It can involve the entire gastrointestinal tract, and although its prevalence is rapidly increasing its etiology remains unclear. Emerging biological and small-molecule drugs have advanced the treatment of CD; however, a considerable proportion of patients are non-responsive to all known drugs.
To achieve a breakthrough in this field, innovations that could guide the further development of effective therapies are of utmost urgency. In this review, we first propose the innovative concept of pan-lymphatic dysfunction for the general distribution of lymphatic dysfunction in various diseases, and suggest that CD is the intestinal manifestation of pan-lymphatic dysfunction based on basic and clinical preliminary data.
The supporting evidence is fully summarized, including the existence of lymphatic system dysfunction, recognition of the inside-out model, disorders of immune cells, changes in cell plasticity, partial overlap of the underlying mechanisms, and common gut-derived fatty and bile acid metabolism. Another benefit of this novel concept is that it proposes adopting the zebrafish model for studying intestinal diseases, especially CD, as this model is good at presenting and mimicking lymphatic dysfunction.
More importantly, the ensuing focus on improving lymphatic function may lead to novel and promising therapeutic strategies for CD. Core Tip: The lymphatic system plays an active role in the pathogenesis, progression, and complications of certain diseases. The lymphatic system in humans consists of lymphatic vessels and lymphoid tissues and organs, allowing the unidirectional transport of fluid, cells, and molecules[ 1 ], and thereby playing a functional role in fluid homeostasis, immune cell trafficking, and lipid absorption[ 2 , 3 ].
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Lymphatic system dysfunction has been demonstrated in various conditions including obesity, cardiovascular disease, chronic inflammation, atherosclerosis, neurological disorders, hypertension, and elephantiasis[ 4 , 5 ]. Recently emerging novel technologies, such as single-cell analysis and intravital imaging, have revealed novel characteristics of lymphatic dysfunction in various diseases and the extensive heterogeneity of lymphatic vessels[ 6 ].
