Before getting into the extensive scientific literature on Crohn's, I thought it would be appropriate to start off with a basic explanation of the disease. Crohn's disease is one of the two most common forms of inflammatory bowel disease (IBD), with ulcerative colitis being the other, in which the patient's immune system inappropriately attacks the gastrointestinal (GI) tract. Many symptoms and manifestations can result from this immune system-mediated destruction of the gut, including weight loss, nutrient malabsorption, and, the ever unpleasant, diarrhea. For many Crohn's patients, damage to the intestines can become so severe that a portion of the gut will have to be surgically removed... thankfully something that I have not had to experience yet.
The pathogenesis (i.e. cause) of Crohn's is not completely understood, although there are many prevailing theories. First and foremost, Crohn's, like most chronic diseases, is extremely complex... there is no single cause that can be identified in most or probably all cases. Genetic, environmental, immune system, and microbiological (bacterial) factors are all important to varying degrees. In fact, the most widely accepted hypothesis of the disease incorporates all of these elements... i.e. Crohn's (and IBD in general) is essentially an abnormal overreaction of the immune system to gut bacteria in individuals predisposed to the disease for genetic and environmental reasons. So, now that that's (hopefully) clear, I will discuss the scientific support for each of these contributing elements individually.
Genes & Crohn's
Some of the best evidence of a genetic component for the disease is the fact that it tends to run in families. If one sibling has Crohn's, the chances of other siblings developing the disease are 30 times greater than for an unrelated person. Several studies have also found particular genes to be mutated, or screwed up, in Crohn's disease (Balfour Sartor. 2006). Interestingly, many of the identified genes seem to serve an important function for determining the GI and immune system responses to foreign material, such as bacteria or other pathogens.
Environmental factors
Although genetic background is important, it is clear that environment also plays a role. While the disease does cluster in families, studies of identical twins (i.e. two individuals with the exact same set of genes) show about a 50:50 split. In 50% of cases where one twin suffers from Crohn's, so will the other twin, but in the other half of cases, the other twin will live free of the disease (Balfour Sartor. 2006). Also, favoring an environmental trigger is the fact that the prevalence of IBD increased in North America and Europe in the latter half of the 20th century, and IBD is becoming more common in other countries that are adopting a more Western lifestyle.
Immune system overactivity
Fundamentally, Crohn's is an autoimmune disorder, in which the immune system goes rogue and attacks the host (patient) as opposed to just fighting off foreign invaders like it should. Thus, some degree of immune system malfunction is clearly part of the disease pathogenesis. Broadly speaking, there are two main arms of the immune system... the innate immune system, which is important for quick and nonspecific responses to infection, and the acquired immune system, which fights the more specific infectious battles and is the reason why you can clear an infection more quickly the second time around versus the first time. In Crohn's disease, both the innate and acquired immune systems are thought to be overactive.
The innate immune system. Macrophages (a word that translates essentially to "large eaters" because these cells gobble up large particles that your body wants to get rid of) are cells of the innate immune system, which are found in abnormally high numbers in the intestines of Crohn's patients (Balfour Sartor. 2006). Also, in response to activation of the innate immune system, many molecular signals get produced by the body, and these molecules, which are more specifically called cytokines, are elevated in active Crohn's disease. These cytokines help serve to keep the immune system going, and, thus, newer medications for Crohn's disease are designed to inhibit these molecules... for example, the TNF inhibitors.
The acquired immune system. As for the acquired immune system side of the matter, Crohn's disease certainly involves an excessive response of CD4 T cells, which are a kind of white blood cell that helps regulate immune responses. Crohn's patients may have more of these cells in their guts, and blocking these T cells has been shown to prevent or reverse immune system-mediated damage (Kucharzik et al. 2006).
Gut bacterial (microbial) involvement
Some of the most convincing evidence that gut bacteria (neat factoid... there are more bacterial cells that live in your gut than there are cells in the rest of your body) are involved in the pathogenesis of Crohn's disease comes from animals free of gut bacteria. Basically, if you prevent an animal from ever having GI bacteria, that animal will not get colitis (colitis = colonic inflammation), and many animal models of colitis will respond to antibiotics and probiotics (Balfour Sartor. 2006). Unfortunately for Crohn's patients, response to antibiotics or probiotics has been more variable in humans. Currently, it is thought that IBD may be caused by a bacterial imbalance in the gut... with "bad" bacteria outnumbering "good" bacteria... thus, several studies have been conducted to better understand which specific species of bacteria are more problematic for the development of GI inflammation.
Concluding thoughts
Many studies conducted to date have helped us better understand the causes and evolution of Crohn's disease, only some of which I have highlighted above, and these investigations have lead to the development of improved therapies for Crohn's patients. Due to the exceeding complexity of human physiology, there is a lot more research that still needs to be done. Hopefully, continued research progress will lead to better, more specific therapeutic options and ways to prevent... or potentially even cure... this disease.
Bibilography:
Balfour Sartor R. (2006) Mechanisms of Disease: pathogenesis of Crohn's disease and ulcerative colitis. Nature Clinical Practice Gastroenterology and Hepatology 3:390-407.
Kucharzik T et al. (2006) Recent Understanding of IBD Pathogenesis: Implications for Future Therapies. Inflammatory Bowel Diseases 12:1068-1083.
Despite the fact that wikipedia is not yet a widely accepted academic source, I have not met a medical student who didn't depend on it for their studying livelihood. While the Crohn's-related entries on wikipedia will not go into as much depth as I intend to do, I strongly recommend reading the wikipedia page on Crohn's (http://en.wikipedia.org/wiki/Crohn%27s_disease) for a basic knowledge of the disease causes and symptoms.
No comments:
Post a Comment