Investigating the lymphatic system in intestinal inflammation

We set out to understand the colonic lymphatic vasculature in the context of outflow from the colon, with the ambition of using this knowledge to develop methods to promote exit of inflammatory cells from the tissue as an alternative way to treat patients with inflammatory bowel disease. Our studies converged on the identification of tissue folds as central anatomical units that orchestrate interstitial fluid outflow from the colon. We observed that the luminal surface of the mammalian colon is characterised by undulations of the mucosa and submucosa forming tissue folds. In humans these included haustral folds and intrahaustral folds of lesser prominence between muscular bands of taenia coli. Mice lacked taenia coli and haustra but nonetheless possessed folds, especially in the proximal colon. The functional significance of these colonic tissue undulations, beyond increasing surface area for absorption, had not previously been determined. Here, through murine in vivo and 3D imaging studies, we show that tissue folds orchestrated the collection and outflow of interstitial fluid from the colon. We demonstrate that lymphatics line the base of colonic crypts and specifically branched toward the epithelium within folds. Colonic folds functioned as reservoirs feeding lymphatic and venous outflow, and phagocytic scavenging by fold-associated mononuclear phagocytes augmented this reservoir property. Colonic lymphoid follicles were enriched within these tissue folds, surrounded by lymphatics and postcapillary venules. Human colonic lymphoid follicles were likewise positioned within the elevation of tissue folds. Our findings suggest that colonic folds are distinct anatomical units conserved across species that organise uptake, immunosurveillance, and outflow of interstitial cargo, while restraining the spread of inflammation. Indeed, the loss of tissue folds during ulcerative colitis may facilitate distal-to-proximal spread of pathology.