Inhibition of glutamine synthetase in monocytes from patients with acute-on-chronic liver failure resuscitates their antibacterial and inflammatory capacity.

OBJECTIVE: Acute-on-chronic liver failure (ACLF) is associated with dysfunctional circulating monocytes whereby patients become highly susceptible to bacterial infections. Here, we identify the pathways underlying monocyte dysfunction in ACLF and we investigate whether metabolic rewiring reinstates their phagocytic and inflammatory capacity. DESIGN: Following phenotypic characterisation, we performed RNA sequencing on CD14+CD16- monocytes from patients with ACLF and decompensated alcoholic cirrhosis. Additionally, an in vitro model mimicking ACLF patient-derived features was implemented to investigate the efficacy of metabolic regulators on monocyte function. RESULTS: Monocytes from patients with ACLF featured elevated frequencies of interleukin (IL)-10-producing cells, reduced human leucocyte antigen DR isotype (HLA-DR) expression and impaired phagocytic and oxidative burst capacity. Transcriptional profiling of isolated CD14+CD16- monocytes in ACLF revealed upregulation of an array of immunosuppressive parameters and compromised antibacterial and antigen presentation machinery. In contrast, monocytes in decompensated cirrhosis showed intact capacity to respond to inflammatory triggers. Culturing healthy monocytes in ACLF plasma mimicked the immunosuppressive characteristics observed in patients, inducing a blunted phagocytic response and metabolic program associated with a tolerant state. Metabolic rewiring of the cells using a pharmacological inhibitor of glutamine synthetase, partially restored the phagocytic and inflammatory capacity of in vitro generated- as well as ACLF patient-derived monocytes. Highlighting its biological relevance, the glutamine synthetase/glutaminase ratio of ACLF patient-derived monocytes positively correlated with disease severity scores. CONCLUSION: In ACLF, monocytes feature a distinct transcriptional profile, polarised towards an immunotolerant state and altered metabolism. We demonstrated that metabolic rewiring of ACLF monocytes partially revives their function, opening up new options for therapeutic targeting in these patients.

Endocoil placement after endoscopic ultrasound-guided biliary drainage may prevent a bile leak.

AIM: To further reduce the risk of bleeding or bile leakage. METHODS: We performed endoscopic ultrasound guided biliary drainage in 6 patients in whom endoscopic retrograde cholangiopancreatography (ERCP) had failed. Biliary access of a dilated segment 2 or 3 duct was achieved from the stomach using a 19G needle. After radiologically confirming access a guide wire was placed, a transhepatic tract created using a 6 Fr cystotome followed by balloon dilation of the stricture and antegrade metallic stent placement across the malignant obstruction. This was followed by placement of an endocoil in the transhepatic tract. RESULTS: Dilated segmental ducts were observed in all patients with the linear endoscopic ultrasound scope from the proximal stomach. Transgastric biliary access was obtained using a 19G needle in all patients. Biliary drainage was achieved in all patients. Placement of an endocoil was possible in 5/6 patients. All patients responded to biliary drainage and no complications occurred. CONCLUSION: We show that placing endocoils at the time of endoscopic ultrasound guided biliary stenting is feasible and may reduce the risk of bleeding or bile leakage.