Kennedy disease

In November 2000, German veterinarian Dr. Heinrich Dahmen began to suffer the unrelenting symptoms of severe pain, cramping, diarrhea, weight loss, and blood loss. After meeting with a gastroenterologist, Dahmen was diagnosed with Crohn's disease and started on conventional treatments for the disease, including immunosuppressive agents and the steroid prednisone.

After brief relief, Dahmen's condition worsened, and he faced invasive surgery to remove part of his inflamed digestive tract. Before undergoing the procedure, he followed up on a tip about the promising work of London investigators who were working on a new radical approach to the disorder. In July 2001, he traveled to London, where the research team found that Dahmen harbored an infectious agent believed to be involved in Crohn's disease. They began treating Dahmen with an antibiotic regimen that proved effective against the pathogen, and his condition slowly improved. Today, Dr. Dahmen is back in his busy veterinary practice, free of symptoms and feeling "cured" of the disease. Follow-up endoscopy and other tests confirm that Dahmen is in remission--his life has returned to normal.

"From that time I felt better and better," Dr. Dahmen told the Post. "I think I'm totally cured now after a two-year therapy."

In the United States, a Florida woman after years of unsuccessful treatments is also experiencing a rebirth after undergoing antibiotic therapy two years ago, which has since eliminated the unpredictable, yet ever-present pain of Crohn's disease,

On the Trail of Crohn's Disease

For decades, researchers have debated the link between an infectious agent and Crohn's, a disease that affects millions of people around the world often in the prime of life. Crohn's numbers among a group of mysterious ailments known as autoimmune disorders, where for as yet unknown reasons the body begins to attack itself, wreaking havoc on normal bodily functions. While scientists are working hard to unravel the cause, of great concern is the fact that the rates of autoimmune disorders, like Crohn's and multiple sclerosis, have more than doubled in the last four decades.

Current treatments focus on the symptoms, but do little to address the root cause of Crohn's, including the potential role of bacteria. Whether infection plays a role remains a hotly contested area among experts. The theory, however, is gaining ground as evidence mounts supporting the connection.

Infection has emerged as a causative agent in other diseases, but not without resistance. Con sider Australian researcher Dr. Barry Marshall, who faced an uphill battle when challenging the medical doctrine by suggesting that a bacterium causes most ulcers--a discovery that has changed the course of treatment and quality of life for millions, At that time, the then-radical notion and its proponents were widely ridiculed. Dr. Marshall believes that infectious agents may play a role in other diseases, including Crohn's.

"My hunch is that they are infectious diseases, and we haven't found the germ yet," Dr. Marshall said in a Post interview several years ago for the book The Saturday Evening Post Investigates Digestive Diseases.

But if a microorganism causes Crohn's, what is it and how is it transmitted?

Researchers point to a persuasive body of evidence linking the bacterium, called Mycobacterium avium subspecies paratuberculosis (MAP), to the disease and underscore the route of transmission into the human population through one of our most popular drinks--milk.

MAP infection causes a debilitating disorder called Johne's disease that commonly occurs in cattle throughout the world, including the United States. Cows with Johne's share similar symptoms to people with Crohn's. infected cows secrete the mycobacterium in their milk. Individuals with a genetic susceptibility to Crohn's may thus pick up the disease. Supporters of the theory note that Crohn's is most frequently found in developed countries where milk consumption is high, except in countries where milk is boiled prior to consumption--an extra measure of precaution that some suggest would be prudent today.

The dairy industry, however, vigorously maintains that current pasteurization techniques are adequate to eliminate the bacteria, while critics highlight studies of the milk supply where MAP survived conventional pasteurization processes. Several European countries, such as Britain, have called for more stringent pasteurization procedures to ensure eradication of the microorganisms from the milk supply.

In 2003, British scientists at St. George's Hospital Medical School in London offered more support for the link between Crohn's and the milk-borne bug. Their study reports that over 90 percent of patients with Crohn's had MAP.

"The rate of detection of MAP in individuals with Crohn's disease is highly significant," said the researchers, writing in the Journal of Clinical Microbiology. "The discovery that the MAP bug is present in the vast majority of Crohn's sufferers means it is almost certainly causing the intestinal inflammation."

Lead researcher of the study. Dr. John Hermon-Taylor, has been studying the MAP and Crohn's connection for many years and successfully treated Crohn's patients with an antibiotic regimen that is restoring health and quality of life in his patients.

The Post spoke with Dr. Hermon Taylor, chairman, department of surgery, St. George's Hospital Medical School in London, to learn more about his research into the milk and Crohn's connection, as well as how antibiotics are bringing new hope to individuals suffering from the devastating disorder.

Post: When did Mycobacterium avium subspecies paratuberculosis (MAP) emerge as a potential causative agent of Crohn's disease?

Hermon-Taylor: The idea was first suggested by Thomas Kennedy Dalziel in a paper published in the British Medical Journal in 1913. The reason that it has taken so long for the issue to become clarified is because the Mycobacterium avium subspecies paratuberculosis, or MAP, doesn't grow consistently in culture, much like the leprosy bacillus which belongs to the same family of organisms. The methods normally used for identifying a bacterium--namely, seeing it through a microscope, growing its culture, or doing a blood test for it--do not work with MAP.

Post: Endoscopy and other techniques would not detect its presence?

Hermon-Taylor: Endoscopy as done in the past wouldn't detect it, but the paper that we published in the U.S. in the July 2003 Journal of Clinical Microbiology shows that if you take endoscopic mucosal biopsies fresh from the endoscopy suite into the lab--and test them by the methods that our science has very carefully optimized and perfected--you can detect MAP with great accuracy.

Using the polymerase chain reaction (PCR) technique, you can show that virtually everyone with chronic inflammation of the Crohn's disease type is infected with the MAP bug. MAP is an organism that is a specific cause of chronic inflammation of the intestine in many different species of animals, including primates.

Post: Could you tell us about your research used to discover the bug in infected individuals?

Hermon-Taylor: We used the PCR test between 1989 and 1992 and found that about two-thirds of people with Crohn's disease were infected with the MAP bug. We published the findings in 1992 in Gut.

In 2000 I at last received a large grant from the U.K. Medical Research Council--our equivalent of the NIH in the United States. This five-year award has enabled us to go back to the beginning and really look at the methods to see why there have been so many conflicting results in the field. Apart from some people actually Just not doing the procedures properly, the main problem is that the MAP bug is present in Crohn's disease in a very tough "Teflon-coated" invisible form. Standard laboratory reagents that would break open ordinary bugs, even tuberculosis bacilli, and release their DNA don't work for MAP. We found that you had to include a special mechanical disruption step in processing the tissue sample to access MAP DNA reliably.

When we did this, we found that virtually everyone with Crohn's disease is infected with MAP. We verified this absolutely by sequencing the DNA amplification products. Furthermore, using improved liquid cultures developed by Becton, Dickinson and Company in the U.S. and applying our DNA test to the cultures, we were able to show that 60 percent of the Crohn's disease-derived cultures incubated for more than 38 weeks contained MAP growing very, very slowly.

Post: Where do the MAP bacteria originate?

Hermon-Taylor: The MAP bug belongs to the group of organisms called mycobacteria. The most notorious mycobacteria are those causing tuberculosis and leprosy. But there is another "basket" of mycobacteria called Mycobacterium avium, so called because they were first found in birds.

MAP is, however, a clandestine bug, and it can live in animals and humans for years without necessarily causing disease. But in animals who become susceptible or inherit a sus ceptibility, or in humans who become susceptible or inherit a susceptibility, MAP infection can slowly lead to the emergence of chronic inflammation of the intestine. MAP demonstrates what scientists call "tissue tropism"; that is to say, if it is inhaled or ingested, it homes in on the gut and ends up causing chronic inflammation of the intestine.

Post: Does this eventually lead to Crohn's disease?

Hermon-Taylor: Our evidence and that of others suggests that the MAP bug causes most Crohn's disease. Expressed in a different way, if there were no MAP bugs in the world, there would hardly be any Crohn's disease at all.

Post: What led to the spread of the organisms?

Hermon-Taylor: The MAP bug was first identified in 1895, causing chronic inflammation of the intestine, in a cow in Germany. What MAP has done almost certainly is to take ad vantage over the last 150 years or so of the opportunities created by the rapidly expanding human populations of Western Europe and North America. This has been accompanied by increasing populations of domestic animals. They are, after all, our food animals. Instead of each sparsely distributed family having one cow, sheep and goat, we congregate in cities, and one family owns 300 cows and 300 sheep. Crowded farm environments, particularly in temperate regions with the animals housed in winter, create biological opportunities for amplification of the MAP organisms. When circumstances provide an ecological opportunity for bacteria in this way, they undergo what is called an adaptive radiation. and they change. This has happened with the cholera bacillus, salmonella bacillus, meningitis bacillus. Helicobacter pylori bacillus, and so on. The MAP which have emerged over the last 100 years have diverged into strains that prefer to infect cows, although they can infect sheep, and strains which prefer to infect sheep but can infect cows. We have evidence of the emergence of a humanized strain of these organisms.

Post: How do MAP bugs spread into humans?

Hermon-Taylor: The herd prevalence of MAP infection--that is to say, the percentage of herds which have two or more animals infected with the MAP bug--in Western Europe and North America runs between about two and 70 percent of herds. The infection is often subclinical, so you don't know the herd is infected. There is a huge regional variation, but herd prevalence in the range of 25 to 55 percent is common. Individual animal infection rates range between about one and eight percent. What all this says is, the domestic livestock of Western Europe and North America are extensively infected with the MAP bug.

And there are wildlife reservoirs. Research in Scotland, for example, has shown that rabbits on farms with infected domestic animals get infected with MAP. The organism is amplified and shed in the rabbit pellets. Grazing cattle will not eat grass contaminated with fox or dog feces, but they eat rabbit droppings. A short-range cycle of reinfection develops. This gives the organism a further opportunity to change. In addition, MAP goes up the rabbit predator chain to the foxes, carrion birds and so on.

Infected animals secrete the organism in their milk. We showed from 1990 to 1994 that there was a very high risk in Britain, that the MAP bug was being transmitted to the human population in retail pasteurized cow's milk supplies. This has since been confirmed by research carried out for the U.K. government's Food Standards Agency. The results of the work done by Dr. Irene Grant were published in 2002 in Applied and Environmental Microbiology. Using the DNA test and our optimized methods, she found that 11.8 percent of hundreds of bottles and cartons of milk from all over Britain tested positive for the MAP bug. She actually cultured live MAP from two percent of milk samples. She DNA-fingerprinted the MAP isolates, and they were not common laboratory strains.

But because MAP is so reluctant to grow in culture, the true proportion of retail cartons and bottles of pasteurized cow's milk in Britain contaminated with live MAP is much more likely to be closer to 10 percent than two percent.

Post: Would the same hold true in the United States?

Hermon-Taylor: Research carried out by the Institute for Food Safety and Hygiene, Faculty of Veterinary Medicine at the University of Zurich in Switzerland, using the methods we provided them, found that 19.7 percent of 1,384 bulk tanks of milk from all over Switzerland tested positive for the MAP bug. Work from the Veterinary Research Institute in Brno in the Czech Republic has reproduced the U.K. work of Dr. Irene Grant and cultured live MAP from two percent of samples of retail pasteurized milk in the Czech Republic.

Given what has been found in other countries, there is likely to be a similar risk that the MAP bug is also conveyed to people in the U.S. in milk supplies.

Post: Is milk then the primary mode of transmission of Crohn's?

Hermon-Taylor: It would be a major route of transmission. Another potential route is from the environment. Unlike the tuberculosis bacillus, tough MAP bugs can survive for months or years in the environment. Organisms that survive in the environment, which are already known to cause disease in animals and humans, include organisms like Cryptosporidium and Legionella, for example. Infected animals shed millions of the MAP bugs onto pastures. We have been doing research over the past 21/2 years which shows, as you would predict, that MAP bugs are flushed into surface waters like rivers. Where a river heavily contaminated with MAP runs through a population center, there is a risk that the organisms--which will aerosol off the water--may reach the human population by inhalation.

Post: Would boiling the milk to a certain temperature kill the bacterium?

Hermon-Taylor: Yes, it would almost certainly kill

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