Elsevier

Autoimmunity Reviews

Volume 3, Issue 5, July 2004, Pages 394-400
Autoimmunity Reviews

Review
Inflammatory bowel disease: the role of environmental factors

https://doi.org/10.1016/j.autrev.2004.03.002Get rights and content

Abstract

Environmental factors are essential components of the pathogenesis of inflammatory bowel disease (IBD) and primarily responsible for its growing incidence around the globe. Epidemiological, clinical and experimental evidence support an association between IBD and a large number of seemingly unrelated environmental factors, which include smoking, diet, drugs, geographical and social status, stress, microbial agents, intestinal permeability and appendectomy. Data supporting the involvement of each of these factors in predisposing to, triggering, or modulating the course or outcome of IBD vary from strong to tenuous. Smoking and the enteric bacterial flora are the ones for which the most solid evidence is currently available. Smoking increases the risk of Crohn's disease (CD) and worsens its clinical course, but has a protective effect in ulcerative colitis (UC). Presence of enteric bacteria is indispensable to develop gut inflammation in most animal models of IBD, and modulation of the quantity or quality of the flora can be beneficial in patients with IBD. Surprisingly, evidence for a major role of the diet in inducing or modifying IBD is limited, while that for nonsteroidal anti-inflammatory drugs is more convincing than for oral contraceptives. Northern geographic location, and a high social, economical, educational or occupational status increase the risk of IBD, an observation fitting the hygiene hypothesis for allergic and autoimmune diseases. Stress is also associated with IBD, but more as a modifier than an inducing factor, and its contribution is more obvious in IBD animal models than human IBD. Finally, an increased intestinal permeability may increase the risk for developing CD, whereas an appendectomy lowers the risk of developing UC.

Introduction

Like most autoimmune and chronic inflammatory diseases, both forms of inflammatory bowel disease (IBD), e.g., Crohn's disease (CD) and ulcerative colitis (UC), are believed to result from the interaction of genetic, immune, and environmental factors [1]. The remarkable increase in the incidence of IBD, and CD in particular, during the last half century points to changes in the environment as major culprits of this evolution, since genetic variations are negligible in such a short period of time, and the “hygiene hypothesis” of allergic and autoimmune diseases has been invoked to explain the world-wide spreading of IBD [2]. The recent surge in IBD and other autoimmune diseases is probably due to a complex disruption of homeostasis that goes beyond an aberrant immune response, and involves altered neuronal and endocrine host responses induced, perhaps, by an attempt to adjust to exceedingly rapid or drastic environmental changes to which the body has not properly adapted [3]. This review will succinctly discuss the most important environmental factors for which there is an evidence-based link to IBD pathogenesis (Fig. 1).

Section snippets

Smoking

The most indisputable example of the influence of the environment on IBD is tobacco use, particularly cigarette smoking. Smoking has a striking opposite effect on CD and UC, supporting the notion that distinct mechanisms underlie the pathogenesis of each form of IBD [4]. Notably, cigarette use is an important risk factor for CD, increasing the frequency of disease relapse and need for surgery, and discontinuation improves the disease course [5]. In contrast, UC patients are frequently

Dietary factors

Given the location of IBD, a potential relationship between components of the diet and disease pathophysiology has been long considered, and immunologic mechanisms have been postulated to link food antigens and the development of intestinal inflammation. This logical and appealing explanation is far from proven, and studies investigating the suggested link are few and unpersuasive, mostly because they provide only indirect evidence of a possible cause-and-effect relationship between specific

Drugs

Oral contraceptives and nonsteroidal anti-inflammatory drugs (NSAIDs) are the two main classes of drugs that have been intensively studied for a possible epidemiological or cause-and-effect relationship with IBD. The relative risk of CD in women taking oral contraceptives is about twice that of controls, although there is no direct evidence for a causative relationship [12]. There has been controversy regarding whether women using oral contraceptives have a worse clinical outcome for IBD, but

Geographical, social, economical, educational and occupational status

This group of interrelated factors is large and difficult to analyze, but translates much of the “westernization” process that is so intimately linked to the emergence of IBD in the last one-half century. Reproducible data have described a “North–South” gradient in IBD incidence in both in Europe and North America, both CD and UC being more common in higher latitudes. Although this gradient exists, more recent observations show that the differences in IBD frequency between north and south are

Stress

THE belief that stress may trigger IBD is popular among sufferers of CD and UC, but stress is more likely to modulate disease manifestations rather than being an initiating factor. Evidence that stress can modulate the course of IBD is provided by clinical observations, animal models of colitis, and studies of neuroimmune interactions in laboratory animals [16]. Exacerbations of clinical disease activity appear to be associated with sustained but not short-term stress [17]. The specific

Specific infectious agents

The history of IBD is dotted by cyclic reports on the isolation of specific infectious agents responsible for CD or UC. Several microorganisms, such as Listeria monocytogenes, Chlamydia tracomatis, Escherichia coli, Cytomegalovirus, Saccharomyces cerevisiae, and many more, have been proposed as having a potential etiologic role. Among the most recent, the suggested etiologic role of Mycobacterium paratuberculosis in CD has been the center of major controversy, since this bacterium is the

Intestinal permeability

Although not an environmental factor per se, increased intestinal permeability has been reproducibly described in patients with CD [32], and has been postulated as an early predisposing factor to the pathogenesis of this condition. Intriguingly, various studies have consistently shown an increase in intestinal permeability in 10–15% of healthy, symptom-free relatives of CD patients [33], and some spouses of CD patients, two puzzling observations that have been interpreted as indicative of

Appendectomy

UC patients have low rate of appendectomy, and appendectomy lowers the risk of developing UC, primarily for patients under the age of 20 years who had the procedure because of acute inflammation [36]. Observations in animals seem to confirm this negative association between appendectomy and UC. In an animal model that spontaneously develops UC-like inflammation, appendectomy at 1 month of age prevented the development of colitis, but the mechanisms through which appendectomy protects against UC

Summary

Various and seemingly unrelated environmental factors have been implicated in the rapid worldwide spreading of IBD. Although in principle all of them are legitimate, the strength of the supporting data varies considerably for each factor. Two factors emerge as particularly credible. The first is smoking because the epidemiological evidence behind it is too strong and reproducible to be dismissed, but its mechanism of action is still obscure. The second is the gut commensal flora, backed by an

Acknowledgements

This work was supported by grants from the Crohn's & Colitis Foundation of America to S.D. and the National Institutes of Health to C.F. (DK30399 and DK50984).

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