Though it has long been recognized that the liver exhibits remarkable immune tolerance, the underlying mechanisms driving this phenomenon remain poorly understood. Here, we explore the liver’s unique immune tolerance—a critical feature that enables it to process gut- and diet-derived inflammogens without eliciting excessive inflammation. We propose that entero-pancreatic peptide hormones (e.g., GLP-1, GIP, CCK, glucagon, VIP, amylin) and postprandially reabsorbed bile acids (BAs), delivered at high concentrations via the portal vein, activate G protein-coupled receptors and trigger cAMP signalling pathways that ultimately promote anti-inflammatory responses through mechanisms such as PKA–CREB and Epac activation. These pathways have been implicated in suppressing inflammation, and fostering a tolerogenic phenotype in resident immune cells.
The liver’s tolerogenic environment, shaped by these endocrine factors, may help explain its reduced rates of transplant rejection as well as its susceptibility to certain pathogens and metastatic cancers. However, this tolerance also poses challenges for the treatment of liver infections and metastases, suggesting potential strategies to therapeutically modulate it. Conversely, leveraging this mechanism could inspire novel anti-inflammatory therapies or “immunologically veiled” gene-edited tissue grafts.
These observations are particularly relevant to the development of GLP-1–based therapeutics and emerging multi-agonists (e.g., targeting glucagon, GIP, and amylin receptors), which all engage similar cAMP-mediated endocrine signalling pathways. This could help explain their broad therapeutic potential across various disease settings beyond diabetes and obesity, as many of these conditions also involve inflammatory components. It also raises the question of whether these hormones could promote immune tolerance in autoimmune diseases, support transplant acceptance, or ameliorate immune dysfunction at the placental interface (e.g., in pre-eclampsia).
Finally, many unanswered questions remain. For instance, other feed/fast endocrine responses (e.g., ghrelin, FGF21, and growth hormone) also regulate immune function, suggesting a much broader role for integrating nutritional cues with immune regulation. These observations also raise questions about how dietary interventions exert their effects via endocrine mediators.

DOI:10.1093/procel/pwaf096