Peptide hormones and bile acids shaping immune tolerance of the liver: implications and applications

Postprandially reabsorbed bile acids, along with various peptide hormones released following a meal, orchestrate complex events associated with digestion and prepare the body for the disposal of incoming nutrients by regulating metabolism. Interestingly, these factors have also been shown to modulate immune function. For example, recent interest in weight-loss agents such as semaglutide has demonstrated their ability to attenuate inflammation and provide benefits in diverse clinical contexts characterized by inflammatory responses. This raises an important question: why do hormones with well-established roles in digestion and metabolism also influence immunity? Here, we propose that the immune-regulatory activity of peptide hormones, together with postprandially reabsorbed bile acids, contributes to another remarkable phenomenon: the exceptional immune tolerance of the liver. While it is well established that the liver is an immunologically tolerant organ, the precise mechanisms underlying this skewed immunological tone remain poorly understood. Hepatic immune tolerance has generally been considered an intrinsic property of the liver, arising from autonomous mechanisms. Here, we highlight that various entero-pancreatic endocrine factors delivered to the liver via the portal vein activate cAMP signalling, thereby promoting immune tolerance and attenuating inflammatory tone within the liver. Critically, because these endocrine factors reach the liver at elevated concentrations through the portal vein before dilution in the systemic circulation, they profoundly shape the hepatic immune environment. Physiologically, this system ensures that the liver tolerates diet- and gut-derived inflammogens. Finally, we discuss several implications of this mechanism.