Immunosuppressive effects of circulating bile acids in human endotoxemia and septic shock: patients with liver failure are at risk
Julia Leonhardt,
Mirrin J. Dorresteijn,
Sophie Neugebauer,
Diana Mihaylov,
Julia Kunze,
Ignacio Rubio,
Frank-Stephan Hohberger,
Silke Leonhardt,
Michael Kiehntopf,
Klaus Stahl,
Christian Bode,
Sascha David,
Frank A. D. T. G. Wagener,
Peter Pickkers,
Michael Bauer
Affiliations
Julia Leonhardt
Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Member of the Leibniz Center for Photonics in Infection Research (LPI)
Mirrin J. Dorresteijn
Department of Intensive Care Medicine, Radboud University Medical Center
Sophie Neugebauer
Institute of Clinical Chemistry and Laboratory Diagnostics and Integrated Biobank Jena, Jena University Hospital, Member of the Leibniz Center for Photonics in Infection Research (LPI)
Diana Mihaylov
Institute of Clinical Chemistry and Laboratory Diagnostics and Integrated Biobank Jena, Jena University Hospital, Member of the Leibniz Center for Photonics in Infection Research (LPI)
Julia Kunze
Institute of Clinical Chemistry and Laboratory Diagnostics and Integrated Biobank Jena, Jena University Hospital, Member of the Leibniz Center for Photonics in Infection Research (LPI)
Ignacio Rubio
Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Member of the Leibniz Center for Photonics in Infection Research (LPI)
Frank-Stephan Hohberger
Department of Oral and Maxillofacial Surgery and Plastic Surgery, Jena University Hospital
Silke Leonhardt
Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin
Michael Kiehntopf
Center for Sepsis Control and Care (CSCC), Jena University Hospital-Friedrich Schiller University
Klaus Stahl
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School
Christian Bode
Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn
Sascha David
Institute of Intensive Care Medicine, University Hospital Zurich
Frank A. D. T. G. Wagener
Department of Dentistry-Orthodontics and Craniofacial Biology, Research Institute for Medical Innovation, Radboud University Medical Center
Peter Pickkers
Department of Intensive Care Medicine, Radboud University Medical Center
Michael Bauer
Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Member of the Leibniz Center for Photonics in Infection Research (LPI)
Abstract Background Sepsis-induced immunosuppression is a frequent cause of opportunistic infections and death in critically ill patients. A better understanding of the underlying mechanisms is needed to develop targeted therapies. Circulating bile acids with immunosuppressive effects were recently identified in critically ill patients. These bile acids activate the monocyte G-protein coupled receptor TGR5, thereby inducing profound innate immune dysfunction. Whether these mechanisms contribute to immunosuppression and disease severity in sepsis is unknown. The aim of this study was to determine if immunosuppressive bile acids are present in endotoxemia and septic shock and, if so, which patients are particularly at risk. Methods To induce experimental endotoxemia in humans, ten healthy volunteers received 2 ng/kg E. coli lipopolysaccharide (LPS). Circulating bile acids were profiled before and after LPS administration. Furthermore, 48 patients with early (shock onset within 0.4 μg/kg/min) and 48 healthy age- and sex-matched controls were analyzed for circulating bile acids. To screen for immunosuppressive effects of circulating bile acids, the capability to induce TGR5 activation was computed for each individual bile acid profile by a recently published formula. Results Although experimental endotoxemia as well as septic shock led to significant increases in total bile acids compared to controls, this increase was mild in most cases. By contrast, there was a marked and significant increase in circulating bile acids in septic shock patients with severe liver failure compared to healthy controls (61.8 µmol/L vs. 2.8 µmol/L, p = 0.0016). Circulating bile acids in these patients were capable to induce immunosuppression, as indicated by a significant increase in TGR5 activation by circulating bile acids (20.4% in severe liver failure vs. 2.8% in healthy controls, p = 0.0139). Conclusions Circulating bile acids capable of inducing immunosuppression are present in septic shock patients with severe liver failure. Future studies should examine whether modulation of bile acid metabolism can improve the clinical course and outcome of sepsis in these patients. Graphical abstract
