Since the identification of Crohn's disease, an inflammatory bowel disease, in 1932, the incidence and prevalence of the disease have increased worldwide. The incidence of Crohn's disease in the population was 1 in 100,000 in the 1940s, but increased to 6.9 in 100,000 by the 1990s (Loftus et al., 1993). Like the increase in prevalence, the causes of Crohn's disease are unknown. Bacterial infections and genetic factors are possible proximate explanations for the disease, while genetic legacies and novel environments are likely ultimate explanations. However, Crohn's disease is most likely caused by genetic factors that favor an intense immune response. This immune response was protective at one time, but recent changes in hygiene and dietary patterns have made it unnecessary.
Crohn's disease is one of the major inflammatory bowel diseases that causes irritation in the lining of the digestive tract. Inflammation can occur anywhere along the digestive tract, but it is most common in the lower part of the small intestine, known as the ileum. While the causes of inflammation are unknown, infection, ischemia, and specific immunologic sensitivities are thought to be responsible (Lennard-Jones, 1989).
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Symptoms range from mild to severe and develop gradually or rapidly over time, often with no warning. The most common symptom that people with Crohn's disease experience is diarrhea. This occurs because the inflammation within the intestine causes the cells in the affected area to secrete water and salt (Mayo Clinic Staff, 2010). The colon is unable to absorb the excess water, which leads to diarrhea.
Abdominal pain and cramping are also common symptoms associated with Crohn's disease. The inflammation and ulceration that often occur with the disease cause the intestinal walls to swell and eventually thicken with scar tissue (Mayo Clinic Staff, 2010). The thickened walls make it difficult and therefore painful for food to move through the GI tract. In people with severe cases of Crohn's disease, the cramping and pain can be serious enough to cause nausea and vomiting.
The disease is also characterized by blood in the stool, which occurs because the movement of food through the digestive tract irritates the inflamed intestinal walls. People with Crohn's disease also experience weight loss because the inflammation interferes with the body's ability to digest and absorb nutrients from food (Mayo Clinic Staff, 2010). Crohn's disease symptoms also include the following: fever, fatigue, arthritis, eye inflammation, skin disorders, inflammation of the liver or bile ducts, and delayed growth or delayed sexual development in children (National Digestive Diseases Clearinghouse, 2006). People experiencing abdominal pain, blood in the stool, persistent diarrhea, and prolonged fever are encouraged to consult a doctor (National Digestive Diseases Clearinghouse, 2006).
In order to diagnose Crohn's disease, a doctor will often have blood tests run in order to check for anemia and elevated white blood cell counts. Anemia indicates bleeding in the intestines, while an elevated white blood cell count indicates inflammation (National Digestive Diseases Clearinghouse, 2006). Diagnoses can also be made by performing an upper GI series of the esophagus, stomach, and small intestine, in which the patient drinks barium. The barium shows up white on the x-rays in order to reveal inflammation and other abnormalities in the intestine. Colonoscopies and sigmoidoscopies can also be used because they allow the doctor to
detect inflammation and bleeding in the lower part of the large intestine (National Digestive Diseases Clearinghouse, 2006).
Unfortunately, there is not a cure for Crohn's disease, but several therapies can be used once the disease is diagnosed in order to alleviate or control symptoms. Patients are often prescribed anti-inflammatories. These drugs often contain mesalamine, which is a substance used to control inflammation (National Digestive Diseases Clearinghouse, 2006). Corticosteroids and immune system suppressors are also common treatments. If these treatments are ineffective, Remicade, a drug that blocks the body's immune response, can be used (National Digestive Diseases Clearinghouse, 2006). Antibiotics have also been used to reduce excess bacterial growth in the small intestine, which often occurs as a result of inflammation. Antidiarrheals and nutritional supplements also help patients. Two thirds to three quarters of patients with Crohn's disease will eventually have to undergo surgery that removes part of their intestine in an attempt to eliminate suffering (National Digestive Diseases Clearinghouse, 2006). The surgery is done after medications can no longer control symptoms.
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The onset of Crohn's disease commonly occurs between ages 15 and 25. Some studies have shown another peak in Crohn's disease rates in those between ages 50 and 80. However, this second peak is refuted because greater susceptibility to disease is common in this age group. People in this group are also more likely to have mesenteric vascular disease, which is often confused with Crohn's disease and can lead to misdiagnoses (Sandler & Golden, 1986). Crohn's disease is thought to be more common in whites, with equal rates seen in males and females. Ashkenazi Jews have higher rates of Crohn's disease than those in the general population, which suggests a hereditary predisposition (Sandler & Golden, 1986). People who have a relative with either Crohn's disease or ulcerative colitis have an increased risk of developing the disease. It is thought that between 4.5% and 16.6%; of patients with Crohn's disease have a family history of the disease (Sandler & Golden, 1986). In a British study of twins, researchers found that in 10% of the pairs, both had an inflammatory bowel disease (Thompson et al., 1995). The use of oral contraceptives has also been tied to Crohn's disease. In another British study, patients with Crohn's disease within the colon were 4.3 times more likely to have taken oral contraceptives than women with either ulcerative colitis or Crohn's disease within the small intestine (Sandler & Golden, 1986). Other studies have looked at the impact of smoking on rates of Crohn's disease, but these findings are inconsistent. While other studies have shown that appendectomies have a protective affect against developing Crohn's disease. People who had appendectomies prior to diagnosis were less likely to require a colectomy, acquired the disease at an older age, and had fewer reoccurring symptoms (Scherl & Dubinsky, 2009).
Inflammatory bowel diseases were first reported between the 1760s and the mid-1800s (Scherl & Dubinsky, 2009). There were conflicting reports of inflammatory bowel diseases in the early 1900s because tuberculosis of the intestine and appendicitis displayed similar symptoms (Scherl & Dubinsky, 2009). However, these conditions differed from Crohn's disease in that they did not cause inflammation, which allowed Burrill Crohn to later diagnose Crohn's disease because he was able to distinguish it from other disorders. In 1932, Chron, Ginzburg, and Oppenheimer described Crohn's disease as a disease limited to the ileum and demarcated at the ileocecal valve with no colonic involvement (Scherl & Dubinsky, 2009). Since the time of Crohn and his colleagues, the definition of Crohn's disease has expanded to include the entire digestive tract.
Crohn's disease is correlated with the modernization, improvements in hygiene, and dietary changes. Therefore, the highest incidence and prevalence of Crohn's disease is in North America and northern/western Europe. The rates of Crohn's disease range from 2.2% to 14.3% in North America and from 0.9% to 9.2% in northern and western Europe (Scherl & Dubinsky, 2009). The rates of Crohn's disease in northern and western Europe are up to 80% higher than those seen in southern Europe. Eastern Europe has the lowest rates of Crohn's disease, which is thought to be caused by the rapid lifestyle changes that have accompanied the fall of the Soviet Union. Surveys have shown that prevalence of the disease is increasing in this area as these nations adopt a more western European lifestyle. The rates of Crohn's disease in Asia range from 0.2% to 6%, while rates range from 1.35% to 4.1% in the Middle East (Scherl & Dubinsky, 2009). The highest rates of Crohn's disease in the Middle East are seen in Israel, with the Jews being significantly more affected than the Arabs. The data pertaining to incidence and prevalence of Crohn's disease in Africa is limited, but whites are more affected than blacks. The data is also limited in Central and South America, but rates have been on the rise in recent decades. The increasing rates of Crohn's disease have been tied to improvements in sanitation.
The presence of certain species of bacteria within the intestine is one explanation for the pathogenesis of Crohn's disease. Patients with Crohn's disease often have lesions where a high density of lymphoid follicles group to form Peyer's patches within the small intestine (Hugot et al., 2003). Peyer's patches are involved in the immune response and develop from birth until age
15 to 20 when they undergo involution (Hugot et al., 2003). Crohn's disease is tied to the number of Peyer's patches, which peak at around the same time that the onset of Crohn's disease occurs (Hugot et al., 2003). Lesions are able to develop on the lymphoid follicles because several infectious agents freely associate with the M cells that are involved in the functioning of Peyer's patches. These infections include: Salmonella, Shigella, E. coli, Vibrio cholera, Campylobacter, Yersinia, reoviruses, poliovirus, HIV, cold tolerant bacteria (psychrotrophic) and others (Hugot et al., 2003). When Yersinia invades the M cells, it becomes pathogenic and destroys the lymphoid follicles, which induces inflammation (Hugot et al., 2003). Invasions of
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Y. enterolitica produce heat shock proteins that are thought to cause diarrhea and autoimmune colitis (Hugot et al., 2003).
While the bacterial causation of Crohn's disease is possible, it is unlikely. If bacteria were responsible for Crohn's disease, the disease or much of the suffering could be alleviated by antibiotics. However, antibiotics are only an effective way to reduce symptoms in some patients. It is more likely that the presence of infectious agents combined with various other factors cause Crohn's disease.
A more likely explanation for Crohn's disease involves genetic factors. It is important to note that the disease cannot be caused solely by genetic factors because the genetic composition of a population does not change rapidly over the course of a few decades, which would be necessary to account for the increasing incidence and prevalence of the disease (Scherl & Dubinsky, 2009). Nevertheless, recent genome wide association studies (GWAS) have identified over 30 new gene variants associated with Crohn's diseases (Barrett et al., 2008). The genetic loci identified have been tied to involvement in many homeostatic mechanisms. These mechanisms include microbial recognition receptors, differentiation of the Th-17 lymphocytes involved in the immune response, autophagy, and epithelial barrier maintenance (Van Limbergen et al., 2009).
By mapping a region on chromosome 16, researchers have identified the NOD2/CARD15 gene (Van Limbergen et al., 2009). This gene is involved in a system of pattern recognition that identifies microbial components (Ogura et al., 2001). When the signal reaching NOD2/CARD15 is uninhibited, it becomes hyperresponsive to toll-like receptors (TLR4 and TLR2). TLR4 is important because of its location on the cell membrane. It serves to bind the fusion proteins of respiratory viruses, subunits of bacterial fimbriae, fibronectin, B-defensin, and heat shock proteins (Limbergen et al., 2009). Since these receptors are designed to bind to immunostimulatory microbial products that are exposed when microorganisms are damaged, they have a very strong pro-inflammatory response (Van Limbergen et al., 2009).
The inflammatory response triggers an adaptive immune response, which is managed by the T (Th17) helper cells. T helper cells used to be considered either Th1 or Th2 cells, but this classification has been replaced with CD4+ lymphocyte populations (Van Limbergen et al., 2009). These cells can differentiate into regulatory and anti-inflammatory T cell populations. As they differentiate, protection against intracellular pathogens results. Variation in the function of these cells causes susceptibility to Crohn's disease because of the potential for a strong immune response.
In people without Crohn's disease, autophagy, a process involved in the delivery of parts of the cytoplasm to the lysosome to be degraded, helps to contain inflammation by eliminating pathogens and controlling signaling, aids in tumor biology, mounts resistance against pathogen induced cell death, and aids the Paneth cells in their secretory function (Van Limbergen et al.,
2009). Autophagy can also eliminate invading microorganisms and prime the immune response. However, in people with Crohn's disease, certain genetic mutations cause several autophagic defects in certain cells within the intestinal lining that impair the way that bacteria are handled and alter the function of the Paneth cells (Van Limbergen et al., 2009).
Alterations in the epithelial barrier of the digestive tract are also thought to increase susceptibility to Crohn's disease because of the increased exposure of the mucosal immune system to antigens derived from the enteric flora (Scherl & Dubinsky, 2009). Antigens are taken up through endocytosis and as a result of changes in the composition and function of tight junctions (Scherl & Dubinsky, 2009). These mechanisms affect the tumor necrosis factor alpha (TNFÎ±). TNFÎ± may be an important regulator of mucosal immune activation, and studies have shown that intestinal and peripheral phagocytes from patients with Crohn's disease secrete more of this factor (Schreiber et al., 1999). Among patients with high concentrations of TNFÎ± (>75pg/mL), the median time to relapse after a symptom free period was 84 days, while it was 216 days in patients with lower concentrations (Schreiber et al., 1999). Therefore, patients that have a high chance of relapse; have an increased capacity for their lamina propria immune cells to secrete pro-inflammatory cytokines (Schreiber et al., 1999).
While a lot is known about the genetic basis of Crohn's disease, three decades of genome wide association system analysis have only revealed 20% of the genes associated with genetic risk (Van Limbergen et al., 2009). Crohn's disease is a complex disease and will require much more genetic analysis, a more complete understanding of mucosal immunology, and further study of the mucosa associated flora within the microbiome (Van Limbergen et al., 2009). Researchers have speculated that certain factors, such as cigarette smoke and appendectomies
have protective effects, but these findings are contested, which just adds to the unknown nature of the disease.
While the exact causes of Crohn's disease remain unknown, genes and novel environments are possible explanations. The fact that Crohn's disease rates are higher in Jews may indicate some sort of genetic predisposition. However, among Jews, the disease is uncommon in Israeli-born and non-Ashkenazi Jews, which indicates that environmental factors may underlie genetics (Sandler & Golden, 1986). Crohn's disease is just one of the many diseases that have a greater prevalence in this population. Other diseases that affect Ashkenazi Jews at higher rates include: Tay-Sachs disease, Canavan disease, Niemann-Pick Disease, Gaucher Disease, Familial Dysautonomia, Bloom Syndrome, Fanconi anemia, mucolipidosis IV, and cystic fibrosis (Victor Center, 2010). By studying these diseases, the question becomes why Ashkenazi Jews have genes that predispose them for these conditions. It is important to understand the history of this group before considering genetic factors.
The Jewish population has a history of dispersal. Originally, they moved peacefully from their biblical home in Israel to the Mediterranean, Yemen, and India (Diamond, 1991). They were then dispersed in a series of conquests that were carried out by the Romans, Babylonians, and Assyrians (Diamond, 1991). During the eighth and ninth centuries, the Jews were invited to live in France and Germany until persecutions caused by the Crusades forced them out (Diamond, 1991). The Crusades caused widespread dispersal of various groups of Jews from their homes in several countries. The Jews living in France and Germany, known as Ashkenazi Jews, fled to Poland, Lithuania and Russia (Diamond, 1991). The Jews remained here for
centuries, while enduring periods of oppression. A series of anti-Semitic raids during the late nineteenth century and the early twentieth century caused many Jews to migrate out of this area. Dispersal of Jews continued throughout the twentieth century as a result of the Holocaust.
Jews differ from other ethnic groups because they have been persecuted and confined for their entire existence. Eastern European Jews were forbidden from owning land, therefore, they moved to cities in order to become business people. They were confined to the crowded life of the ghetto, where rates of infectious disease were high. Since the Jews were forbidden to leave these areas, they experienced strong selection pressure to evolve genetic resistance to infectious diseases (Diamond, 1991). However, the genes that evolved to protect this population have put them at higher risk for more chronic conditions, including Crohn's disease. Other possible explanations for the genetic differences among Ashkenazi Jews that predispose them to certain diseases include genetic drift and the Founder effect. Recently, researchers have refuted these factors because both occur in small populations, and Ashkenazi Jews are a relatively large group (Ostrer, 2001).
While rates of Crohn's disease are not nearly as high in the general population as they are in Ashkenazi Jews, the disease predominately affects whites. There are three mutations within the CARD15 gene that are associated with this increased risk. These mutations may have occurred in response to outbreaks of the plague during the 1300s and 1400s, which were caused by the bacteria Yersinia pestis (Hugot et al., 2003). CARD15 mutations may have provided carriers with advantages during outbreaks because the mutations are thought to cause a more intense reaction to the plague causing bacteria. Therefore, people with these specific mutations had a greater chance of survival and were more likely to pass on their genes to future generations.
Even though plague disappeared, other species of Yersinia bacteria continue to circulate. When Yersinia reaches the intestinal site of a person with a mutation in their CARD15 gene, a large immune response is mounted because of the body thinks that it is fighting plague. The extreme nature of this immune response is unnecessary and causes swelling and inflammation, which are associated with Crohn's disease.
In addition to genetics, novel environments are another potential cause for Crohn's disease. Crohn's disease is a relatively young disease, being indentified in 1932, but incidence rates have been increasing rapidly in recent decades, from 1 in 100,000 to 6.9 in 100,000 (Loftus et al., 1993). The increase has been tied to lifestyle changes. Significant changes have occurred with respect to food, housing, transport, leisure, and clothing even between the first half and the second half of the twentieth century (Hugot et al., 2003). Recently the cold chain hypothesis has emerged as a possible explanation for the increasing prevalence of Crohn's disease. This hypothesis links Crohn's disease to the advent of refrigeration.
Domestic refrigeration began with the development of ice boxes in 1875 (Hugot et al., 2003). The use of ice boxes during the first part of the 20th century became widespread in the United States, while usage remained lower in other countries. The first domestic refrigerator was developed in 1918, and by 1937, 49% of Americans had a refrigerator (Hugot et al., 2003). In the 1930s only wealthy Europeans had refrigerators, and by 1958 only 10% of French and 12% of British families had refrigerators (Hugot et al., 2003). According to the cold chain hypothesis, the increasing prevalence of Crohn's disease in a country is tied to the time that domestic refrigeration became widespread. The United States saw an increase in the prevalence of Crohn's disease during the 1940s, Sweden saw an increase in the 1950s, England saw an
increase in the 1960s, and southern Europe saw an increase later than the 1960s (Hugot et al., 2003). Researchers believe that refrigeration lead to the existence of bacteria that were capable of surviving and developing at low temperatures. These psychrotrophic bacteria included members of the Listeria, Yersinia, Clostridium, and Bacillus families, which are thought to cause inflammation and diarrhea when exposed to the M cells that are associated with the lymphoid follicles in the intestine (Hugot et al., 2003).
If psychotrophic bacteria contribute to Crohn's disease, then novel environments are a likely culprit for disease causation. Humans have only been using refrigeration for a short period of time, which has resulted in exposure to less virulent forms of ancient pathogens. When human ancestors were initially exposed to these pathogens, an intense immune response was needed for survival. Those that survived passed on their genes to future generations, but the intense immune response became less necessary over time. Today this immune response causes unnecessary inflammation and other symptoms that are associated with Crohn's disease.
While the cold chain hypothesis is plausible, the misregulation of the immune response is more likely to be tied to the hygiene hypothesis. Some pathogens can induce regulatory cells to evade immune elimination in order to maintain normal functioning of the immune system, but increasingly hygienic lifestyles have reduced exposure to these microorganisms (Guarner et al., 2006). Helminths are parasitic worms that affect over 2 billion people worldwide (Guarner et al., 2006). Most helminth infections occur in warm climates, where there is poor sanitation and unclean food. The host acquires the helminth through contact with infected food, soil, or water (Elliot et al., 2000). Infestation induces a Th2 inflammatory response that can regulate the Th1 immune response to other parasites, virus, and bacteria (Elliot et al., 2000). Prior to the 1930s it
was possible that all children were infected with at least one parasite (Elliot et al., 2000). Rates of parasitic infection remained at 40% in the United States during the 1940s, but dropped to 5% by the 1960s and remain around 0.5% today (Elliot et al., 2000). The decreasing frequency of helminth infection is correlated with an increase in the prevalence of Crohn's disease because the parasites are no longer around to regulate the immune response. Rates of Crohn's disease are lower in places that still have heavy parasite burdens, like Africa and South America. Parasites have coexisted with humans since the beginning of human history, which has caused the immune system to develop in a certain way. The modern environment is more hygienic than any environment experienced in history, but the legacy of intestinal parasites remains. Without parasites, the Th1 pathways become over reactive and the immune system attacks itself, which is how Crohn's disease has emerged (Summers et al., 2004). It is interesting to note that recent treatments for Crohn's disease have actually involved the use of parasites. The porcine whipworm, Trichuris suis, has been selected for these treatments because it can colonize humans for brief periods without causing disease (Summers et al., 2004). Treatment with this particular parasite has yielded an 80% rate or remission because the parasites are able to regulate the Th1 response (Summers et al., 2004).
The last proposed ultimate cause for Crohn's disease has to do with the impact of diet on the gut microbiota. The gut contains between 500 and 1000 different species of microorganisms that are obtained at birth and during the first year of life (Guarner et al., 2006). Of these microbiota, over 50% of them cannot be grown in culture (Guarner et al., 2006). The relationship between the host and the microbiota is a beneficial symbiotic relationship, where the host provides the nutrients and the bacteria play a role in the immune system (Guarner et al., 2006). The
Lactobacillus species has even been shown to inhibit proinflammatory cytokine production (Guarner et al., 2006). As a result of dietary changes, the composition of the microbiome within
the gut can be altered. Breastfeeding is vital in the establishment of the gut microbiota. However, many people choose to feed their infants formula, which has impacted the microbiome. Crohn's disease is common in Americans born after World War II because breastfeeding declined during this time period (Sandler & Golden, 1986). However, humans have been breastfeeding their children throughout history and changes in this pattern have resulted in novel environments that have contributed to disease. Diets high in meat, dairy products, and refined sugar, and low in fiber, fresh fruit, and vegetables have also been linked to Crohn's disease (Sandler & Golden, 1986). The modern diet lies in contrast to the ancestral diet that was high in fiber, fresh fruit, and vegetables, and low in meat, dairy products, and refined sugars. This environmental mismatch has been a contributing factor in several diseases.
By understanding the proximate and ultimate explanations for Crohn's disease, researchers will be better equipped to develop treatments. Genome wide association studies continue to be done in order to determine the genetic basis behind the disease. Once the genetic basis is understood, treatments that target specific DNA sequences could be developed. However, much work still needs to be done in this area because after decades of work, only 20% of the genome has been analyzed (Van Limbergen et al., 2009). There are also several evolutionary explanations for Crohn's disease. Crohn's disease is more common in certain groups because of mutations acquired in order to combat infectious diseases obtained through life in the ghetto or during epidemics. Those that survived passed on these genes to future generations. As time
passed, the immune system no longer had to deal with these pathogens, which caused hypersensitivity and has lead to disease. There is also a mismatch between the current environment of humans and the environment in which their ancestors developed throughout history. Modern life is far more hygienic than that of the past. By eliminating the symbiotic relationship between humans and parasites, rates of disease have risen. Dietary changes have also served to change the gut immune system. These changes have only occurred in the past century, which has not provided the body adequate time to adapt.