Revisiting the gut-liver axis: gut lymphatic system in liver cirrhosis and portal hypertension

The lymphatic vascular system runs parallel to the blood vascular system, comprising a network of lymphatic vessels and secondary lymphoid organs. The intestinal lymphatic capillaries (lacteals) and the associated collecting vessels in the mesentery form the gut lymphatic system. The gut lymphatic vasculature comprises the longest-studied lymphatic vessel bed and plays a significant role in the uptake and transport of dietary fat, abdominal fluid balance, and gut immunosurveillance. Gut is closely connected to liver through the portal circulation. In several experimental and clinical studies, the "gut-liver-axis" has been demonstrated to contribute to the pathogenesis of portal hypertension, liver cirrhosis, and its complications. Given a significant impact of gut health on the liver, in the current review, we highlight "gut-liver axis" in context to the circulatory physiology of gut lymphatic vessels. Despite their paramount importance in maintaining fluid and immune homeostasis in the gut, gut lymphatic vessels remain one of the most understudied physiological systems in liver disease pathology. In the current review, we delineate the connections of gut lymphatics with abdominal fluid homeostasis and bacterial translocation in the pathogenesis of liver cirrhosis and portal hypertension. We describe mechanisms and factors that drive gut lymphangiogenesis and lymphatic vessel dysfunction during inflammation. The review also underscores the role of gut lymphatic endothelial cells in regulating gut and liver immunity. We finally discuss the prognostic and therapeutic prospects of studying gut lymphatic vessels in advanced liver cirrhosis.