Gut microbial translocation corrupts myeloid cell function to control bacterial infection during liver cirrhosis

Abstract

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.

Gut microbiota and Toll-like receptors set the stage for cytokine-mediated failure of antibacterial responses in the fibrotic liver

“…Another key novelty of the current study is the discovery of a gut microbiota–Toll-like receptor (TLR)-mediated mechanism through which the leaky gut impairs antibacterial responses in the liver in the setting of fibrosis. In experiments with germ-free mice and with macrophages from TLR-deficient mice, the authors show an important role of gut-derived PAMPs in the tonic increase of IFNβ levels after bile duct ligation 6. Moreover, hepatic CD11b+ cells from bile duct-ligated germ-free mice showed an ameliorated phagocytic capacity in comparison with those from their specific pathogen-free counterparts.…”

“…Mice with liver fibrosis displayed up to 25-fold increased bacterial titres and high mortality, whereas the majority of non-fibrotic control animals cleared the infection and survived 6. While there were increased titres of CD11b+ cells in fibrotic livers, bacterial cultures showed decreased clearance of hepatic bacteria.…”

“…In this issue, Hackstein et al 6 found that the presence of liver fibrosis—induced either by bile duct ligation (BDL) or carbon tetrachloride (CCl 4 ) injection—drastically hampered the ability of mice to respond to infection with the intracellular bacterium Listeria monocytogenes. Mice with liver fibrosis displayed up to 25-fold increased bacterial titres and high mortality, whereas the majority of non-fibrotic control animals cleared the infection and survived 6.…”

“…is the discovery of a cytokine-mediated and potentially targetable pathway that mediates the failing antibacterial defence in the setting of liver fibrosis. The authors found a tonic increase of interferon β (IFNβ) in fibrotic livers and a subsequent IFNβ-mediated induction of interleukin 10 (IL-10) upon infection with intracellular bacteria, which were responsible for the suppressed antibacterial defence in the fibrotic liver 6. Accordingly, fibrotic mice deficient for interferon α-receptor (IFNAR) displayed reduced IL-10 levels after Listeria infection and were protected from Listeria -induced death, but not from BDL-induced fibrosis.…”

Detection of human polyomaviruses JC and BK in liver pretransplant patients

“…In addition to the decreased count of neutrophils due to hypersplenic sequestration or increased rate of apoptosis, these patients also have the cirrhosis‐associated immune dysfunction syndrome (CAIDS), which is a multifactorial state of immune dysfunction in which the patient presents reticuloendothelial system dysfunction, decreased monocyte activation, decreased mobilisation of neutrophils and low phagocytic activity (Albillos et al., ; Bonnel, Bunchorntavakul, & Reddy, ; Hackstein et al., ; Sipeki, Antal‐Szalmas, Lakatos, & Papp, ).…”