Microbial cues and T cell immunity: deciphering their interactions in chronic liver disease

Chronic liver disease (CLD) poses a major global health challenge, as its progression to cirrhosis and hepatocellular carcinoma significantly contributes to worldwide morbidity and mortality. Mounting evidence has identified the gut microbiota as a critical modulator of CLD progression, primarily via the gut-liver axis. The liver is continuously exposed to gut-derived signals through the portal circulation, while reciprocally secreting bioactive mediators that shape intestinal microbial composition and function. This bidirectional network enables intricate crosstalk between the gut microbiota and the host immune system. In particular, T lymphocytes, the central effectors of adaptive immunity, are tightly regulated by gut microbiota and their metabolites. Conversely, T cells also modulate the gut microbial ecosystem. Herein, we summarize current knowledge on this bidirectional crosstalk, focusing on how gut microbiota shape T cell differentiation, function and plasticity, as well as the reciprocal impact of T cells on the gut microbiota. Furthermore, we evaluate how these interactions influence the development and progression of various CLDs, including autoimmune liver diseases, alcohol-associated liver disease, metabolic dysfunction-associated steatotic liver disease and viral hepatitis. Finally, we discuss the therapeutic potential of targeting gut microbiota-T cell interactions through immunomodulatory and microbiota-directed strategies to offer novel therapeutic approaches.