| Causes of Crohn's Disease |
| Written by Samuel Blue | |
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The exact cause of Crohn's disease is still unknown, although more and more details are emerging. Research has shown conclusively that the disease has a genetic component; it runs in families and those with a sibling with the disease are 30 times more likely to develop it than the normal population. Some ethnic groups, notably Eastern European Jews, appear to be genetically predisposed to Crohn's because of inherited mutations in the CARD15 gene (also known as the NOD2 gene). Even so, people who have the mutation have a very low probability (approximately 1:200) of getting the disease. In earlier studies, only two genes were linked to Crohn's, and scientists believed that among people with mutations in those two genes, a variety of pathogenic bacteria could directly cause the disease. The disease appears now to be far more complicated than that. In contrast to the classic view of Crohn's as an allergic reaction, in which the immune system goes into overdrive, another, more recent hypothesis about the origins of the disease -- based on the findings described above -- is that Crohn's patients are born with genetic mutations which, when combined with a "perfect storm" of environmental factors, actually causes the machinery of the immune system to malfunction. Crohn's disease, therefore, is an innate immune deficiency, in which the body compensates for the reduced function of the immune system by developing adaptive immunity in the form of an over-active Th1 cytokine response. In some cases the side effect of this "adaptive immunity" is chronic intestinal inflammation. More specifically, among people with Crohn's disease, genetic mutations have caused the protective layer of mucus in the walls of the intestinal tract to be underdeveloped, or abnormally thin and weak. A variety of microorganisms take advantage of their host's weakened mucosal layer by multiplying in large numbers, and as a result, Crohn's patients have a difficult time clearing bacteria from the intestinal walls, and produce more cytokine to combat them, thus causing intestinal inflammation. Simply put, healthy people have millions of bacteria in their digestive systems that help them process the food they eat. Their immune systems keep these useful intestinal microbes under control, preventing them from spreading to other parts of the body where they will cause harm rather than do good. Crohn's patients have the same intestinal microbes as healthy people, but their immune systems are too weak to prevent those microbes from multiplying in the intestine until they cause chronic inflammation. The most recent gene to be implicated in Crohn's disease is ATG16L1, which may induce autophagy and hinder the body's ability to attack invasive bacteria. As a result, bacteria in the colon multiply and cause inflammation. An increasing body of evidence in favor of this hypothesis suggests that Crohn's disease results not from the overactive immune response, but rather from impaired cytokine secretion by macrophages as a result of a mutation on ATG16L1. When scientists combined results from genetic data with the direct assessment of patient immunity, they found that Crohn's patients were born with compromised immune systems with a greater-than-normal likelihood of malfunctioning. Scientists now believe there are over thirty genes that play a role, either by causing Crohn's directly, or by acting as a mediator variable that increases the likelihood of other genes causing the disease. For example, anomalies in the XBP1 gene have recently been identified as a factor, pointing towards a role for the unfolded protein response pathway of the endoplasmatic reticulum in inflammatory bowel diseases. Other studies have suggested that Mycobacterium avium subspecies paratuberculosis plays a role in Crohn's disease, in part because it causes a very similar disease, Johne's disease, in cattle. The mannose bearing antigens (mannins) from yeast may also elicit an antibody response. Other studies have linked specific strains of enteroadherent E. coli to the disease. Still, this relationship between specific types of bacteria and Crohn's disease remains unclear. One group of scientists has discovered that some symptoms common to Crohn's disease, ulcerative colitis and irritable bowel syndrome may have the same underlying cause. All three patient groups in their study had colons with an abnormally high level of serine protease, a chemical which, when injected into experimental mice, causes the mice to feel the same painful symptoms that are associated with irritable bowel syndrome and colitis in humans. The authors of that study did not discover why the extra protease was there. Although a genetic link to Crohn's has been found, genetic abnormalities do not cause the disease on their own. Environmental factors are just as important. For example, the relatively high prevalence of Crohn's disease in industrialized countries may be linked to a diet rich in protein and dairy products. Among Crohn's patients, cigarette smoking appears increase the risk of "flares," or the recurrence of Crohn's symptoms after a period of remission. In the United States during the 1960s, after birth control pills and other hormone-based contraceptives became common, there was a dramatic increase in the incidence rate of Crohn's disease. No scientists have yet demonstrated a statistically significant relationship between birth control pills and Crohn's, but many suspect nevertheless that these drugs disrupt the digestive system in ways similar to smoking. Another interesting statistical correlation was found between the advent of the use of refrigeration in the United States and various parts of Europe and the rise of the disease. Later studies have provided support for this hypothesis. |
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