Apr. 29, 2002 A synthetic form of bacterial DNA, when administered to mice bred to model Inflammatory Bowel Disease (IBD), reduces the harmful effects of this serious intestinal disorder while enhancing the immune system. And, because it’s a man-made version of bacterial DNA, the synthetic compound inhibits the “experimental colitis” in mice without imposing a bacterial infection.
The findings are reported in the May 2002 issue of the journal Gastroenterology, by researchers at the University of California, San Diego (UCSD) School of Medicine, Shaare Zedek Medical Center, Jerusalem, and Tel-Aviv Sourasky Medical Center, Tel-Aviv.
“We’ve shown that synthetic bacterial DNA prompts the immune system to safely respond to the onset of IBD,” said the study’s senior author, Eyal Raz, M.D., UCSD associate professor of medicine. “Previous studies have shown the beneficial effects of bacterial DNA in treating allergies, but this is the first time it has been used for bowel disease.”
The study’s first author, Daniel Rachmilewitz, M.D., professor and head of the Division of Internal Medicine at Shaare Zedek Medical Center, Jerusalem, Israel, added that the results in mice are so promising that they hope to begin human clinical trials of the synthetic bacterial DNA.
In addition to offering a potential treatment for IBD, the study supports previous findings that allergic reactions and other immune disorders may be the result of our sanitized, ultra-clean industrial world. Called the “hygiene hypothesis,” the theory suggests that vaccinations, antibiotics and sanitized living have shielded people from microbes and parasites that do little or no harm. Because human immune systems lack ‘practice’ in fighting off these common bacteria, the body’s immune response becomes overly aggressive with invading pathogens, attacking both the invader and its own tissues. This leads to the inflammation that is indicative of allergy and disorders like IBD.
“Inflammatory Bowel Disease is a disorder prevalent in the western world,” Rachmilewitz said. “While we have this disorder, you hardly see IBD in Mexico or in third world countries.”
Raz agreed with his colleague, noting that “we pay for being sterile. Bacterial DNA in your gut is good for you.”
Affecting an estimated 1 million Americans, IBD includes two closely related disorders that involve inflammation in the intestines – Crohn’s Disease and ulcerative colitis. In Crohn’s disease there is inflammation deep within the intestinal wall. Ulcerative colitis affects the tissue lining the colon. The symptoms in both diseases are abdominal pain, diarrhea and rectal bleeding.
The two disorders are considerably more serious than irritable bowel syndrome, a common intestinal condition that also causes abdominal discomfort and diarrhea. Severe cases of IBD frequently lead to patient surgery involving removal of a portion of the small intestine or all of the colon. While the cause of IBD is unknown, physicians and researchers believe the disorder is multifactorial, involving susceptibility genes and environmental factors, such as invading viruses or bacteria.
The compound used by the research team to treat the experimental colitis in mice was developed a few years ago by Raz and his UCSD team. It is a synthetic form of bacterial DNA called immunostimulatory (ISS) oligonucleotide (ODN), which is a short segment of bacterial DNA which has immunostimulatory properties.
Rachmilewitz noted that “when we test the efficacy of this treatment in human clinical trials, we hope to show that IBD patients can take an oral form of this compound once a week to prevent the flare-up periods typical of the disease.”
In the study reported in Gastroenterology, the researchers gave the ISS-ODN to mice that had developed experimental colitis, the mouse model of human IBD. Whether administered systemically or orally, the ISS-ODN ameliorated the colitis.
The researchers then determined that single administration of ISS-ODN does not provide a long-term protective effect for colitis. They induced the disease in mice, then treated it with the synthetic bacterial DNA which quashed the disease symptoms. Two weeks later, they re-introduced colitis to the mice and found that the protective effects of the ISS-ODN were gone; the disease became active again. When ISS-ODN was administered on an ongoing basis, the mice remained disease free.
May 18-22, at the annual meeting of the American Association of Gastroenterology in San Francisco, Raz and Rachmilewitz will present their findings. In addition, they will describe follow-up studies in lab cultures. The investigators took biopsies from the colons of both Crohn’s disease and ulcerative colitis human patients, placed the tissue in culture dishes and added ISS-ODN. The team noticed an impressive reduction in the generation of molecules that lead to inflammation in human tissue.
### In addition to Rachmilewitz and Raz, who is also a member of the UCSD Stein Institute on Research and Aging, additional authors of the study were Fanny Karmeli, B.SC., Leonor Leider-Trejo, M.D., Tel-Aviv Sourasky Medical Center; and Kenji Takabayashi, Ph.D., Tomoko Hayashi, M.D., Ph.D., Jongdae Lee, Ph.D., and Lorenzo M. Leoni, Ph.D., UCSD Department of Medicine.
Funding was provided by the National Institutes of Health and private grants to Rachmilewitz.
The University of California has filed for a patent on the use of ISS-ODN for IBD.
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