Elevated endotoxin levels in non-alcoholic fatty liver disease

Alison L Harte,Christopher P Day,Nancy F Da Silva,Hayat M Sharada,Sudhesh Kumar,Steven J Creely,Gyanendra Tripathi,Philip G Mcternan,Esmat Ashour,Elham M Youssef-Elabd,Mohga S Abdalla,Ashraf I Amin,Kirsty C Mcgee,Alastair D Burt,Thomas Billyard

doi:10.1186/1476-9255-7-15

Abstract

BackgroundEmerging data indicate that gut-derived endotoxin may contribute to low-grade systemic inflammation in insulin resistant states. This study aimed to examine the importance of serum endotoxin and inflammatory markers in non-alcoholic fatty liver disease (NAFLD) patients, with and without type 2 diabetes mellitus (T2DM), and to explore the effect of treatment with a lipase inhibitor, Orlistat, on their inflammatory status.MethodsFasted serum from 155 patients with biopsy proven NAFLD and 23 control subjects were analysed for endotoxin, soluble CD14 (sCD14), soluble tumour necrosis factor receptor II (sTNFRII) and various metabolic parameters. A subgroup of NAFLD patients were re-assessed 6 and 12 months after treatment with diet alone (n = 6) or diet plus Orlistat (n = 8).ResultsEndotoxin levels were significantly higher in patients with NAFLD compared with controls (NAFLD: 10.6(7.8, 14.8) EU/mL; controls: 3.9(3.2, 5.2) EU/mL, p < 0.001); NAFLD alone produced comparable endotoxin levels to T2DM (NAFLD: T2DM: 10.6(5.6, 14.2) EU/mL; non-diabetic: 10.6(8.5, 15.2) EU/mL), whilst a significant correlation between insulin resistance and serum endotoxin was observed (r = 0.27, p = 0.008). Both sCD14 (p < 0.01) and sTNFRII (p < 0.001) increased with severity of fibrosis. A positive correlation was also noted between sTNFRII and sCD14 in the NAFLD subjects (r = 0.29, p = 0.004).Sub-cohort treatment with Orlistat in patients with NAFLD showed significant decreases in ALT (p = 0.006), weight (p = 0.005) and endotoxin (p = 0.004) compared with the NAFLD, non-Orlistat treated control cohort at 6 and 12 months post therapy, respectively.ConclusionsEndotoxin levels were considerably increased in NAFLD patients, with marked increases noted in early stage fibrosis compared with controls. These results suggest elevated endotoxin may serve as an early indicator of potential liver damage, perhaps negating the need for invasive liver biopsy. As endotoxin may promote insulin resistance and inflammation, interventions aimed at reducing endotoxin levels in NAFLD patients may prove beneficial in reducing inflammatory burden.

Highlights

Emerging data indicate that gut-derived endotoxin may contribute to low-grade systemic inflammation in insulin resistant states
Endotoxin levels were considerably increased in non-alcoholic fatty liver disease (NAFLD) patients, with marked increases noted in early stage fibrosis compared with controls
As endotoxin may promote insulin resistance and inflammation, interventions aimed at reducing endotoxin levels in NAFLD patients may prove beneficial in reducing inflammatory burden

Summary

Introduction

Emerging data indicate that gut-derived endotoxin may contribute to low-grade systemic inflammation in insulin resistant states. NAFLD and other insulin resistant states are associated with activation of the innate immune system resulting in chronic sub-clinical inflammation, affecting the adipose tissue [5,6]. The major outer membrane constituent of gram-negative bacteria, lipopolysaccharide (LPS), referred to as endotoxin, has been implicated as potentially important in this regard - as it is a potent inducer of inflammation. It activates the innate immune pathway via stimulation of toll-like receptors (TLRs), enabling a rapid reaction to infection, and represents the first line of defence against gram-negative infections [7]. An acute phase response [8] is initiated, in conjunction with the liver, as the latter is the primary site of endotoxin clearance under typical physiological conditions

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