The path to Crohn's disease: is mucosal pathology a secondary event?

Current models of Crohn's disease (CD) invoke an initial disturbance of the epithelial interface between the gut mucosa and intestinal microbiota. This "outside-in" paradigm, mirroring the pathophysiology of acute gastroenteritis, suggests that mucosal damage by luminal bacteria is an early, initiating factor in the etiopathogenesis of disease. However, a number of features of CD argue against a primary mucosal process, including phenotypic studies of CD patients that point to a macrophage defect and genetic studies that predict impaired innate immunity to intracellular bacteria. Intracellular pathogens, such as Listeria, Salmonella, and Mycobacteria, invade via the gastrointestinal tract with minimal or no acute mucosal pathology. These organisms then infect and persist in lymphatic tissues before inducing pathology, in the gut or elsewhere, as a secondary process. In a disease resulting from impaired macrophage responses to intracellular pathogens, mucosal damage could instead represent a terminal event in the pathogenesis of disease. Such an "inside-out" model is also compatible with observations on postoperative disease relapses where subepithelial pathology precedes ulceration. This alternative disease paradigm suggests that clinical and experimental research efforts should be directed at deeper processes in the gut wall and attached mesentery to understand how intracellular bacteria could initiate or exacerbate this chronic inflammatory disease.