Abstract
BackgroundNon-alcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular risk irrespective of conventional risk factors. The role of gut-liver interaction is implicated in its development. We investigated the effects of VSL#3® probiotic supplementation on biomarkers of cardiovascular risk and liver injury in patients with NAFLD.MethodsA randomised, double-blinded, placebo-controlled, proof-of-concept study was undertaken. Patients with NAFLD were randomly allocated to take 2 sachets VSL#3® probiotic or placebo twice daily for 10 weeks. Measurements of endothelial function (digital photoplethysmography, sVCAM-1 and cGMP), oxidative stress (glutathione ratio and LHP), inflammation (hsCRP), insulin resistance (HOMA-IR) and liver injury [transaminases, fibrosis risk score and acoustic structure quantification (ASQ)] were undertaken before and after intervention. Difference in baseline characteristics between the treatment groups was analysed using independent t-test or Mann Whitney U test for non-parametric data. Independent t-test was used to compare the outcomes at the end of the study between the two treatment groups. Wilcoxon Signed Rank test was used to determine the difference in fibrosis risk scores before and after treatment. Spearman’s correlation was used to determine any association between cardiovascular and hepatic markers at baseline.ResultsThirty-five patients completed the study (28 males and 7 females) with a mean age of 57 ± 8 years, body mass index of 32.6 ± 5.0 kg/m2 and a relatively short duration of NAFLD (median duration 0.3 IQR 2.0 years). No significant difference was observed in biomarkers of cardiovascular risk and liver injury following VSL#3® supplementation. Significant correlations were noted between sVCAM-1 and hsCRP (rho = 0.392, p = 0.01), and HOMA-IR and AST (rho = 0.489, p < 0.01) at baseline.ConclusionsThis is the first study to evaluate the effect of VSL#3® on ASQ in patients with NAFLD. VSL#3® did not significantly improve markers of cardiovascular risk and liver injury in patients with NAFLD. However, the study supports an association between endothelial dysfunction and inflammation in patients with NAFLD and suggests that NAFLD is linked with insulin resistance.Trial registration: ISRCTN05474560 (https://doi.org/10.1186/ISRCTN05474560) Registered 9 August 2012 (retrospectively registered).
Highlights
Non-alcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular risk irrespective of conventional risk factors
The aim of this study was to examine the effects of VSL#3® probiotic supplementation on biomarkers of cardiovascular risk and biomarkers of liver injury in patients with NAFLD
One patient was withdrawn as he was due to undergo bariatric surgery whilst 6 patients withdrew from the study for various reasons
Summary
Non-alcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular risk irrespective of conventional risk factors. The role of gut-liver interaction is implicated in its development. Lipopolysaccharide (LPS) is the active component of gut-derived endotoxins which exerts metabolic and inflammatory effects on the liver. A high fat diet is associated with intestinal dysbiosis resulting in higher proportion of LPS-producing bacteria in the gut and a 2–3 fold increase in LPS concentration [8]. LPS compromises intestinal barrier integrity and increases gut permeability, facilitating translocation of endotoxins into the portal circulation [9, 10]. LPS activates the Toll-like receptor 4 (TLR4)-dependent pathway in Kupffer cells resulting in activation of inflammatory pathways and impairment of insulin signaling [9]
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