ReviewInflammatory bowel disease: the role of environmental factors
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).
References (38)
Inflammatory bowel disease: etiology and pathogenesis
Gastroenterology
(1998)- et al.
Inflammatory bowel disease and smoking—a review
Am. J. Gastroenterol.
(1998) On smoking, rats, and inflammatory bowel disease
Gastroenterology
(1999)- et al.
Comparison of enteral nutrition and drug treatment in active Crohn's disease. Results of the European Cooperative Crohn's Disease Study: IV
Gastroenterology
(1991) - et al.
Rapid development of colitis in NSAID-treated IL-10-deficient mice
Gastroenterology
(2002) - et al.
Geographic variation of inflammatory bowel disease within the United States
Gastroenterology
(1991) - et al.
Stress and exacerbation in ulcerative colitis: a prospective study of patients enrolled in remission
Am. J. Gastroenterol.
(2000) - et al.
Crohn's disease after in-utero measles virus exposure
Lancet
(1996) Prevention is the best defense: probiotic prophylaxis of pouchitis
Gastroenterology
(2003)- et al.
Probiotics in inflammatory bowel disease: new insight to pathogenesis or a possible therapeutic alternative?
Gastroenterology
(1999)
Mucosal flora in inflammatory bowel disease
Gastroenterology
Lessons from Nod2 studies: towards a link between Crohn's disease and bacterial sensing
Trends Immunol.
Clustering of increased small intestinal permeability in families with Crohn's disease
Gastroenterology
CD45RO expression on circulating CD19+B cells in Crohn's disease correlates with intestinal permeability
Gastroenterology
Appendectomy is followed by increased risk of Crohn's disease
Gastroenterology
The germless theory of allergic diseases: revisiting the hygiene hypothesis
Nat. Rev.
Integrated evolutionary, immunological, and neuroendocrine framework for the pathogenesis of chronic disabling inflammatory diseases
FASEB J.
Smoking and inflammatory bowel disease
Eur. J. Gastroenterol. Hepatol.
Effects of cigarette smoke on the immune system
Nat. Rev., Immunol.
Cited by (324)
Risk of venous thromboembolism in autoimmune diseases: A comprehensive review
2023, Autoimmunity ReviewsTriclosan and triclocarban as potential risk factors of colitis and colon cancer: Roles of gut microbiota involved
2022, Science of the Total EnvironmentCitation Excerpt :In recent decades there has been a dramatic increase in the incidence and prevalence of IBD (Molodecky et al., 2012). While accumulating evidence supports that the rapid increase of IBD is mainly caused by exposure to environmental factors (Ananthakrishnan, 2013; Danese et al., 2004; Chassaing et al., 2015; Devkota et al., 2012), the identities of the environmental risk factors, as well as the mechanisms connecting environmental exposure with IBD, remain largely unknown (Ho et al., 2019). This represents a significant knowledge gap within the pathogenesis of IBD, hampering our efforts to reduce the risks of IBD in the human populations.
Compound loss of GSDMD and GSDME function is necessary to achieve maximal therapeutic effect in colitis
2022, Journal of Translational AutoimmunityCitation Excerpt :Genetic predispositions and environmental factors contribute to the pathogenesis of chronic inflammatory bowel disease (IBD), of which ulcerative colitis (UC) and Crohn disease (CD) are the most common manifestations [1,2].
Oral Administration of Platinum Nanoparticles with SOD/CAT Cascade Catalytic Activity to Alleviate Ulcerative Colitis
2023, Journal of Functional Biomaterials