Abstract
OBJECTIVES: Decompensated cirrhosis represents the end-stage of chronic liver diseases and is characterized by cirrhosis-associated immune dysfunction (CAID). Our goal was to characterize the peritoneal immune landscape, focusing on monocytic myeloid-derived suppressor cells (M-MDSCs), and elucidate their association with clinical outcomes and potential regulatory mechanisms involving ascites metabolites in decompensated cirrhosis. METHODS: Fifty-five patients with decompensated cirrhosis were prospectively recruited, and subsequently classified as survivors (n = 24) and non-survivors (n = 31). Immune cell compartments in ascites and peripheral blood were analyzed by flow cytometry. Targeted metabolomics of ascites supernatant was performed using targeted ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Human peritoneal M-MDSCs were differentiated in vitro in the presence of glycoursodeoxycholic acid (GUDCA), followed by transcriptomic, metabolic (mitochondria stress test), and functional (coculture with T cells) analyses. RESULTS: Survivors had significantly higher frequencies of peritoneal M-MDSCs with an active immunosuppressive phenotype and elevated expression of chemotactic markers. GUDCA levels in ascites were significantly elevated in survivors and positively correlated with peritoneal M-MDSC levels. In vitro, GUDCA induced the expansion and enhanced the suppressive capacity of peritoneal M-MDSCs via the TGR5-TREM2-oxidative phosphorylation axis. Furthermore, TREM2 expression on peritoneal M-MDSCs was associated with improved survival, serving as a potential prognostic marker. CONCLUSIONS: Peritoneal M-MDSCs play a critical protective role in immune dysfunction associated with decompensated cirrhosis. GUDCA and TREM2 emerge as key regulators of M-MDSC function, providing a conceptual framework for future investigation into immunomodulatory strategies aimed at restoring immune balance in decompensated cirrhosis.