S100B in brain-gut-liver crosstalk: from glial activation to multiorgan inflammation.

S100 calcium-binding protein B (S100B) is conventionally viewed as a marker of astrocytic injury, blood-brain barrier (BBB) disruption, and neurological disorders. Emerging evidence places S100B within the broader brain-gut-liver axis of inflammatory signaling. This review proposes that S100B is a glial-derived integrating effector that couples enteric glial activation, barrier dysfunction, hepatic fibrosis, and hepatic encephalopathy (HE) into a multi-organ inflammatory network. Its spatial expression map, release kinetics, alarmin (damage-associated molecular pattern, DAMP) activity, and immune-cell infiltration differ among the gut, liver, and brain, shaping axis signaling. S100B is predominantly expressed in astrocytes of the central nervous system, Schwann cells, and enteric glial cells and is also detected in liver tumor immune cells, biliary epithelial cells, and activated hepatic stellate cell (HSC)-associated lesions. It exerts context-dependent functions: at low, nanomolar concentrations it supports neurotrophic activity and barrier integrity, whereas sustained elevation acts as a DAMP that amplifies inflammatory responses through receptor for advanced glycation end products (RAGE), Toll-like receptor 2 (TLR2)/Toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) and a disintegrin and metalloproteinase 10 (ADAM10)/β-catenin pathways. Clinically, S100B kinetics, a rapid release with a short half-life after acute injury versus chronic multi-organ spillover in cirrhosis, determines whether elevation reflects a local glial event or systemic disease burden. S100B has been implicated in enteric infectious enteritis, inflammatory bowel disease (IBD), diarrhea-predominant irritable bowel syndrome (IBS-D), cholestatic fibrosis, metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), viral hepatitis, hepatocellular carcinoma (HCC), and HE with comorbid neuroinflammation. Available evidence suggests that S100B is a candidate link between glial responses, barrier dysfunction, hepatic inflammation, and neuroinflammation within the brain-gut-liver axis, although its causal role, tissue origin, and clinical utility require further validation.