title: Pro-Inflammatory Cytokines but Not Endotoxin-Related Parameters Associate with Disease Severity in Patients with NAFLD.
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.
authors.affiliation: Laboratory of Hepatology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Johannie
authors.initials: J
authors.lastname: du Plessis
authors.affiliation: Laboratory of Hepatology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.|Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Hannelie
authors.initials: H
authors.lastname: Korf
authors.affiliation: Laboratory of Hepatology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Jos
authors.initials: J
authors.lastname: van Pelt
authors.affiliation: Laboratory of Hepatology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Petra
authors.initials: P
authors.lastname: Windmolders
authors.affiliation: Laboratory of Hepatology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Vander Elst
authors.affiliation: Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Verrijken
authors.affiliation: Department of Abdominal Surgery, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Hubens
authors.affiliation: Department of Gastroenterology and Hepatology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Van Gaal
authors.affiliation: Laboratory of Hepatology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.|Department of Internal Medicine, Division of Liver and biliopancreatic disorders, KU Leuven, Leuven, Belgium.
authors.forename: David
authors.initials: D
authors.lastname: Cassiman
authors.affiliation: Laboratory of Hepatology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.|Department of Internal Medicine, Division of Liver and biliopancreatic disorders, KU Leuven, Leuven, Belgium.
authors.forename: Frederik
authors.initials: F
authors.lastname: Nevens
authors.affiliation: Department of Gastroenterology and Hepatology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
authors.forename: Sven
authors.initials: S
authors.lastname: Francque
authors.affiliation: Laboratory of Hepatology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.|Department of Internal Medicine, Division of Liver and biliopancreatic disorders, KU Leuven, Leuven, Belgium.
authors.forename: Schalk
authors.initials: S
authors.lastname: van der Merwe
mesh_terms: D000209:Acute-Phase Proteins; D000328:Adult; D050110:Bariatric Surgery; D002352:Carrier Proteins / Q000097:blood*; D018925:Chemokines / Q000097:blood*; D016000:Cluster Analysis; D016207:Cytokines / Q000097:blood*; D004731:Endotoxins / Q000378:metabolism; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000097:blood*; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood*; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D009765:Obesity / Q000276:immunology / Q000378:metabolism / Q000601:surgery*; D011446:Prospective Studies; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D018925:Chemokines; D016207:Cytokines; D004731:Endotoxins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D000099231:Lipopolysaccharide-Binding Protein