Axonal Necrosis of Enteric Autonomic Nerves in Continent Heal Pouches Possible Implications for Pathogenesis of Crohn's Disease

OBJECTIVE Axonal necrosis was first described in samples of small intestine from patients with Crohn's disease (A.M. Dvorak et al. Hum Pathol 1980; 11:620-634). Clinically evident inflammation of continent ileal reservoirs (pouches) has clinical features that resemble Crohn's disease. Possible similarities in the pathogenesis of Crohn's disease and pouchitis were sought using ultrastructural and microbiologic tools to identify damaged enteric nerves and tissue bacteria. METHODS An encoded ultrastructural and microbiologic study of replicate biopsies from 114 samples of human intestine was done. Biopsies from ileum, colon, conventional ileostomy or continent pouch were obtained from patients with ulcerative colitis, Crohn's disease, or familial polyposis and grouped into three clinical study groups (control, normal pouch, pouchitis), based on clinical and endoscopic criteria. Biopsies were prepared for electron microscopy with standard methods; replicate biopsy samples were washed extensively before preparing cultures designed to identify aerobic as well as facultative and obligate anaerobic bacteria (Onderdonk et al. J Clin Microbiol 1992; 30:312-317). The ultrastructural diagnosis of damaged enteric nerves was based on previously published criteria for axonal necrosis (A.M. Dvorak and W. Silen. Ann Surg 1985; 201:53-63). Intergroup comparisons were tested for significance using Chi-square analysis. RESULTS The highest incidence of axonal necrosis was present in Crohn's disease control biopsies (53%), regardless of whether bacteria were present (or not) in cultures of replicate biopsies. Axonal necrosis also occurred in more ulcerative colitis and familial polyposis biopsies (regardless of biopsy site) that had positive bacterial cultures than in those that did not (p < 0.001). In addition, axonal necrosis was documented in 42% of the pouch biopsies from ulcerative colitis and familial polyposis patients, particularly in those pouches that were found to be inflamed by clinical criteria and that also had positive bacterial cultures of the biopsied tissues. Control biopsies from patients with ulcerative colitis and familial polyposis had significantly less nerve damage than pouch biopsies in the presence of positive cultures (p < 0.01). Among the clinically inflamed pouches biopsied in ulcerative colitis or familial polyposis patients, we found that none had damaged enteric nerves when bacterial cultures were negative (p < 0.005). If the presence of axonal necrosis alone was compared with the presence of undamaged enteric nerves in all biopsies from patients with ulcerative colitis, a highly significant number of ulcerative colitis biopsies with axonal necrosis occurred in pouches (72%) compared with controls (p < 0.001). CONCLUSIONS The ultrastructural finding of axonal necrosis in Crohn's disease confirms previous studies. The presence of damaged enteric nerves in patients with pouchitis provides ultrastructural support to the clinical impression of similarities between pouchitis and Crohn's disease. The association of damaged nerves and invasive bacteria in pouchitis suggests mechanistic similarities for the pathogenesis of Crohn's disease that requires further investigation.