Etiology of Ulcerative Colitis—Environmental Factors
As depicted in Fig.594, the environment exerts a significant influence on the development of inflammatory bowel disease (IBD), playing an important role in the current theory that IBD arises in a genetically susceptible host in combination with an abnormal immune response to exposure to an environmental "trigger."
In addition to the environmental factors listed
below, some patients with ulcerative colitis (UC) and their caregivers
have reported that disease remission and exacerbation varies with
change in seasons, resulting in relapse during the same season each
year. This has lead to an interest in studying this phenomenon with
conflicting results. Lewis and colleagues2646 conducted
a large multicenter retrospective study of 1,587 patients, identifying
disease exacerbations through prescription records in patients who
had an interval of at least 4 months without prescriptions for either
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.
Some figures may not display clearly when rendered as a PDF or printed.
Infectious Agents
Commonalities in presentation of IBD with infectious colitis have led to multiple investigations aimed toward identifying specific pathogens that may play a key role in the development of UC and Crohn’s disease (CD) or in the exacerbation of existing disease. Supporting the theory of pathogenic origin is the fact that many patients with IBD report a prodromal enteric infection and that there are similarities of gastrointestinal symptoms between infection and IBD. UC closely resembles chronic Campylobacter, Shigella, and amebic colitis. Despite rigorous research and numerous suspect bacteria, no specific pathogens have been implicated for either CD or UC.
The efficacy of immunosuppressant medications in the treatment of IBD provides a strong argument against an infectious etiology, as these types of medications would allow infection to proliferate and worsen disease instead of alleviating symptoms, as observed. It is also a reasonable conclusion that the host response to luminal contents drives the inflammation, precluding the ability to identify a specific pathogen 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 IBD, 2 have been studied extensively: Mycobacterium avium subspecies paratuberculosis and measles (rubeola). 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 section.
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Mycobacterium avium, subspecies paratuberculosis (MAP) is a pathogenic bacterium in the genus Mycobacterium. It is genetically related to but not the same as M 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, Animal and Plant Health Inspection Service, an integral part of US Department of Agriculture, determined that approximately 22% of US dairy farms had at least 10% of their herd infected with Johne’s disease.2606 Similarities between Johne’s disease in affected animals and Crohn’s disease (CD) in humans has led to considerable research, and strong evidence confirms a link between MAP and CD.2585 MAP, however, has not been linked as a causative agent in ulcerative colitis.
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Measles (rubela virus) is an enveloped, non-segmented, 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 inflammatory bowel disease (IBD), primarily Crohn’s disease. 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
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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 raises its potential for nosocomial infection in health care settings, as the infection can be carried on inadequately washed hands of health care providers. C difficile has been associated with relapse of IBD in case reports and prospective studies. There are no reports of a primary etiologic association between C difficile and IBD. In other words, while data exist documenting that IBD patients may have exacerbations caused by C difficile, there is no evidence that the organism itself causes an individual to develop IBD.
In an early series of case reports, LaMont and Trnka identified an association between the presence of C difficile toxin and IBD exacerbation.2109 In a prospective study by the same investigators, C difficile toxin was found in the stool of 19% of IBD patients, leading to the conclusion that C difficile can cause worsening of disease activity in patients with IBD. In this study, C difficile was not necessarily associated with antibiotic use.6683 In contrast, a second group of investigators found toxin present only in the stool of patients who had been exposed to antibiotics and concluded that there was no association with IBD activity.2610
In a retrospective evaluation of 54 patients experiencing 62 relapses of IBD, Meyer and colleagues determined that 20% of relapsing patients had a positive stool test for C difficile toxin. C difficile was observed in 10 of 12 patients whose stool specimens were positive for any pathogen, all of whom improved clinically with treatment for C difficile. Furthermore, antibiotic use was associated with 90% of the patients who tested positive for C difficile.2611 C difficile has been recently identified as an important epidemic in separate studies of health care institutions in Canada2612 and in the United States.2613 Implications for the existence of this virulent, frequent, and more resistant strain of C difficile for the IBD population are unknown.
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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 suggested that either primary or reactivation of CMV infection can IBD and that CMV-associated exacerbations may respond to anti-viral therapy.2165 This is an area of some controversy, and recommendations vary on whether the finding of CMV in the setting of IBD should prompt CMV-specific therapy. Matsuoka and colleagues studied CMV reactivation in a cohort of 69 ulcerative colitis (UC) patients, concluding that CMV is frequently reactivated during active flares of UC but has little effect on the course of the disease and resolves without anti-viral therapy.2122 Overall, evidence for the role of CMV in exacerbation of IBD is incomplete and there is a need for prospective studies to determine the significance of this virus in relation to IBD exacerbation. While some believe reactivation of CMV may exacerbate IBD, particularly UC, CMV has not been proposed to cause IBD.
Diet
Numerous studies have been undertaken to determine whether diet plays a role in development of inflammatory bowel disease (IBD). Predominance in industrialized areas has led to hypotheses that a "westernized diet" confers risk of IBD.
The effect of breast-feeding on subsequent development of both Crohn’s disease (CD) and ulcerative colitis (UC) has been investigated with the hypothesis that the immunoregulatory properties of human milk have a positive effect on the infant’s developing immune system and have been suggested as conferring protection against development of IBD. Although some studies have suggested that breast-feeding is beneficial, others have not reached statistical significance or have shown no measurable effect. Klement and colleagues performed a meta-analysis of 17 studies, 4 of which were rated as being of "highest quality." Pooled odds ratio was found to be 0.45 for CD and 0.56 for UC. Investigators concluded that their meta-analysis supports, but does not confirm, the benefit of breast-feeding in the prevention of IBD.2627
In combination with observations regarding geographic distribution of disease, anecdotal reports from patients with both CD and UC suggest that certain foods may lead to risk of disease and/or disease exacerbations. Hypotheses involving a causal relationship between diet and IBD have been generated and investigated with no conclusive result. Dietary intake, including mono- and polyunsaturated fat and vitamin B6, has been identified in a Netherlands study as posing a risk of UC,2628 and high consumption of sweets was implicated in a separate study conducted in Japan.2629 In the United Kingdom, dietary intake of meat, protein, and alcohol were identified by 1 group of investigators as a risk for exacerbation in patients with established disease.2630
None of these findings have been duplicated in follow-up investigations. For the most part, studies to date are limited by their retrospective nature and the confines of patient recall. These analyses are further compromised by poor controls and the fact that patients are studied after development of disease, with potential changes in dietary intake after symptoms evolved. As a result, the role of dietary antigens in development or exacerbation of disease remains ill-defined.2631
Tobacco Smoking
Possibly the strongest epidemiologic factor in IBD is its link with tobacco smoking. While smoking has been identified as a risk factor for Crohn’s disease (CD), nonsmoking and smoking cessation have been identified as risk factors for both development of and clinical course of ulcerative colitis (UC). Multiple studies have been conducted that duplicated results of early investigations into these phenomena. A meta-analysis of 9 studies, conducted in 1989, determined that there was remarkable consistency regarding the association between not smoking or smoking cessation with UC, demonstrating a 3-fold risk for UC in lifetime nonsmokers and about 65% elevated risk for former smokers.2632
The precise mechanism by which smoking and nicotine play a role in UC is unknown. Whether nicotine itself or another component of cigarette smoke is responsible for the association with UC is also unknown. One possible mechanism of action is the ability of nicotine to downregulate pro-inflammatory cytokines while upregulating anti-inflammatory cytokines. Additional possible mechanisms include the effect of smoking on gut permeability, the effect of nicotine on nicotinic acetylcholine receptors in the gut, and numerous other possible properties of nicotine that could exert an influence on the immune system.2633
The potential role of nicotine as therapy for UC has been studied with mixed results. Trials have been complicated by high dropout rates due to side effects associated with high systemic doses of nicotine, leaving the study population without enough subjects to demonstrate statistical significance.2633
Psychologic Stress
Historically, interest in the identification and stratification of IBD began in the early 1930s, most notably with the identification of "regional ileitis" by Crohn, Ginzberg, and Oppenheimer.2078 The disease was later renamed Crohn’s disease (CD) for the first author of this landmark publication. During the era in which IBD was being defined, there was a coincident rise in the popularity of psychosomatic medicine, especially in the 1940s and 1950s. Early publications presented case studies that described preexisting psychiatric conditions or emotional upset prior to the development of gastrointestinal symptoms, leading to speculation regarding a psychologic etiology for the disease. These early studies did not select patients consecutively and did not include control groups.2623 The efficacy of steroid therapy in the management of UC improved medical management and decreased enthusiasm for the psychosomatic hypothesis for the etiology of the disease. Lingering questions remain regarding the role of psychogenic factors in the disease process. Mawdsley, et al., investigated the effect of psychologic stress on the inflammatory process. In this study, 25 patients with inactive UC and 11 healthy controls were subjected to an experimental stress test. Autonomic and systemic inflammatory responses were measured before and after introduction of psychologic stress. Both groups had similar response with increased values for various inflammatory markers (tumor necrosis factor-α and interleukin 6 by lipopolysaccharide-stimulated whole blood, leukocyte count, natural killer cell numbers, and platelet count). Rectal mucosal biopsies were examined in 17 of the patients with quiescent UC, demonstrating no change in histologic score in patients who had a score of 0 prior to the stress event but increased histologic score in all 5 patients who had some degree of inflammation in the prestress biopsy specimen. The authors concluded that "acute psychologic stress induces systemic and mucosal pro-inflammatory responses, which could contribute to exacerbations of UC in ordinary life."2624 In a separate study, Levenstein, et al., determined that short-term stress did not contribute to disease exacerbation, while long-term stress increased the risk for disease flares.10603 Despite data that support the role of stress in disease flares in patients with established disease, its role in the onset of disease is significantly less clear. Lerebours and colleagues determined that there was no association between stressful life events and disease onset in a cohort of 74 patients who were diagnosed with UC.2626
Hygiene Hypothesis
Both ulcerative colitis (UC) and Crohn’s disease (CD) are most prevalent in developed areas of the world. This fact underscores the importance of the role of environment in the development of inflammatory bowel disease (IBD). As with other inflammatory diseases (asthma, multiple sclerosis, rheumatoid arthritis), there is an inverse relationship between the degree of sanitation and protection against IBD; geographic locations with poor sanitation are associated with a smaller incidence of IBD. This phenomenon provides credence for the hygiene hypothesis, which postulates that exposure to infections during childhood provides protection against certain diseases, although this is not universally accepted. For example, Amre, et al., disputed this hypothesis, demonstrating an increased risk of CD in children with infection-related exposures, such as overcrowding, daycare, infrequent use of personal towels, and owning a pet.6635 The observation that IBD occurs rarely in geographic areas in which people are infected with helminths has led to intriguing research into the role that helminths may play a role in protection against development of IBD. The presence of helminths upregulates TH2 cytokine release, while downregulating TH1 cytokine release, providing a possible mechanism for a protective effect with regard to IBD.
A possible protective organism, Trichuris suis is a parasite that infects animals, particularly pigs. In humans, these parasites colonize the host for a few weeks and are eliminated uneventfully. Utilizing ova from T suis, Summers and colleagues conducted a small trial of 7 patients (4 with CD, 3 with UC), demonstrating that the therapy provided positive results without evidence of toxicity.2619 This phenomenon was further explored in a randomized, double-blind, placebo-controlled trial using T suis in the treatment of UC. Thirty patients were given T suis and 24 patients were given placebo. Disease improvement as measured by UC Disease Activity Index and Simple Index was statistically significantly better in the treated group compared with the placebo group.2620 Further studies are underway.
Other Environmental Factors
Patients with UC and their caregivers have reported
that disease remission and exacerbation varies with change in seasons,
resulting in relapse during the same season each year. This has lead
to an interest in studying this phenomenon with conflicting results.
Lewis and colleagues2646 conducted
a large multicenter retrospective study of 1,587 patients, identifying
disease exacerbations through prescription records in patients who
had an interval of at least 4 months without prescriptions for either
Content on this page was last reviewed on October 31, 2009.
Content on this page was last changed on March 19, 2009.
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| 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. |
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| 2630. | Jowett SL, Seal CJ, Pearce MS, et al. Influence of dietary factors on the clinical course of ulcerative colitis: a prospective cohort study. Gut . 2004;53(10):1479-1484. |
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