Mesenteric Lymphatic Dysfunction as the Initiating Event in Crohn's Disease: Toward an Outside‐In Paradigm

ABSTRACT Crohn's disease (CD) has traditionally been explained by an “inside‐out” model, in which disruption of the intestinal mucosal barrier allows luminal bacteria to invade the bowel wall and trigger transmural inflammation. This concept has supported therapeutic strategies that emphasize mucosal healing. However, accumulating pathological and anatomical evidence suggests that the earliest abnormalities in CD may arise outside the mucosa, particularly within the mesenteric lymphatic system. In this review, we reconsider the pathogenesis of CD and propose an alternative “outside‐in” model, in which intestinal inflammation is initiated by mesenteric and subserosal lymphatic dysfunction. Histopathological studies have demonstrated that lymphatic vessel dilation, obstruction, and granulomatous inflammation frequently occur in the subserosal layer along the mesenteric border, even in macroscopically normal intestinal segments. These findings suggest that mucosal lesions are secondary changes following lymphatic injury. The segmented architecture of intestinal lymphatic drainage also explains the characteristic skip lesions of CD, as localized lymphatic dysfunction can generate regionally confined inflammation. Genetic susceptibility pathways related to bacterial recognition, autophagy, and lymphangiogenesis intersect with lymphatic endothelial biology, promoting lymphatic stasis and immune activation. Mesenteric adipose tissue, particularly creeping fat, further amplifies inflammation through immunometabolic interactions with lymphatic vessels and immune cells. Collectively, these observations support the concept that mesenteric lymphatic dysfunction plays a central role in initiating and sustaining CD. The proposed outside‐in model provides an integrated framework that links lymphatic injury, transmural inflammation, and mesenteric pathology and highlights the mesenteric lymphatic system as a potential therapeutic target in CD.