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Etiology of Crohn’s Disease

Despite considerable research, there is little understanding of the underlying cause of Crohn’s disease (CD). Researchers agree that CD is the result of a combination of factors, including genetic predisposition, environmental trigger(s), and immune dysregulation.

In healthy people, the intestine becomes inflamed in response to an environmental trigger or potential pathogen, then returns to a normal state once the trigger is no longer present or the pathogen is eradicated from the gut. In individuals with inflammatory bowel disease, perhaps due to a genetic predisposition, inflammation is not downregulated, the mucosal immune system remains chronically activated, and the intestine remains chronically inflamed.2095 

Figure 594 – Role of the Environment in IBD


Figure 1, Page 395, Autoimmun Rev. 2004;3:(5) is used with permission of Elsevier Inc. All rights reserved.

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Genetic Factors in Crohn’s Disease

It is clear that there is a genetic predisposition toward Crohn’s disease (CD), because relatives of patients with CD are more likely to develop the disease. In large studies from the United Kingdom, Sweden, and Denmark, the risk of development of CD in 1 monozygotic twin was shown to be as high as 60%, if the other twin has CD. The concordance rate in dizygotic twins and siblings is 4%, still far above the rate in the background general population.2089  Furthermore, there are ethnic predispositions to CD — the prevalence in Ashkenazi Jewish populations is 2 to 9 times higher than in the general population.2160 

Gene-linkage studies have been undertaken to determine the identity and number of possible susceptibility genes. Susceptibility genes appear to be located on chromosomes 3, 7, and 12. In 2001, in a major discovery, the NOD2/CARD15 gene (NOD2) was identified as a susceptibility gene for CD. It was determined that the relative risk for the development of CD was increased 3-fold in individuals with a mutation in 1 copy of this gene and approximately 40-fold in individuals with mutations in both copies of this gene.2089  Individuals with NOD2 mutations tend to present younger and have more ileal disease and more fibrostenotic disease.2160  NOD2 mutations have been shown to occur more frequently in the pediatric CD population than in the adult CD population, suggesting that this mutation plays a strong role in age at presentation.11344  Children with NOD2 mutations have shown a tendency toward more ileocolitis than isolated ileal disease, and children without the mutation were more prone to isolated colitis.11345  These mutations have also been associated with lower weight at diagnosis11346  and risk for early surgery in affected pediatric patients.11347  It is also clear that mutation of NOD2 is not involved in most CD cases, and there is much more to be learned about the genetic basis of CD.2089  It is now thought that 3% to 15% of CD patients have two NOD2 mutations, and 10% to 30% have one.2160  Nonetheless, insight into the function of NOD2 and how its mutation may bring about disease have shed much light on the pathogenic mechanisms that may underlie CD.

NOD2 encodes an intracellular protein that is activated by muramyl dipeptide, a component of the bacterial cell wall.2089  The NOD2 protein functions as an intracellular "sensor" for bacteria. NOD2 is expressed in macrophages and also in Paneth cells in the intestine. Paneth cells, which are most abundant in the ileum, synthesize and secrete antimicrobial proteins called defensins. It has been shown that patients with ileal CD have a deficiency of defensins, and that this deficiency is particularly pronounced in patients with NOD2 mutations. It is interesting to note that the mucosa in CD is heavily contaminated with adherent and sometimes invading bacteria from the lumen, while the normal mucosal surface is virtually sterile when rinsed with saline.2087  Intestinal cells from NOD2-knockout mice have been demonstrated to have a profoundly decreased ability to clear certain bacteria, and the mice themselves are more susceptible to infection with bacterial pathogens.2071  CARD15 mutations appear to impair ileal protection to invading bacteria as a result of impaired defensin production.2089,  2092,  2168 

Another theory focuses on the expression of NOD2 in macrophages, as it has been shown that cells of this type from NOD2-knockout mice produce markedly increased amounts of interleukin 12 (IL-12), a known potent stimulator of the immune system. It can be postulated that patients with NOD2 mutations produce excessive amounts of IL-12 in response to nonpathogenic organisms in the intestinal microflora.2168  Regardless of the precise underlying mechanism, the identification of NOD2 has highlighted that an inappropriate response to normally present bacteria likely plays an important role in CD and demonstrates a genetic link to an individual’s susceptibility for development of CD.

Environmental Factors in Crohn’s Disease

It is also clear that environmental factors play an important role in the pathogenesis of Crohn’s disease (CD). The disease is most prevalent in developed countries, especially the United States, United Kingdom, and Scandinavia. There has been an apparent dramatic increase in CD in the past 100 years, and it has been noted that rates are climbing most sharply in countries that are in the process of becoming westernized. The precise nature of the associated environmental factor(s) that are responsible is unknown. The "hygiene hypothesis" has developed as a result of the notable relationship between the degree of sanitation and risk of disease development. Supporting the role of decreased exposure to infection and disease development, some report that children raised in conditions where they do not have to share a bedroom or bathroom have a higher risk of developing CD.2095  Conflicting data from a Canadian study indicated that lesser crowding in homes was protective. In addition, day care attendance during the first 6 months of life and "physician-diagnosed infections" between 5 and 10 years of age were associated with increased risks of CD.6635 

A large number of factors have been suggested as potentially environmentally important, but all remain controversial. Among these factors are a high-fat diet, increased intake of fast food, increased exposure to pollution and industrial chemicals, and decreased exposure to sunlight, refrigeration, and toothpaste. Specific bacterial infections and viral infections, such as Mycobacterium paratuberculosis and measles, have been postulated as possible antigens to which exposure may have some degree of causality for inflammatory bowel disease.2108 

Inflammatory Cytokine Involvement in Crohn’s Disease

Antigens activate resting macrophages to release a wide variety of cytokines. Cytokine is a collective term for a group of low-molecular-weight peptides that are active at very low concentrations and bind to specific receptors to produce autocrine, paracrine, and endocrine effects. Interleukin 1 (IL-1), IL-6, tumor necrosis factor-α (TNF-α), and IL-8 are all important pro-inflammatory cytokines. These cytokines cause differentiation of lymphocytes to different types of T cells. Helper T cells type-1 (TH1) have traditionally been thought to be associated principally with Crohn’s disease (CD), whereas TH2 cells have traditionally been thought to be associated with ulcerative colitis and CD.2142 

TNF-α is a key mediator of the inflammatory response in CD. TNF-α is a cytokine that can transmit signals between immune and other cells and is involved in cell death (apoptosis), metabolism, inflammation, thrombosis, and fibrinolysis. Increased production of TNF-α has been shown in various models of granulomatous inflammation. The number of TNF-α – producing lamina propria cells is increased in CD. Studies in children with active CD document elevated concentrations of TNF-α in stool samples, but serum concentrations are low, even in patients with very active disease. In contrast, the serum concentrations of both soluble TNF receptors are increased in active disease.2164 

An important role for TNF-α as a pivotal pro-inflammatory mediator in CD has emerged, and this has resulted in the development of several therapeutic strategies that target TNF-α.2164 

Microbial Exposure and Infection in Crohn’s Disease

Commonalities in presentation of inflammatory bowel disease (IBD) with infectious colitis have led to multiple investigations directed toward identifying specific antigens that may play a key role in development of ulcerative colitis (UC) and Crohn’s disease (CD) or in the exacerbation of existing disease. Validating the theory of pathogenic origin is the fact that many patients with IBD report a prodromal enteric infection and the similarities of gastrointestinal symptoms between infection and IBD. Despite rigorous research and numerous suspect bacteria, no specific antigens have been implicated for either CD or UC. It is a reasonable conclusion that the host response to luminal contents drives the inflammation, precluding the ability to identify a specific antigen for all populations. Two possible infectious scenarios have been postulated as having a role in IBD. One is infection as a causative factor for disease development, while the other is infection as a causative factor for exacerbation of existing disease. Although numerous infectious agents have been postulated in the etiology of inflammatory bowel disease, 2 have been studied extensively: Mycobacterium avium subspecies paratuberculosis and measles. Theoretically, any enteric infection could lead to inflammation and potentially exacerbate IBD. Clostridium difficile and Cytomegalovirus have been studied extensively in disease exacerbation and will be discussed in this module.

Mycobacterium Avium in Etiology of Crohn’s Disease

Mycobacterium avium subspecies paratuberculosis (MAP) is a pathogenic bacteria in the genus Mycobacteria. It is genetically related to, but not the same as Mycobacterium tuberculosis, the organism responsible for tuberculosis in humans. MAP has been identified as the causative agent in Johne’s disease. Worldwide in distribution, Johne’s disease is a contagious, chronic, and usually fatal infection that affects primarily the small intestine of ruminants (e.g., cattle, sheep, goats). In a 1996 study of dairy herds within the United States, the Animal and Plant Health Inspection Service, an integral part of US Department of Agriculture, determined that approximately 22% of US dairy farms have at least 10% of their herds infected with Johne’s disease. Similarities between Johne’s disease in affected animals and CD in humans has lead to considerable research, but to date no strong evidence has been generated that confirms a link between MAP and CD. MAP also has not been postulated as a causative agent in ulcerative colitis.2606 

Measles Virus in Etiology of Crohn’s Disease

Measles (rubeola) virus is an enveloped, nonsegmented, negative-stranded RNA virus of the Paramyxoviridae family. Exposure to measles virus, through contracting the disease or vaccination, has been hypothesized to have a role in the etiology of IBD, primarily CD. As with Mycobacterium avium subspecies paratuberculosis, studies of the measles virus have been conflicting, resulting in inadequate support for measles as a causative agent for the development of IBD.2144 

Clostridium Difficile in Exacerbation of Crohn’s Disease

Clostridium difficile is a gram-positive anaerobic bacillus that colonizes the colon of individuals under certain conditions that alter the normal colonic flora. The classic setting in which C difficile occurs is with the use of antibiotics. Through release of Toxin A, an enterotoxin, and Toxin B, a cytotoxin, C difficile is able to cause inflammation and tissue injury when these toxins bind to receptors in the intestinal mucosa. C difficile may be part of the normal colonic flora in a small percentage of adults and is transmitted via the fecal-oral route. The ability of the organism to live on inanimate surfaces for several months establishes its potential for nosocomial infection in health care settings, as the infection can be carried on the inadequately washed hands of health care providers. C difficile has been associated with relapse of IBD in case reports and prospective studies. In an early series of case reports, LaMont and Trnka identified an association between the presence of C difficile toxin and IBD exacerbation.2109 

Cytomegalovirus in Exacerbation of Inflammatory Bowel Disease

Cytomegalovirus (CMV), a member of the herpes virus group, is found throughout all geographic regions of the world. Infection with the virus rarely causes significant symptoms, except in vulnerable populations, such as newborns and immunocompromised individuals. Infection of a fetus with the virus during pregnancy can cause significant postnatal complications, such as mental retardation. Early case reports suggest that either primary or reactivation of CMV infection can complicate IBD and that CMV-associated exacerbations may respond to antiviral therapy.2165  In contrast, Matsuoka and colleagues studied CMV reactivation in a cohort of 69 patients with UC, concluding that CMV is frequently reactivated during active flares of UC, but has little effect on the course of the disease and resolves without antiviral therapy.2122  Evidence for the role of CMV in exacerbation of IBD is sparse, and there is a need for prospective studies to determine the significance of this virus in relation to IBD exacerbation.

Content on this page was last reviewed on October 31, 2009.

Content on this page was last changed on March 25, 2009.

References:

2071.  Cario E. Bacterial interactions with cells of the intestinal mucosa: Toll-like receptors and NOD2. Gut. 2005;54(8):1182-1193.
2087.  Fellermann K, Wehkamp J, Herrlinger KR, Stange EF. Crohn’s disease: a defensin deficiency syndrome? Eur J Gastroenterol Hepatol. 2003;15(6):627-634.
2089.  Gaya DR, Russell RK, Nimmo ER, Satsangi J. New genes in inflammatory bowel disease: lessons for complex diseases? Lancet. 2006;367(9518):1271-1284.
2092.  Grimm MC, Pavli P. NOD2 mutations and Crohn’s disease: are Paneth cells and their antimicrobial peptides the link? Gut. 2004;53(11):1558-1560.
2095.  Hanauer SB. Inflammatory bowel disease: epidemiology, pathogenesis, and therapeutic opportunities. Inflamm Bowel Dis. 2006;12(Suppl 1):S3-S9.
2108.  Korzenik JR. Past and current theories of etiology of IBD: toothpaste, worms, and refrigerators. J Clin Gastroenterol. 2005;39(4)(suppl 2):S59-S65.
2109.  LaMont JT, Trnka YM. Therapeutic implications of Clostridium difficile toxin during relapse of chronic inflammatory bowel disease. Lancet. 1980;1(8165):381-383.
2122.  Matsuoka K, Iwao Y, Mori T, et al. Cytomegalovirus is frequently reactivated and disappears without antiviral agents in ulcerative colitis patients. Am J Gastroenterol. 2007;102(2):331-337.
2142.  Radford-Smith G, Jewell DP. Cytokines and inflammatory bowel disease. Baillieres Clin Gastroenterol. 1996;10(1):151-164.
2144.  Robertson DJ, Sandler RS. Measles virus and Crohn’s disease: a critical appraisal of the current literature. Inflamm Bowel Dis. 2001;7(1):51-57.
2160.  Tamboli CP, Cortot A, Colombel JF. What are the major arguments in favour of the genetic susceptibility for inflammatory bowel disease? Eur J Gastroenterol Hepatol. 2003;15(6):587-592.
2164.  Van Deventer SJ. Tumour necrosis factor and Crohn’s disease. Gut. 1997;40(4):443-448.
2165.  Vega R, Bertrán X, Menacho M, et al. Cytomegalovirus infection in patients with inflammatory bowel disease. Am J Gastroenterol. 1999;94(4):1053-1056.
2168.  Watanabe T, Kitani A, Strober W. NOD2 regulation of Toll-like receptor responses and the pathogenesis of Crohn’s disease. Gut. 2005;54(11):1515-1518.
2606.  USDA. Animal and Plant Health Inspection Service. APHIS fact sheet: Johne’s disease. USDA website. http://www.aphis.usda.gov/lpa/pubs/fsheet_faq_notice/fs_ahjohnes.pdf . March 2003. Accessed February 1, 2007.
6635.  Amre DK, Lambrette P, Law L, et al. Investigating the hygiene hypothesis as a risk factor in pediatric onset Crohn’s disease: a case-control study. Am J Gastroenterol. 2006;101(5):1005-1011.
10938.  Danese S, Sans M, Fiocchi C. Inflammatory bowel disease: the role of environmental factors. Autoimmun Rev. 2004;3(5):394-400.
11344.  de Ridder L, Weersma RK, Dijkstra G, et al. Genetic susceptibility has a more important role in pediatric-onset Crohn’s disease than in adult-onset Crohn’s disease. Inflamm Bowel Dis . 2007;13(9):1083-1092.
11345.  Levine A, Kugathasan S, Annese V, et al. Pediatric onset Crohn’s colitis is characterized by genotype-dependent age-related susceptibility. Inflamm Bowel Dis . 2007;13(12):1509-1515.
11346.  Tomer G, Ceballos C, Conception E, Benkov KJ. NOD2/CARD15 variants are associated with lower weight at diagnosis in children with Crohn’s disease. Am J Gastroenterol . 2003;98(11):2479-2484.
11347.  Kugathasan S, Collins N, Maresso K, et al. CARD15 gene mutations and risk for early surgery in pediatric-onset Crohn’s disease. Clin Gastroenterol Hepatol . 2004;2(11):1003-1009.

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