Abstract
Intestinal dysbiosis and elevated lipopolysaccharides (LPS) levels have been implicated in the development of obesity, insulin resistance and non-alcoholic steatohepatitis (NASH). In order to determine if LPS levels are elevated in patients with NASH compared to patients with non-alcoholic fatty liver (NAFL) and, if elevated LPS levels correlated with histological severity of non-alcoholic fatty liver disease (NAFLD) we compared LPS, markers of LPS bioactivity and pro-inflammatory cytokines/chemokines in patients undergoing bariatric surgery. At the time of surgery a liver biopsy was taken allowing the stratification into well-delineated subgroups including: No NAFL/NAFL; NASH; NASH with fibrosis and NASH cirrhotics, using the NAFLD Activity Score (NAS). Anthropometric data and plasma were collected for assessment of LPS, lipopolysaccharide binding protein (LBP), soluble CD14 (sCD14), intestinal-type fatty acid binding protein (iFABP), Toll-like receptors 2 and 4 (TLR2, 4) and a panel of cytokines/chemokines. Similar analysis was performed on plasma from a cohort of healthy controls. Our data indicate elevated levels of LPS, LBP, sCD14, iFABP and TLR2,4 in obese patients compared to healthy controls, however, these parameters remained unaltered within patients with limited liver disease (NAFL) compared to NASH/NASH with fibrosis subgroups. Hierarchic cluster analysis using endotoxin-related parameters failed to discriminate between lean controls, NAFLD. While similar cluster analysis implementing inflammation-related parameters clearly distinguished lean controls, NALFD subgroups and NASH cirrhotics. In addition, LPS levels was not associated with disease severity while TNFα, IL8, and CCL3 featured a clear correlation with transaminase levels and the histological severity of NALFD. In conclusion our data indicate a stronger correlation for circulating inflammatory- rather than endotoxin-related parameters in progression of NAFLD and highlights the need for additional larger studies in unravelling further mechanistic insights.
Highlights
Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome [1,2,3], is characterized by the development of simple steatosis or non-alcoholic fatty liver (NAFL), a condition that runs a benign course
The pathogenesis of non-alcoholic steatohepatitis (NASH) is unknown but is characterized by an increased delivery of lipotoxic free fatty acids (FFA’s) to the liver which is associated with persistent low grade systemic inflammation [28]
LPS levels are elevated in animal models of obesity and steatosis and are increased in obese patients with NASH when compared to a healthy control population [29,30]
Summary
Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome [1,2,3], is characterized by the development of simple steatosis or non-alcoholic fatty liver (NAFL), a condition that runs a benign course. Important work over the last decade has shed light on the intricate cross talk between the gut and intestinal microbiota in obesity and how changes in microbiota composition and diversity may influence NAFLD pathogenesis in animal models [5,6] These studies showed that altered bacterial flora in obese mice harvested energy more efficiently and that weight gain could be transferred from obese to lean mice [7]. Hepatic inflammation, lipid peroxidation and insulin resistance were markedly reduced in mice deficient for TLR4 suggesting a role for LPS and TLR4 in steatohepatitis mouse models [16]. We show that increased levels of the cytokines/chemokines IL8, TNFα and CCL3 correlated with markers of NAFLD disease severity including liver inflammation and fibrosis scores
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