Decompression of portal hypertension by transjugular intrahepatic portosystemic shunt reverses markers of gut barrier dysfunction and cirrhosis-associated immune dysfunction.

Abstract

Decompensated cirrhosis is associated with cirrhosis-associated immune dysfunction (CAID), predisposing patients to bacterial infections and poor outcomes. The mechanisms driving CAID remain incompletely understood. To examine whether portal hypertension (PH) is a key upstream driver of CAID and whether its reduction by transjugular intrahepatic portosystemic shunt (TIPS) reverses immune dysfunction. In a prospective cohort study, patients undergoing TIPS (n=75) and controls with compensated cirrhosis (n=15) were included. Plasma markers of gut barrier dysfunction, bacterial translocation, systemic inflammation and monocyte activation were measured in controls and longitudinally before and after TIPS. The effects of patient sera from different stages of cirrhosis on healthy donor-derived monocytes were assessed in vitro. Bulk RNA sequencing was performed on patient monocytes. Immunological findings were correlated with clinical outcomes, which were also validated in an external prospective cohort and a retrospective multicentre cohort of 1180 patients. Patients with decompensated cirrhosis showed elevated markers of gut barrier dysfunction, bacterial translocation, systemic inflammation and monocyte activation compared with compensated controls. These markers significantly decreased after TIPS. Sera from decompensated patients, but not from post-TIPS patients, induced anti-inflammatory markers (MER Tyrosine Kinase (MERTK), CD163) and suppressed interleukin 6 secretion in monocytes in vitro. Transcriptomic analysis identified an anti-inflammatory monocyte signature in decompensated cirrhosis that resolved after TIPS. CAID improvement occurred only in patients with ascites resolution and was associated with fewer bacterial infections. PH is a central driver of CAID in decompensated cirrhosis. Its reduction by TIPS restores gut barrier integrity, reduces inflammation and re-establishes immune homeostasis.