The Gut–Spleen Axis in Liver Disease: Mechanistic Insights Into Metabolism, Metabolome, and Microbiome Interactions

This review consolidates existing knowledge on the gut–spleen axis and its pivotal role in the pathophysiology of metabolic liver disease by summarizing the interconnected tripartite network connecting the gut, spleen, and liver through vascular, lymphatic, and neurological pathways, emphasizing the role of the spleen as an active mediator rather than a passive participant. Gut dysbiosis and impaired intestinal barrier function promote the translocation of microbial metabolites (e.g., short-chain fatty acids, bile acids, lipopolysaccharides) to the spleen through the portal vein. Splenic immune cells react by secreting proinflammatory cytokines (e.g., TNF-α, IL-6) and profibrogenic mediators (e.g., TGF-β1), which intensify hepatic inflammation, fibrosis, and hinder regeneration. Splenomegaly and hypersplenism in cirrhosis exacerbate liver damage through feedback loops mediated by portal hypertension. The mesenteric immune system and vagus nerve act as crucial mediators in gut–spleen communication, regulating systemic immunometabolic responses. Significantly, splenic dysfunction exacerbates liver pathology by providing fibrogenic immune cells to the liver and impacting hepatocyte regeneration. Therapeutic approaches aimed at gut microbiota (e.g., probiotics, prebiotics), barrier integrity, or splenic immune function (e.g., splenectomy) may interrupt this pathogenic pathway. Future research needs to elucidate the molecular pathways by which microbial metabolites affect splenic cells and validate translational therapies to alleviate disease progression driven by the gut–spleen–liver axis.