RT Journal Article
SR Electronic
T1 Gut microbial translocation corrupts myeloid cell function to control bacterial infection during liver cirrhosis
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 507
OP 518
DO 10.1136/gutjnl-2015-311224
VO 66
IS 3
A1 Carl-Philipp Hackstein
A1 Lisa Mareike Assmus
A1 Meike Welz
A1 Sabine Klein
A1 Timo Schwandt
A1 Joachim Schultze
A1 Irmgard Förster
A1 Fabian Gondorf
A1 Marc Beyer
A1 Daniela Kroy
A1 Christian Kurts
A1 Jonel Trebicka
A1 Wolfgang Kastenmüller
A1 Percy A Knolle
A1 Zeinab Abdullah
YR 2017
UL http://gut.bmj.com/content/66/3/507.abstract
AB Objective Patients with liver cirrhosis suffer from increased susceptibility to life-threatening bacterial infections that cause substantial morbidity.Methods Experimental liver fibrosis in mice induced by bile duct ligation or CCl4 application was used to characterise the mechanisms determining failure of innate immunity to control bacterial infections.Results In murine liver fibrosis, translocation of gut microbiota induced tonic type I interferon (IFN) expression in the liver. Such tonic IFN expression conditioned liver myeloid cells to produce high concentrations of IFN upon intracellular infection with Listeria that activate cytosolic pattern recognition receptors. Such IFN-receptor signalling caused myeloid cell interleukin (IL)-10 production that corrupted antibacterial immunity, leading to loss of infection-control and to infection-associated mortality. In patients with liver cirrhosis, we also found a prominent liver IFN signature and myeloid cells showed increased IL-10 production after bacterial infection. Thus, myeloid cells are both source and target of IFN-induced and IL-10-mediated immune dysfunction. Antibody-mediated blockade of IFN-receptor or IL-10-receptor signalling reconstituted antibacterial immunity and prevented infection-associated mortality in mice with liver fibrosis.Conclusions In severe liver fibrosis and cirrhosis, failure to control bacterial infection is caused by augmented IFN and IL-10 expression that incapacitates antibacterial immunity of myeloid cells. Targeted interference with the immune regulatory host factors IL-10 and IFN reconstitutes antibacterial immunity and may be used as therapeutic strategy to control bacterial infections in patients with liver cirrhosis.