Colonic Folds as Immunological and Lymphatic Hubs of the Large Intestine

Abstract The colon’s architecture features distinctive histological undulations that support fecal formation by resorbing water. While the human colon has prominent haustral and intrahaustral folds, the murine colon lacks these typical features, instead displaying consistent V-shaped luminal folds, particularly in the proximal region. Using advanced intravital and three-dimensional imaging in both murine and human tissues, we revealed a previously unknown function of these colonic folds: guiding the drainage of interstitial fluid through a specialized lymphatic network embedded within the folds. Unlike the uniform lymphatic organization in the small intestine, colonic lymphatics are spatially limited and converge within these folds. We found that these folds act as conduits for interstitial fluid, containing CD115+ phagocytes and lymphoid aggregates that coordinate antigen uptake and immune surveillance. Submucosal lymphatic vessels, closely associated with these folds, collect tissue-derived cargo and interact with local antigen-presenting cells. Intravital tracking of fluorescent tracers confirmed that interstitial flow follows distinct patterns along the folds and leads to the draining of lymph nodes, emphasizing their role in regulating fluid outflow and immune function. These immune hubs are further characterized by high endothelial venules, indicating coordinated regulation of immune cell entry, local sampling, and lymphatic exit. In murine colitis models, we observed collapse of fold structure, decreased lymphatic drainage, and disorganized phagocyte distribution. These structural changes were linked to the proximal spread of inflammation. Notably, histological analysis of human Ulcerative Colitis samples showed a striking loss of intrahaustral folds, mirroring findings in colitic mice and suggesting a conserved disease mechanism across species. In conclusion, our findings identify colonic folds as structurally and immunologically specialized regions that coordinate lymphatic drainage and macrophage-driven surveillance. Their disruption in colitis reveals a previously overlooked mechanism of inflammatory spread. By highlighting the lymphatic–phagocyte–structural axis of colonic physiology, this work opens up new opportunities to develop therapies that preserve or restore fold integrity, improve interstitial clearance, and enhance immune regulation in patients with inflammatory bowel disease.