lymphangitis, 4 the latter often underappreciated. In the past, an experimental animal model of "regional enteritis" was created by injecting sclerosing agents into regional intestinal lymphatics. The result was segmental bowel wall thickening, sclerosis, granulomas, mucosal ulcerations, and fistulas. 5 A number of important features of CD are well-recognized elements of infectious small bowel diseases, such as, salmonellosis, Yersinia infections, and tuberculosis. The earliest lesions in these diseases occur in the lymphoid follicles of Peyer's patches. These "tonsils" of the lower gut are concentrated in an incomplete circumferential ring at the distal end of the ileum, and distributed at "skip" intervals in more proximal intestine. 6 Bacteria and viruses are taken up regularly by the M cells in the epithelium overlying the lymphoid follicles, for the sampling of antigens that occur in the intestinal lumen. Many organisms use Peyer's patches as portals of entry, including even the prions of transmissible spongiform encephalopathies. Thus, the place of onset and the distribution of lesions suggest that CD is microbial in origin. Loop-to-loop adhesions, localized peritonitis, abscesses, granulomas, and fistulas are all evidence of bacterial invasion.
What causes us to doubt that bacteria are the primary causative agent of CD is the failure to reproduce disease by animal inoculation (a standard method for the demonstration of bacterial diseases), failure to consistently culture a pathogen from diseased tissue, failure to find antibodies or cell-mediated immunity against a causative bacterium, and failure to cure with short or even long courses of antibiotics. There is also the absence of a spontaneously occurring animal model. Spontaneous regional enteritis of pigs is bacterial in origin and has many features of CD, 7 but few investigators recognize the comparative aspects of the disease or study its origins and pathogenesis.
Attempts to find bacteria that might be responsible for CD have yielded conflicting and controversial results. Polymerase chain reaction (PCR) seems to have compounded the problem, with various laboratories reporting positive evidence of M. paratuberculosis, Yersinia, Listeria, and Escherichia coli. Results cannot be confirmed among laboratories, and when broad-based searches for 16S rDNA are done on tissues, none, save perhaps E. coli, can be demonstrated. This author has reviewed the many reasons why Johne's disease and CD are not equivalent, 8 and recently suggested that E. coli may be the most relevant bacterium demonstrated in CD. 9 There is evidence that some strains of E. coli induce lepromatous granulomatous disease, of meninges, urinary tract, intestine, and gall bladder. In Hjarres disease of fowl the intestinal response to E. coli is tuberculoid granulomas. 9 Immunohistochemistry has demonstrated E. coli antigen in the diseased tissues of patients with CD, 10 E. coli DNA has been detected in microdissected granulomas, 11 and patients have been shown to have higher antibody titers and titers directed against a greater variety of E. coli than in controls. 12 The age of onset of CD prompts consideration of the viruses of adolescence, i.e., those responsible for tonsillitis, appendicitis, mononucleosis, and Hodgkin's disease. Given the age group affected most frequently, it may be important to recognize the possibility that CD could be the result of 2 pathogens, a persistent or recurring virus, which initiates disease (with a short episode of gastroenteritis) and then flares in activity from time to time, and an E. coli of the granuloma-inducing kind. Such 2-pathogen sequences are well recognized in pneumonias of all species, albeit these being acute, and in chronic respiratory disease of fowl, in which a respiratory coronavirus or paramyxovirus is accompanied and abetted by E. coli. 13 Antibiotics help patients with CD and there may be resolution of some clinical manifestations, but antibiotics do not cure the condition. A persistent viral agent such as Epstein-Barr virus (EBV), or one that commonly recurs, such as influenza or the enteroviruses, may ultimately be shown to initiate CD. That multiple cases occur within families and even in spouses suggests exposure to a shared environmental agent. 14 