frantzides, Northwestern University, Evanston Hospital, Evanston, IL, USA.

  • Laura Harrell,

    1. Department of Gastroenterology, University of Chicago, Chicago, IL, USA
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  • Mary M. Kwasny,

    1. Department of Community and Mental Health Nursing, Rush University, Chicago, IL, USA
    2. Department of Health Systems Management, Rush University, Chicago, IL, USA
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  • Ali Keshavarzian

    1. Department of Medicine, Division of Digestive Diseases and Nutrition, Rush University, Chicago, IL, USA
    2. Department of Molecular Biophysics and Physiology, Rush University, Chicago, IL, USA
    3. Department of Pharmacology, Rush University, Chicago, IL, USA
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Correspondence
Ashkan Farhadi, MD, MS, FACG Section of Gastroenterology and Nutrition, Rush University Medical Center, 1725 W. Harrison, Suite 206, Chicago, IL 60612, USA
Tel: +312 563 3890
Fax: +312 563 3883
e-mail: ashkan_farhadi@rush.edu

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.

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