Molecular biology of Crohn's disease mycobacteria.

A Glasgow surgeon, T.K. Dalziel, published a detailed description of chronic enteritis in humans in 1913. He proposed that the disease was caused by the same organisms as those responsible for chronic enteritis, Johne's disease, in animals described a few years earlier (1895). Dalziel's dilemma was that he could see acid-fast bacilli in the diseased animal tissues but not in the diseased human tissues. Little real progress in the medical understanding of the causes of chronic enteritis in humans occurred over the next half a century or more. From 1978, a decade of research in many laboratories using improved methods for the culture of environmental mycobacteria showed that these could be grown in bacillary form from about one in five cases of Crohn's disease, from the same proportion of cases of ulcerative colitis, and from about one in ten control tissues. Spheroplasts were grown from two in five cases of Crohn's disease, one in five cases of ulcerative colitis, and rarely from control tissues. The nature of these agents was often uncertain. We describe work which began in 1985 and led rapidly to the identification of IS900, a DNA repetitive element in an uncharacterized Crohn's disease mycobacterial isolate. With other isolates, these were then shown by DNA fingerprinting to be indistinguishable from Mycobacterium paratuberculosis, Johne's bacillus. Similar techniques also demonstrated the wood-pigeon strain of M. avium in some Crohn's disease cultures. This bacillus can also cause chronic enteritis in calves. IS900 is the first of a family of unusual DNA insertion sequences which extend widely throughout environmental mycobacteria. Use of assays based on PCR amplification of highly specific DNA sequences from these insertional elements, and recombinant and synthetic peptides from their predicted proteins, will revolutionize the detection and characterization of these agents. These methods, applied to animal, human and environmental samples, will indicate new ways for the prevention and treatment of chronic enteritis, as well as other disorders associated with infections by environmental mycobacteria.