Research paper showing a relationship between a specific bacteria and an inherited gene to ulcerative colitis

The November 9, 1996 issue of Science News magazine (vol 150, #19) has an article entitled, Gastrointestinal Blues, by Kathleen Fackelmann. It describes some recent developments in research into the causes of IBD.
One of the studies started with some genetically engineered rats that had had a human gene, HLA-B27 inserted. This gene has been linked to arthritis, the condition the scientists were interested in studying. (It's also been linked recently to susceptibility to IBD in humans.) The rats, as expected, developed arthritis. They also developed a progressive inflammation of the intestines. They had created rats with UC, by accident, which gives them an animal model with which to study the disease. The interesting thing they did next was to raise a strain of these rats in a completely sterile environment. These rats didn't develop either Arthritis or colitis, but similar rats raised in standard lab conditions, which means they were exposed to all kinds of germs, did get the diseases.

These results were published in the December 1994 Journal of Experimental Medicine by Joel Taurog, a rheumatologist at the University of Texas Southwestern Medical Center in Dallas, and his colleagues. The problem was, which germs were the culprits?

Along came a gastroenterologist at the University of North Carolina at Chapel Hill, R. Balfour Sartor, who teamed up with Taurog's group. The plan was to expose groups of rats to specific mixes of common bacteria. They picked the most common normal intestinal bacteria, and also bacteria species previously connected to gastrointestinal inflammation. Basically they had three mixes, or cocktails. One group of rats got a cocktail with normal rat gut bacteria. Another group got certain bacteria from humans with IBD. The third group got that mix, plus a specific kind of bacteria that are common to human guts and cause a colitis-like disease in guinea pigs, called Bacteroides.

Group number 1 got diarrhea. So did group number 3. Group number 2 had no significant inflammation. In fact their intestines looked as healthy as the sterile group from the previous experiments. The experiments were reported in the August Journal of Clinical Investigation. The authors' conclusion was that Bacteroides had the most impressive ability to induce colitis. When the intestinal tissue was examined microscopically, definite inflammatory cells were seen. Such cells are part of the immune system's response to infection. This fits with the theory that colitis is an auto-immune disorder. It is speculated that in people with the HLA-B27 gene, white cells recognize Bacteroides in the gut, and their immune response leads to the production of natural chemicals that inflame the intestines.

In the article, Sartor stresses that HLA_B27 is a normal gene, not a mutation. The HLA genes are known to regulate the immune system, but no one knows how HLA-B27 may create a vulnerability to colitis and arthritis. He and his colleagues have begun research into possible therapies. In unpublished research they describe giving Bacteroides-killing antibiotic, metronidazole, to rats with inflamed intestines. This significantly calmed the colon inflammation. It's not clear whether similar treatment would work in humans. One question is whether the Bacteroides would develop resistance to an antibiotic, which would foil any long-term treatment. One possible way around this would be to kill the Bacteroides and then introduce another bacteria that would occupy the same niche in the gut's ecology. They're looking at Lactobacillus as a candidate.

The article goes on to talk about the research around Mycobacterium paratuberculosis. In the late 1980's some Crohnies were treated with drugs aimed at mycobacterial infection but generally showed no improvement. Most researchers ruled out that organism as the cause of CD after that study was published. A more recent study, by Robert J. Greenstein at the Veterans Affairs Medical Research Center in New York, reported in the Sept 3 Proceedings of the National Academy of Sciences does show a connection, though, and presents what is considered a controversial explanation for the disparity in the studies. The authors suggest that there are two forms of Crohn's Disease.

One is a less severe, or indolent form. This form, according to their theory, results when a patient's immune system succesfully fights off an infection by M. paratuberculosis. The infection starts with an inflammation but ends with scarring that results in obstruction.

The other form of the disease is more aggressive, often leading to abnormal pockets in the intestine or even a perforation of the intestinal wall. This form of CD happens when the immune system can't fight off the bacterial infection. So goes the speculation. The evidence for the two forms of CD was presented in the Dec 20, 1994 Proceedings of the National Academy of Sciences. In this article, they show that people with the indolent version of CD mount a stronger inflammatory response than those with the aggressive version. The researchers believe that the immune system's response plays a significant role in the development of the disease, but do not implicate HLA-B27.

Dr. Greenstein suggests that antimicrobial drugs might be effective for people with the aggressive form, but probably not those with the less aggressive form, whose infection has probably already cleared. Those people might benefit from therapy designed to prevent scarring. He says that the earlier studies made no distinction between the two forms.

Reaction to this latest report has been very sceptical. Most critics say they just need more data to prove their point, like a large-scale study that would examin the two forms of the disease separately. Greenstein mentions the Helicobactor pylori connection to peptic ulcer disease, and the reported link between exposure to the measles virus and increased risk of CD, as previous examples of dubious theories that are now well-accepted.

Of course, the bottom line in all of this is, it will take years before such investigations yield a practical solution to those of us with these diseases.
TYPE GASTROINTESTIONAL BLUES BY KATHLEEN FACKELMANN IN THE SEARCH WINDOW OF GOOGLE FOR MORE INFORMATION.



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