Implications of lymphatic alterations in the pathogenesis and treatment of inflammatory bowel disease

Inflammatory bowel disease (IBD) is characterized by intense immune dysregulation, gut microbiota imbalance, and intestinal epithelium destruction. Among the factors that contribute to the pathogenesis of IBD, lymphatics have received less attention, hence less studied, characterized, and explored. However, in recent years, the role of the lymphatic system in gastrointestinal pathophysiology continues to be highlighted. This paper examines the implications of lymphatic changes in IBD pathogenesis related to immune cells, gut microbiota, intestinal and mesenteric epithelial barrier integrity, and progression to colorectal cancer (CRC). Therapeutic targets of lymphatics in IBD studies are also presented. Available studies indicate that lymph nodes and other secondary lymphatic tissues, provide highly specialized microenvironments for mounting effective immune responses and that lymphatic integrity plays a significant role in small intestine homeostasis, where the lymphatic vasculature effectively controls tissue edema, leukocyte exit, bacterial antigen, and inflammatory chemokine clearance. In IBD, there are functional and morphological alterations in intestinal and mesenteric lymphatic vessels (more profoundly in Crohn's disease [CD] compared to ulcerative colitis [UC]), including lymphangiogenesis, lymphangiectasia, lymphadenopathy, and lymphatic vasculature blockade, affecting not only immunity but gut microbiota and epithelial barrier integrity. While increased lymphangiogenesis is primarily associated with a good prognosis of IBD, increased lymphangiectasia, lymphadenopathy, and lymphatic vessel occlusion correlate with poor prognosis. IBD therapies that target the lymphatic system seek to increase lymphangiogenesis via induction of lymphangiogenic factors and inhibition of its antagonists. The resultant increased lymphatic flow coupled with other anti-inflammatory activities restores gut homeostasis.