A small but increasing number of researchers and clinicians are focusing intense research efforts on a microorganism, called Mycobacterium avium paratuberculosis (MAP), which may be a key player in Crohn's disease in some individuals.
For over a century, scientists have debated whether bacteria were involved in Crohn's but they lacked substantiating scientific proof to support the claim. Recently, however, advances in diagnoslic technology have enabled scientists to detect the presence of MAP bacteria in the tissues of Crohn's patients, paving the way to medications targeting the invading bacteria. In Europe, Australia, and the United States, researchers are conducting clinical trials using antibiotics to kill the bacteria and reporting positive results.
"Two decades ago, another researcher challenged conventional wisdom by claiming that the bacterium Helicobacter pylori, not stress, caused most forms of ulcers--a theory that revolutionized ulcer treatment and dramatically improved the quality of li fe for millions of sufferers.
"The H. pylori experience has taught us that the underlying cause of disease we are taught by our mentors may not turn out to be the real etiology," says Toro Borody. M.D., a leading researcher in gastroenterological disorders at the Digestive Diseases Centre in Sydney, Australia. "I was taught that ulcers are caused by an excess of acid and aggravated by stress. We now know that the majority of ulcers are caused by a simple but chronic infection which is difficult to eradicate and requires triple therapy, which still may not be completely successful."
To learn more about recent developments on the role of MAP in Crohn's disease, the Post interviewed Dr. Saleh A. Naser, associate professor of molecular biology and microbiology at the University of Central Florida. Dr. Naser is collaborating with gastroenterologist Ira Shafran on a study using a novel blood test to identify Crohn's patients. By monitoring the impact of antibiotic therapy, they hope to keep patients' Crohn's disease in check.
Post: Would you tell us about the blood test you recently developed, and how it may help patients with Crohn's?
Naser: What causes Crohn's disease remains controversial. There are several schools of thought. One gaining momentum and receiving increased respect by gastroenterologists and experts in the field is the role of Mycobacterium avium subspecies paratuberculosis (MAP) in the disorder. There is a great similarity in terms of symptoms and pathology between Crohn's disease in humans and Johne's disease, also known as paratuberculosis, in animals. This has been acknowledged for more than 100 years now. In animals, the MAP bacterium has been cultured, and the microorganism can be observed following 8 to 12 weeks of incubation in culture media. However, in humans, it is a different story. The outcome of many studies attempting to isolate and culture MAP from tissue has been inconsistent and obviously became controversial.
I was very determined to understand the nature of MAP in human tissue, hoping to develop a simple, specific and accurate test for diagnosis of MAP in Crohn's disease tissue, if present. We tried different culture media and experimented with different additives. We struck gold when we identified a modified culture media developed by Becton Dickinson supplemented with some of our derivatives. We were able to culture, isolate, and identify MAP in human tissue from Crohn's disease patients following 10 to 12 weeks of incubation. Of course, this is considered a breakthrough compared to earlier reports where months or two years were needed to identify MAP in culture media. We presented and published our work, which also was shared with other laboratories. We were very pleased to see our work confirmed when other investigators reported success in the Journal of Clinical Microbiology and other publications.
Post: What are your major findings?
Naser: The most significant finding came out of our lab at the University of Central Florida two years ago when we successfully isolated MAP from breast milk obtained from young lactating mothers with Crohn's disease. This alone provided a critical piece of the puzzle regarding the involvement of MAP in Crohn's disease etiology. In animals, MAP is known to infiltrate through the lymphatic system and appears in the milk. It iss also well known that young calves get infected through milk red from their mothers. What that means in terms of human milk and breast-feeding by a Crohn's disease mother remains to be answered. More studies are needed to elucidate this.
Regarding our test, we also have been working with colleagues at Baylor College of Medicine on the development of a blood test for an easier way to diagnose inflammatory bowel disease--specifically to distinguish Crohn's disease from others. We developed a couple of proteins, known as p35 and p36, and now we are in the process of using them in a quantitative immunologic assay for testing the presence of MAP antibodies in sera, or blood, from patients with Crohn's disease. Obviously, this will go a long way toward diagnosing and monitoring treatment in patients with this disease. The idea of a blood test for MAP originally came from the idea that if Crohn's disease is caused by MAP, anti-MAP antibodies should naturally be present in patients' blood. Our data have shown so far that at least two thirds of CD patients have antibodies to MAP, compared to 25 percent of non-Crohn's patients. Ultimately, testing can be used to screen patients' blood for choosing the best treatment protocol, such as using anti-MAP antibiotics. We can then test the blood before, during, and after the treatment for monitoring anti-MAP antibodies.
Post: Are you testing only Crohn's patients?
Naser: We are doing random blinded testing. Recently funded by the NIH, we are comprehensively looking at Crohn's disease etiology. The participating subjects in our study vary from patients with Crohn's disease, ulcerative colitis, irritable bowel syndrome, colon cancer, celiac disease, or other GI disease.
Our samples are blindly coded. The main goal is to seek those patients who are scheduled for surgery for possible tissue removal. We require full-thickness, surgically removed tissue along with a blood sample from each subject. In our lab, we look at the tissue in a comprehensive way. We use it for culturing the MAP bacteria, to study it under laser microscopy using fluorescence labeling tags, and we also do PCR [polymerase chain reaction], a fingerprinting type of technique, to investigate the presence of the MAP or its derivatives. We also investigate the immune response, both the humoral and the cellular responses: the humoral by using our ELISA test for anti-MAP antibodies; the cellular by investigating the ability of the immune system to deal with MAP (if present) and what kind of immune cell activity is present in the tissue.
Post: Do you have any preliminary findings that you can share?
Naser: Our data so far suggest that there is a potential immunologic defect in Crohn's disease patients where the immune system fails to deal effectively with MAP, which consequently leads to inflammation and tissue destruction.
Post: What did you find?
Naser: If you look at the statistics and the data we have so tar, we estimate that a minimum of two thirds of Crohn's patients have MAP infection. This is based on culture, PCR and immunologic techniques. The potential of an immunologic defect in Crohn's patients' immune systems may lead to exploring a different treatment approach. Specifically, instead of using anti-inflammatory drugs on some patients, I believe treatment using granulocyte stimulating factors may be required. The use of a blood test to screen for MAP diagnosis, as well as during the treatment, will save the patients and the healthcare community significant time, effort and cost. Simply, if the patient's blood is positive for MAP, a course of anti-MAP antibiotics will go a long way toward curing, rather than managing, the disease. Anti-inflammatory and cytokine inhibitors should be wisely used and only as needed.
Post: Do you believe that an infectious agent is a cause of Crohn's?
Naser: Absolutely, I do--at least in two thirds of Crohn's patients I tested. I also would like to focus attention on a possibility of co-infection where Crohn's and ulcerative colitis diseases are present in the same patient, which may lead to a misleading outcome if Crohn's disease symptoms disappear but ulcerative colitis symptoms remain. There is also increasing evidence that some patients with irritable bowel syndrome have MAP infection. Much research remains. I hope that more investigators will study and more resources will be devoted to researching these lifetime diseases.
Post: Is genetic susceptibility also important?
Naser: Absolutely. The latest discovery of two gene abnormalities hinted at the genetic susceptibility of the host and the involvement of the germ theory (possibly MAP or others) in order to develop Crohn's disease. My own take on this is that a host susceptibility may exist in the presence of an additional (defect) adhesive protein expressed somewhere on the gastrointestinal tract. This is complementary to another adhesive protein expressed on the surface of MAP. If such a patient is exposed to MAP, naturally MAP will bind, phagocytosed [consumed] by host immune cells where MAP outsmarts the immune system and starts causing inflammation. More work is needed in order to identify persons at risk, and then alternative measures, such as a vaccine, may be used to block MAP entry to the patient's tissue.
Post: If MAP is present in pasteurized milk, should one just boil one's milk or consume the ultrahigh temperature (UHT) milk?
Naser: We don't know who is at risk. If we can identify who is genetically susceptible to MAP, we can say don't drink milk or stick with UHT milk. The current pasteurization procedure does not completely eradicate MAP from milk. In England and other European countries, they already modified their pasteurization procedure, resulting in significantly improved eradication of MAP. Current literature clearly suggests that a good percentage of U.S. cattle is infected with MAP and that a better and more modified pasteurization protocol is needed.
Boiling definitely reduces the number of viable MAP in milk; however, there is a risk of losing some of the vital nutrients. Heating the milk to a few degrees above the current pasteurization temperature may help in killing more MAP cells.
Post: Have you treated patients?
Naser: My collaborators
Dr. Ira Shafran and Dr. John Valentine in Florida have many patients on different treatment protocols. In an article published in 2003, we reported that almost 70 percent of Crohn's disease patients who were treated with RMAT (rifabutin and macrolide antibiotic therapy--Rifabutin and Biaxin) moved into remission, and many of them are still off all medications. We chose this regimen following challenges and skepticism from many gastroenterologists who claimed that they used many anti-TB drugs and their patients' conditions had not improved.
This challenge motivated me to study the efficacy of 15 anti-TB drugs against MAP that we isolated from Crohn's patients. My biggest surprise was when we observed that MAP was resistant to 14/15 drugs, which may explain why traditional anti-TB medication may not be successful in Crohn's disease treatment. Following several experiments, we ended with a cocktail of two drugs called rifabutin and macrolide antibiotic therapy (RMAT) (rifabutin [Mycobutin], and Biaxin [(clarithromycin]) that showed significant synergistic activity, and MAP was killed instantly in the tube. This experiment confirmed the first successful use of RMAT in Crohn's treatment by Professor John Hermon-Taylor in London [Mar/Apr 2004 Post]. Many patients who are visiting with Drs. Shafran and Valentine seem to be responding to the antibiotic treatment.
Post: What advice do you offer Crohn's patients?
Naser: I encourage patients to research the Internet on MAP bacterium and to talk to their physicians, because not too many gastroenterologists are aware of current literature regarding MAP involvement in Crohn's and possibly more GI diseases. There are many Web sites and much literature now available that may bring awareness about this disease. For the patients, don't settle for anti-inflammatory treatment as a first resort. Test for MAP, for immune response defect or other agents, before choosing the treatment. Regarding milk: UHT milk or heated milk may be the best choice if you are at risk. Test early and don't ignore IBD symptoms.
Florida gastroenterologist and Crohn's researcher Ira Shafran reports significant success in treating a subset of Crohn's patients with an antibiotic regimen. Susceptible patients may have picked up the bacteria from conventionally pasteurized milk or other daily products. "More and more work using sophisticated technology to identify this organism in the milk supply shows that certain cheeses, milks, and dairy products, in fact, contain the bacteria," says Dr Shafran, Health advocates advise that consuming ultra-pasteurized milk (UHT) products, boiling milk to kill the bacteria, and cooking meat well can help reduce your exposure to the bacteria.
For 18 years, Cecelia Matchett suffered from the painful, incapacitating symptoms of Crohn's. In 1999, Matchett enrolled in a clinical trial, conducted by Drs, Ira Shafran and Saleh Naser, to investigate the potential of antibiotic therapy in Crohn's patients infected with the MAP bacteria. Five years later, Matchett remains symptom-free and off Crohn's medications.
"Not only am I in clinical remission, but they tested my blood again, and my antigen response has converted back to negative," the Florida resident reports. "I am willing to tell anyone about this, because even if it only works for some Crohn's patients, it is worth it."
To help promote intestinal health, Dr Shafran also recommended that Matchett supplement her daily diet with probiotics. Probiotics are organisms--including lactobacilli or bifidobacteria, among others--that contribute to the health and balance of the intestinal tract. Probiotic supplements contain so called "friendly bacteria" that, when consumed, help maintain the inteqrity of the digestive tract, a key player in the body's immune system.
(Yield: 10 cups of milk)
1 cup of soybeans
A pitch of ginger or a slice of ginger root
Soak the soybeans with two cups of water for 4-6 hours. By then, we should have 3 cups of beans. Use mixer to grind the beans-adding 3 cups of water or the same amount of water to the beans. After grinding, drain them with cheesecloth into a pan of lukewarm water (8 cups). Squeeze the milk. Boil the milk. Keep it in the refrigerator. Milk should be good for at least a week.
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