Crohn's and Mycobacterium avium paratuberculosis IBD link?

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Crohn's and Mycobacterium avium paratuberculosis IBD link?

Postby malernee » Wed Jan 26, 2005 8:34 pm

Crohn's and Mycobacterium avium paratuberculosis (MAP):
Is There a Link?

It was in 1932 that Burrill B. Crohn, MD, and his two colleagues published their landmark paper describing the features of the condition we now know as Crohn's disease. But more than 70 years later, we still don't know what causes this chronic intestinal inflammation that affects as many as half a million Americans.

Most experts think that there is a multifactorial explanation behind Crohn's disease, a number of circumstances working together to bring about the illness—including these top three suspects:
• Heredity
• Something in the environment
• An inappropriate reaction by the immune system

Here's the probable scenario: It appears quite likely that one or more genes that an individual has inherited set the stage for the development of Crohn's disease. The next requirement is some sort of environmental "trigger." This could be a virus or a bacterium, but not necessarily. Whatever it is, it prompts the person's immune system to "turn on" and launch an attack against the foreign substance. That's when the inflammation begins, damaging the intestines and causing the symptoms of Crohn's disease. Not only may the environmental trigger fire up the process, it may also be involved in maintaining the chronic inflammation. Unfortunately, the immune system perpetuates the process; it cannot "turn off."

Tracking down the trigger
As early as 1913, scientists began to look at one potential trigger in particular. This is a species of bacteria called Mycobacterium avium subspecies paratuberculosis, or MAP for short. The organism is closely associated to the mycobacterium that causes tuberculosis; it is more remotely linked to the one that causes leprosy.

In animals, MAP is responsible for an intestinal illness known as Johne's disease. Johne's disease is found principally in cattle, affecting as many as 40% of the herds in the United States—a number that appears to be on the rise. Johne's disease also has been seen in sheep, goats, elk, bison, and even primates. The infection tends to be silent for a long period of time; the animals eat and appear to be well. Eventually, though, they develop diarrhea and their condition goes into a downward spiral.

The silent phase of the disease means that cows infected with MAP may continue to provide milk for human consumption. Of interest is the fact that Crohn's disease is found most often in developed countries, which also are the ones in which milk consumption is highest. In theory, pasteurization should kill the bacterium. However, some strains of MAP evidently can survive the process.

Some strong resemblances
Although it is not identical to Crohn's disease in humans, Johne's disease does share a number of similarities. Here are some of the common characteristics:

• Animals with Johne's and people with Crohn's suffer from persistent
diarrhea, malabsorption, and weight loss
• Both diseases tend to begin in childhood or early adulthood
• Both conditions largely affect the ileum
(the lower part of the small intestine)
• Johne's and Crohn's cause comparable injury to intestinal tissue
(such as granulomatous lesions)

It was those similarities that prompted some researchers to regard Crohn's as an infectious disease and MAP as the probable cause. In fact, what is now known as Crohn's disease was at one time referred to as "intestinal tuberculosis." It wasn't until 20 years ago, though, that investigators were able to culture MAP in the intestinal tissue of people with Crohn's disease—lending the MAP theory more credibility. But that's hardly the end of the story, and this discovery has generated two decades of heated scientific discussion.

More questions than answers
Several issues appear to challenge the role of MAP as a causative agent in Crohn's disease. For example, there is the milk connection. If it is true that people develop Crohn's disease after drinking milk from MAP-infected cows and also true that many thousands of cows are infected, why then don't more individuals have Crohn's?

Another problem is that some but not all attempts to culture MAP from Crohn's patients have been successful. A further complicating factor is that MAP also has been isolated in people who do not have Crohn's disease, which calls into question the accuracy of a positive mycobacterial culture finding. Even more sophisticated methods—such as the use of polymerase chain reaction technology to detect the DNA of MAP—have yielded conflicting results. Although MAP DNA has turned up in a fairly high percentage of people with Crohn's disease, it has been found in unaffected individuals as well.

Doctors, both in this country and abroad, who maintain that MAP is responsible for Crohn's disease point to the success they have achieved using antimycobacterial therapy—usually a combination of drugs that may include rifabutin and clarithromycin—to treat their patients. These physicians claim that the medication "cocktail" causes the inflammation to abate and the symptoms to resolve. But that's easily explained, according to other specialists who find flaws with the MAP explanation. A number of those antimycobacterial drugs are broad-spectrum antibiotics that are effective against a wide variety of bacteria in the gut, not just MAP. Any one of these bacteria could also be responsible for Crohn's.

Moreover, not all studies have shown clinical improvement with antimycobacterial therapy. Several "open-label" trials (ones in which specific therapeutic regimens are being tested) have had positive results, but findings from randomized trials have been less convincing. Randomized trials are used to directly compare two or more treatment groups, with patients chosen arbitrarily to be in those groups.

Another strike against the MAP theory is the response of Crohn's disease to immunosuppressive medications such as azathioprine, 6-mercaptopurine, methotrexate, or infliximab. Such medications often increase the risk of reactivation of latent infections with viruses such as cytomegalovirus or, more importantly, mycobacteria such as the one that causes tuberculosis. Indeed, physicians typically obtain a skin test for TB and a chest x-ray prior to administering infliximab, to minimize the chance of causing widespread reactivation of tuberculosis, a serious infectious complication. If Crohn's were caused by a mycobacterium, wouldn't patients significantly worsen after receiving infliximab?

Where we stand now
These inconclusive findings lead many investigators to view the role of MAP in Crohn's disease with considerable reservations, particularly when other contributing factors—such as genes and a probable malfunction in the immune system—are taken into consideration.

Crohn's and Colitis Foundation of American
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