Increased versican and fibrosis in mesenteric lymph nodes disrupts immune surveillance and drives systemic bacterial dissemination in cirrhosis

Background and ObjectiveMesenteric lymph nodes (MLN) are immunological barriers against bacterial translocation (BT). Enhanced gut BT through MLN facilitates bacterial spread and higher mortality in cirrhosis. We aimed to elucidate mechanisms underlying MLN failure to effectively contain BT during advanced cirrhosis. DesignBT and immune cells were analyzed in lymphoid organs and circulation of control and CCl4 models, with and without MLN (MLNx). MLN proteomics identified versican (VCAN) as major upregulated protein in cirrhosis, whose immunomodulatory function was examined in vitro and in vivo in CCl and (Bile duct ligation) BDL models. Plasma VCAN were measured in end-stage cirrhosis patients and analyzed as mortality predictor. ResultsIn control rats, bacteria were confined to MLN, whereas cirrhotics showed BT to MLN, lymph, and portal blood. Compared to control, CCl4 rats had increased activated Th-cells in MLN but reduced in circulation. In control-MLNx rats, activated Th-cells were reduced in circulation vs controls. In BDL models, MLN CFU correlated with VCAN level. In vitro, VCAN enhanced T cell suppression and impaired migration which was reversed by CD44 blockade. In vivo VCAN knockdown reduced fibrosis and bacterial burden in MLN, while restoring Th-cell activation locally and systemically. Clinically, plasma VCAN levels were elevated in advanced cirrhosis patients and remained an independent predictor of 28-day sepsis-related mortality. ConclusionIncreased VCAN impairs T cell activation and migration in MLN, fostering immune suppression and bacterial persistence. Plasma VCAN levels serve as promising biomarker for MLN dysfunction and prognostic factor for predicting sepsis-related mortality in end-stage cirrhosis. What is already known on this topic - Enhanced gut bacterial translocation through mes-enteric lymph nodes (MLN) facilitates systemic bacterial spread and increases mortality in cirrhosis. The mechanisms underlying MLN failure to effectively contain bacterial spread during advanced cirrhosis remain largely unknown. What this study adds - The study unveils a critical role of lymph node fibrosis and elevated versican (VCAN) expression in causing deranged immune responses and bacterial clearance in MLN, increasing systemic bacterial load and immunosuppression. Most importantly, high plasma VCAN emerges as a prognostic biomarker for functional failure of MLN and 28-day mortality predictor in critically ill patients with cirrhosis. How this study might affect research, practice or policy - VCAN, representing enhanced MLN fibrosis and dysfunction, emerges as a predictive biomarker of adverse clinical out-comes in patients with advanced cirrhosis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/690350v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@369f4eorg.highwire.dtl.DTLVardef@14c232org.highwire.dtl.DTLVardef@d99b21org.highwire.dtl.DTLVardef@57ac95_HPS_FORMAT_FIGEXP M_FIG C_FIG