The role of immune effector cell dysregulation in acute and chronic liver failure and its upstream mechanism of the gut–liver axis

Abstract

: Acute-on-chronic liver failure (ACLF) is one of the most severe clinical syndromes in patients with chronic liver disease, particularly cirrhosis, and is associated with extremely high short-term mortality. Emerging evidence indicates that ACLF is not merely the terminal aggravation of decompensated cirrhosis, but an independent disease state driven by systemic inflammation, multi-organ dysfunction, and immune dysregulation. Disruption of gut–liver axis homeostasis is regarded as a key upstream mechanism: portal hypertension, gut microbiota dysbiosis, and intestinal barrier dysfunction promote bacterial translocation and the entry of pathogen-associated molecular patterns (PAMPs) into the portal circulation, which subsequently activate hepatic innate immune responses through Toll-like receptors (TLRs) and amplify systemic inflammation. At the same time, innate immune cells such as monocytes, macrophages, and neutrophils become persistently hyperactivated, whereas adaptive immune cells including T cells and natural killer (NK) cells gradually develop functional exhaustion and immunosuppression, resulting in a unique immunopathological state characterized by the coexistence of “hyperinflammation” and “immune paralysis.” The Two-to-tango model provides a useful framework to explain the simultaneous occurrence of high infection rates, organ failure, and short-term mortality in ACLF. This review summarizes the evolution of the ACLF concept, gut–liver axis imbalance, amplification of systemic inflammation, and dysregulation of immune effector cells, and discusses potential therapeutic strategies based on gut–liver axis intervention and immune stratification, with the aim of providing insights for mechanistic research and precision treatment of ACLF.