In this study gnotobiotic mice were inoculated with a human isolate of Mycobacterium paratuberculosis (strain Linda; ATCC 43015) in an attempt to investigate the pathogenesis of intestinal paratuberculosis. Mycobacterium paratuberculosis-monoassociated nu/+ mice developed a persistent low-level intestinal infection but did not support progressive bacillary multiplication. In contrast, monoassociated nu/nu mice eventually harbored approximately 10(7) M. paratuberculosis per g of intestinal tissue. Acid-fast bacilli and granulomas were observed in the intestinal mucosa and livers of nu/nu but not nu/+ mice. Similar results were obtained after intragastric inoculation of M. paratuberculosis into nu/+ and nu/nu flora-defined mice. These observations suggest that the presence of an intact cellular immune system is important for limiting intestinal multiplication of M. paratuberculosis. The results of this study may be relevant to our understanding of the pathogenesis of Johne's disease in ruminants and of human inflammatory bowel diseases that have a mycobacterial etiology (e.g., some cases of Crohn's disease and Mycobacterium avium-Mycobacterium intracellulare enteritis in patients with acquired immunodeficiency syndrome).