Elevated endotoxin levels in non-alcoholic fatty liver disease

University of Warwick, Unit for Diabetes and Metabolism, Warwick Medical School, Clinical Sciences Research Institute, UHCW, Clifford Bridge Road, Coventry, CV2 2DX, UK. .
Journal of Inflammation (Impact Factor: 2.02). 03/2010; 7(1):15. DOI: 10.1186/1476-9255-7-15
Source: PubMed


Emerging 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.
Fasted 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).
Endotoxin 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.
Endotoxin 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.

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Available from: Philip G McTernan, Oct 03, 2015
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    • "Recent results indicate that obesity-associated inflammation, besides being driven by dietary factors and nutrients such as glucose and lipids, is mediated by LPS [23], [24]. Indeed, fat deposition compromises intestinal permeability, liver function and the ability of Kuppfer cells to adsorb endotoxin [25], [26], whose circulating concentration is, therefore, increased. This in turn, mediates chronic low-grade of inflammation through the activation of TLR and the inflammosome pathway to exacerbate the insulin resistant state [27]–[30]. "
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    ABSTRACT: To explore the mechanisms underlying the suggested role of the vitamin D/vitamin D receptor (VDR) complex in the pathogenesis of obesity we performed genetic and immunologic analyses in obese and non-obese Saudi individuals without other concomitant chronic diseases. Genomic DNA was genotyped for gene single nucleotide polymorphisms (SNPs) of VDR by allelic discrimination in 402 obese (body mass index -BMI≥30 kg/m2) and 489 non-obese (BMI<30 kg/m2) Saudis. Q-PCR analyses were performed using an ABI Prism 7000 Sequence Detection System. The inflammosome pathway was analysed by PCR, cytokines and plasma lipopolysaccaride (LPS) concentrations with ELISA assays. Results showed that the VDR SNPs rs731236 (G) (TaqI) and rs1544410 (T) (Bsm-I) minor allele polymorphisms are significantly more frequent in obese individuals (p = 0.009, β = 0.086 and p = 0.028, β = 0.072, respectively). VDR haplotypes identified are positively (GTA) (p = 0.008, β = 1.560); or negatively (ACC) (p = 0.044, β = 0.766) associated with obesity and higher BMI scores. The GTA "risk" haplotype was characterized by an up-regulation of inflammosome components, a higher production of proinflammatory cytokines (p<0.05) and a lower VDR expression. Plasma LPS concentration was also increased in GTA obese individuals (p<0.05), suggesting an alteration of gut permeability leading to microbial translocation. Data herein indicate that polymorphisms affecting the vitamin D/VDR axis play a role in obesity that is associated with an ongoing degree of inflammation, possibly resulting from alterations of gut permeability and microbial translocation. These results could help the definition of VDR fingerprints that predict an increased risk of developing obesity and might contribute to the identification of novel therapeutic strategies for this metabolic condition.
    PLoS ONE 07/2014; 9(7):e102141. DOI:10.1371/journal.pone.0102141 · 3.23 Impact Factor
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    • "This likely increases the formation of ox-LDL; and uptake of ox-LDL by Kupffer cells induces secretion of inflammatory cytokines [24]. A second source of inflammatory agents is endotoxin from the gut [25,26]. The increase in plasma endotoxin may be due to increased gut permeability or co-transport with chylomicron [26,29,30]. "
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    PLoS ONE 12/2013; 8(12):e83756. DOI:10.1371/journal.pone.0083756 · 3.23 Impact Factor
    • "Interestingly it appears that fragments of Gram negative bacteria derived from the gut (endotoxin) can cross the intestinal mucosa to enter the circulation, and may represent an important mediator of low-grade systemic inflammation influenced by the host's own gut microbiota and metabolic state. Previous studies have shown that low levels of endotoxin can enter the blood circulatory system, which may stimulate an innate immune response from adipose tissue, liver and skeletal muscle, leading to production of pro-inflammatory cytokines [4-9]. Endotoxin has been shown to act as a mediator of inflammation in liver disease [10,11], whilst cross-sectional and longitudinal studies have indicated that a reduction in circulating endotoxin leads to a reduction in inflammatory cytokines and inflammatory response [12-15]. "
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    Trials 07/2013; 14(1):195. DOI:10.1186/1745-6215-14-195 · 1.73 Impact Factor
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