REVIEWS Epidemiology and risk factors for IBD Ashwin N. Ananthakrishnan Abstract | IBD, comprising Crohn’s disease and ulcerative colitis, is a chronic immunologically mediated disease at the intersection of complex interactions between genetics, environment and gut microbiota. Established high-prevalence populations of IBD in North America and Europe experienced the steepest increase in incidence towards the second half of the twentieth century. Furthermore, populations previously considered ‘low risk’ (such as in Japan and India) are witnessing an increase in incidence. Potentially relevant environmental influences span the spectrum of life from mode of childbirth and early-life exposures (including breastfeeding and antibiotic exposure in infancy) to exposures later on in adulthood (including smoking, major life stressors, diet and lifestyle). Data support an association between smoking and Crohn’s disease whereas smoking cessation, but not current smoking, is associated with an increased risk of ulcerative colitis. Dietary fibre (particularly fruits and vegetables), saturated fats, depression and impaired sleep, and low vitamin D levels have all been associated with incident IBD. Interventional studies assessing the effects of modifying these risk factors on natural history and patient outcomes are an important unmet need. In this Review, the changing epidemiology of IBD, mechanisms behind various environmental associations and interventional studies to modify risk factors and disease course are discussed. Ananthakrishnan, A. N. Nat. Rev. Gastroenterol. Hepatol. 12, 205–217 (2015); published online 3 March 2015; doi:10.1038/nrgastro.2015.34

Introduction

Massachusetts General Hospital Crohn’s and Colitis Centre, 165 Cambridge Street, 9th Floor, Boston, MA 02114, USA. aananthakrishnan@ mgh.harvard.edu

Crohn’s disease and ulcerative colitis are chronic, progressive immunologically mediated diseases that often have an onset during young adulthood and a course characterized by remission and relapse.1–3 IBD affects an estimated 1.5 million Americans, 2.2 million people in Europe, and several hundred thousands more worldwide.1,4 The protracted nature of these diseases exerts a major toll on patients in burden of therapy, hospitalizations, surgery, health-related quality of life, economic productivity and social functioning. The past three decades have witnessed notable progress towards unravelling the mystery of IBD. The familial nature of these diseases has been recognized: the first Crohn’s-diseaseassociated gene was described in 20015,6 and subsequent studies identified 163 distinct risk alleles in white populations.7 This progress has been paralleled by an increase in our understanding of the functional consequences of these loci. In addition, there is recognition that the genetic risk factors do not act in isolation but in synergy with the external environment as well as the internal ‘environment’, namely the gut microbiota. The development of IBD is governed by a series of interactions between these three spheres, which simultaneously not only increase the complexity of disease pathogenesis, but also offer several avenues for intervention and improvement of patient outcomes (Figure 1). This Review summarizes the epidemiological trends in the incidence and Competing interests A.N.A. has served on the scientific advisory boards for Abbvie and Cubist pharmaceuticals.

prevalence of IBD in established and emerging populations, and how environmental factors might affect incidence and natural history of IBD, their potential mechanisms of effect and how they might be intervened upon to improve patient outcomes.

Epidemiology Established populations The annual incidence of ulcerative colitis varies from 0–19.2 per 100,000 in North America and 0.6–24.3 per 100,000 in Europe, corresponding to a prevalence of 37.5–248.6 per 100,000 and 4.9–505 per 100,000, respectively.4 The incidence of Crohn’s disease is similar (0–20.2 per 100,000 in North America; 0.3–12.7 per 100,000 in Europe). However, this incidence has changed substantially in the past several decades. In a population-based study from Olmsted County, MN, USA, the incidence of ulcerative colitis rose substantially from 0.6 per 100,000 person-years in 1940–1943 to 8.3 per 100,000 person years in 1984–1993, with the steepest increase in the 1970s.8 A similar pattern was observed for Crohn’s disease;9 however, the rate of increase might now have slowed for both diseases.10 A systematic review summarizing population trends identified an increase in incidence in three-quarters of studies of Crohn’s disease, and nearly two-thirds of studies of ulcerative colitis confirmed this trend to be a general phenomenon.4 No studies have suggested a consistent decline in incidence rates. Within a defined geographical area, incidence rates and patterns of change are heterogeneous. Incidence is higher in urban than in rural populations, and the increase in

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REVIEWS Key points ■■ Crohn’s disease and ulcerative colitis are complex immunologically mediated diseases that arise due to a dysregulated immune response to commensal flora in a genetically susceptible host ■■ The incidence of IBD has traditionally been highest in North America and Western Europe with many cohorts suggesting a substantial secular increase over the second half of the twentieth century ■■ However, incidence of IBD is increasing in emerging populations such as Asia, suggesting that changing environmental factors play an important part ■■ Smoking and appendectomy were initially described to increase the risk of Crohn’s disease and confer protection from ulcerative colitis; however, this relationship seems more complex and could be mediated by genetics ■■ Diet, lifestyle and behaviour, as well as perturbations of the gut microbiota through use of antibiotics, might also have important roles in disease pathogenesis ■■ Modification of IBD risk factors offer avenues of intervention for disease prevention and improvement of natural history

Hygiene Vitamin D UV exposure

Diet

Stress

Sleep

Smoking

Medications

Microbiome

Appendectomy

Physical activity

Genetic susceptibility

Figure 1 | The interaction between genetics, immunology, environment and Nature Reviews | Gastroenterology & Hepatology microbiome. IBD develops at the intersection of genetic predisposition (leading to immunological abnormalities), dysbiosis of the gut microbiota and environmental influences. None of the risk factors alone are sufficient for development of disease and complex interactions between each factor occurs, leading to development of IBD.

incidence in urban populations preceded that in rural populations by one decade.8,9 A north–south gradient in terms of latitudes of residence exists, demonstrating a higher incidence of Crohn’s disease in northern latitudes than in southern latitudes.11,12 A similar inverse relationship might exist in the Southern hemisphere, as a high incidence of IBD has been reported in New Zealand.13 206  |  APRIL 2015  |  VOLUME 12

Within countries considered to have a high incidence of IBD, some populations have a markedly reduced incidence when compared with the general population, such as the First Nations population in Canada14 or the Arab Bedouin population in Israel.15 In most studies, the peak incidence of IBD is in the second to fourth decade of life and has remained so over several decades. Some cohorts have suggested a bimodal incidence rate with a modest second peak in the sixth and seventh decades of life.1,2,4 Incidence in established populations is similar in men and women, but is influenced by race and ethnicity. The risk of IBD is threefold higher in the Jewish population than in non-Jewish populations.16 Furthermore, risk of IBD is higher particularly among Ashkenazi populations (compared with Sephardim populations) and American and European Jewish populations compared with those residing in Israel. Although initial estimates suggested a markedly lower prevalence of IBD in those who were African-American or of Hispanic ethnicity than white populations, studies suggest that the gap in incidence between white and nonwhite populations is n­arrower than first thought, with comparable phenotypes.17,18

Emerging populations and migration Traditionally, IBD has been considered a disease of the West and infrequent in the East, a premise compounded by the scarcity of incidence data from non-Western populations. However, data suggest that both Crohn’s disease and ulcerative colitis are no longer rare in these emerging populations and such epidemiological trends can provide informative clues towards disease epidemiology (Figure 2). Japan, Hong Kong and Korea all demonstrated an increasing incidence of disease between 1980 and 2003.19 Interestingly, in most of these populations, the incidence of ulcerative colitis is greater than and often precedes the rising incidence of Crohn’s disease by one decade. In the population-based Asia–Pacific Crohn’s and Colitis study, the incidences of ulcerative colitis and Crohn’s disease were 0.76 and 0.54 per 100,000, respectively, which is considerably lower than for Western countries.20 IBD remains rare in Africa and South America, but case series suggest an increasing frequency of occurrence.21,22 An increasing incidence of IBD in Saudi Arabia has also been observed with a disease course similar to that observed in the West.23 The peak age of onset in emerging populations seems similar to that reported from Western countries.20 The distinct genetic background of these emerging populations in contrast to IBD in white populations, the lack of replication of some of the risk loci identified in white individuals,24 and the rapid rise in incidence paralleling changing lifestyle and behaviour emphasize a key role of the environment in disease pathogenesis. Added emphasis comes from studies of immigrants. An initial report by Probert et al.25 identified the incidence of ulcerative colitis in first-generation and second-generation Indian migrants to the UK to be similar to the native UK population, and higher than the incidence in the countries of origin, whilst the incidence of Crohn’s disease was lower.26



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REVIEWS

High incidence of paediatric IBD in South-Asian population in BC, Canada. Male predominance; more colonic disease28

Low incidence in First Nation populations14 Rising incidence from 1940 to 1993 Similar rates of ulcerative colitis and Crohn’s disease8,9 Older age of onset and milder disease in foreignborn Hispanics in the USA30

Increased risk of IBD in second-generation immigrants from Asia in the UK25–27

Rising incidence in Asia paralleling ‘Westernization’ (1980–2003)19

Greater incidence in Northern latitudes12

Higher incidence of IBD in Israeli Jewish individuals than Arab individuals15

No association with NOD2 CARD15 or IL-23R variants24

Uncommon occurrence, although small studies suggest a rising incidence in Africa21,22

Increasing incidence in Saudi Arabia Similar morbidity as in the West23

Incidence in Asia lower than in white individuals Ulcerative colitis more common than Crohn’s disease Milder natural history of disease20

High incidence of IBD in Canterbury, New Zealand13

NatureofReviews | Gastroenterology & Hepatology Figure 2 | Global map of IBD in established and emerging populations. Patterns changing incidence of IBD worldwide provide important clues to potential environmental factors, timing of exposure and genetic predisposition to the development of IBD.

Subsequent studies from the UK and Sweden suggested that the increase in risk was most apparent in the second generation whereas the first-generation immigrants from low incidence countries continued to have lower risk than those from the country migrated to.27 This change in disease risk is more prominent in migrants from West or South Asia to the West, and less so within areas of similar socioeconomic status.27 In BC, Canada, the incidence of paediatric IBD among immigrant South Asians was even higher than in the native white population.28 In one of the largest studies examining the effect of immigration on disease risk, Benchimol et al.29 found a markedly lower risk of IBD in immigrants, particularly from East Asia, than in the general population of ON, Canada. Older age at immigration was associated with a greater reduction in risk of IBD and the attenuation in risk persisted in children from East Asia, Central Asia and Latin America but not the Middle East, South Asia, Africa, or Western Europe. The phenotype of IBD in emerging populations and with migration also seems distinct and milder than in established Western populations, though to what extent this phenomenon is a reflection of the natural history of disease compared with differences in health-seekin­g behaviour, and patient and provider preferences is unclear. The immigrant Indian population in the UK and native population in India and rest of Asia have markedly lower rates of surgery than rates from Western countries.25,26 Foreign-born Hispanic individuals in the USA had lower rates of surgery or need for biologic therapy than non-Hispanic white individuals.30

Genetic epidemiology and genetics

Support for a role for genetics in the pathogenesis of IBD was initially derived from familial aggregation studies and twin studies, which suggested an important hereditary component.3,31–38 Between 2% and 14% of patients with Crohn’s disease report a family history of the condition whereas a small proportion of these patients will have a family history of ulcerative colitis. A similar proportion, 8–14%, of patients with ulcerative colitis will have a family history of IBD, more commonly ulcerative colitis. Consequently, the relative risk of developing IBD for first-degree relatives of a patient with Crohn’s disease is estimated to be around 5% in non-Jewish and 8% in Jewish patients, with the corresponding risk of ulcerative colitis being 1.6% and 5.2%, respectively.38 If both parents were affected, the risk of the offspring developing IBD before the age of 30 years is estimated to be as high as one-in-three.31 Twin studies have also suggested a key heritable component for both Crohn’s disease and ulcera­ tive colitis. For Crohn’s disease, concordance rates in monozygotic twins is 20–50% whereas that for dizygotic twins is 10%. The corresponding figures for ulcerative colitis are lower and are estimated at 16% for mono­ zygotic and 4% for dizygotic twins, suggesting a weaker heritable component for this disease. Within twin pairs, there might be discordance both in the type of IBD as well as natural history of disease, influenced in part by the environment; for example, a twin who smokes might develop Crohn’s disease whereas the nonsmoking twin might develop ulcerative colitis.31,34–36,39

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REVIEWS Genetic loci associated with IBD were initially identified using linkage studies, which first demonstrated an association with a locus on chromosome 16.40 This locus was subsequently characterized as the NOD2 locus in 2001 with three common variants that influence susceptibility to Crohn’s disease.5,6 Homozygosity at the NOD2 locus is associated with a 20–40 fold increase in disease risk whereas heterozygosity confers a more modest (yet strongest among the loci identified so far) 2–4 fold elevation in disease risk.5,6 A subsequent international collaborative effort identified 163 distinct risk loci mapping to a much larger number of potentially associated genes.41 The vast majority of loci are shared between both diseases with similar directions of effect, although some loci (such as NOD2 and ATG16L1) are specifically associated with Crohn’s disease alone and others only with ulcerative colitis.7 Despite the divergence in their effects on the immune system, many of the putative genes can be broadly divided into those influencing innate immune responses, autophagy, maintenance of the integrity of the epithelial barrier, adaptive immune responses, restitution and injury repair, response to oxidative stress and microbial defence and antimicrobial activity.32 Several risk loci might influence immunological function within a single pathway; for example, ATG16L1, NOD2, IRGM, LRRK2 all exert an influence on autophagy. Genetic polymorphisms might also act in synergy and influence cellular phenotypes such as Paneth cell function.42 A full discussion of the genetics of these diseases is beyond the scope of this Review and the reader is directed to several e­xcellent articles on the topic.3,32,43 Extreme phenotypes, such as very-early-onset disease characterized by treatment refractoriness and severe perianal fistulization, might have distinct monogenic origins (for example, IL‑10 receptor mutations). In contrast to the polygenic pathogenesis of idiopathic IBD, these pheno­ types might respond durably to stem cell transplantation.44 In spite of the advances in the field, the known risk loci account for less than one-quarter of the heritability of these diseases, suggesting a strong role for the environment (discussed later).7,32 Furthermore, genetics also highlight the key part played by the interaction between the internal microenvironment in the form of gut microbial dysbiosis and associated immunological response, both processes influenced by the external environment. In addition, the sharing of risk loci between those influencing risk of IBD and also response to infections (such as leprosy or tuberculosis) also further highlights the complex interplay.7,32

Microbiota

The key pathways associated with microbial response and innate immunity highlighted by the latest advances in genetic analysis has led to a resurgence in the interest in the gut microbiota in IBD.45–49 Detailed reviews have been published on this topic highlighting associations between microbiota and disease, but a few key findings merit being highlighted in relation to the environment.46,49 Several epidemiological clues point towards the role of altered host microbiota in IBD. Cohort studies 208  |  APRIL 2015  |  VOLUME 12

and case–control analyses have demonstrated larger family size, early life exposure to pets and farm animals, and greater number of siblings to be inversely associated with risk of IBD, whereas breastfeeding seems to be protective.50–52 All these early life parameters are known to be important determinants of the gut microbiota in adulthood, lending plausibility to the role of the gut microbiota in disease pathogenesis. Patients with IBD demonstrate a dysbiosis in their luminal microbiota, most consistently characterized by a reduction in diversity of this microbial community compared with healthy individuals.45–49 This difference in microbial diversity is greater for Crohn’s disease than ulcerative colitis, which resembles the microbiota of healthy individuals to a greater degree. Additionally, twin studies also suggest that the microbiota is different between healthy siblings and discordant twins.53 Mucosal transcripts (showing mucosal gene expression) from healthy siblings show greater correlation with bacterial genera than in those with ulcerative colitis or their healthy twins, suggesting a disordered interaction between the mucosa and microbiota in IBD.54 Although pathogenic microorganisms have not been identified in all scenarios, specific phenotypes might be associated with certain microbial triggers. A more promising pathogen as a potential causative agent in IBD is adherent–invasive Escherichia coli (AIEC). DarfeuilleMichaud et al. 55 identified AIEC strains in 22% of patients with Crohn’s disease compared with only 6.2% of healthy controls, with localization in the ileum. AIEC might have a role in Crohn’s disease because of its ability to invade the epithelium and persist within macro­ phages. By contrast, certain microbial subpopulations might confer protection from disease. Bacteria belonging to the Firmicutes phylum are often less commonly found in those with Crohn’s disease.46,49 In particular, Faecalibacterium prausnitzii, a butyrate-producing bacteria belonging to the Firmicutes phylum, occurs less frequently in patients with IBD than healthy controls and inversely correlates with severity of endoscopic recurrence after resection. In addition, this bacteria ameliorates colitis in mice when administered intragastrically via an anti-inflammatory effect mediated by an increase in IL‑10 and suppression of IL‑17.56–58 The external environment is a strong determinant of the gut microbiota, as might be host genetics. Both long-term and short-term diets affect the intestinal microbiota and these changes in microbial composition could mediate the influence of diet on risk of incident disease. 59,60 Long-term diet clusters the gut micro­ biome into two enterotypes: enterotype 1 is enriched in Bacteroides spp. and correlates with a Western-style diet with high intake of animal proteins and saturated fat; enterotype 2 is enriched in Prevotella spp. and is seen in individuals with a carbohydrate and fibre-predominan­t diet. 59 In addition, short-term dietary changes alter diversity and composition of the gut microbiota and offer plausible mechanisms of the effect of diet on IBD.60 The effect of the gut microbiota on IBD is not restricted to bacterial dysbiosis and there might be important roles for viruses, Archaea and fungi. Both Crohn’s disease



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REVIEWS and ulcerative colitis were associated with expansion of bacterio­phages belonging to the Caudovirales family independent of bacterial dysbiosis.61 Moreover, in studies in mice, altered immune responses to indigenous fungi in the gut mediated through the innate immune response receptor Dectin‑1 influenced susceptibility to chemically induced colitis.62

Environmental risk factors Smoking The association between smoking and ulcerative colitis was first described by Harries et al.63 who noted a reduced frequency of smokers among patients with ulcerative colitis compared with healthy controls. A meta-analysis quantified the increase in risk associated with smoking to be twofold for Crohn’s disease (OR 1.76, 95% CI 1.40–2.22).64 The same magnitude of association was seen between former smoking and ulcera­tive colitis, but not for current smoking, which demonstrated a strong inverse association (OR 0.58, 95% CI 0.45–0.75). In a prospective cohort of female nurses, the risk of ulcerative colitis increased within 2–5 years after smoking cessation and remained elevated for 20 years.65 Early life exposure to smoke and passive smoking have similar effects.66 However, although smoking is one of the most consistently replicated risk factors, gender and ethnic variations in susceptibility suggest complex gene–environment interactions. Not all cohorts have uniformly identified an effect of smoking on IBD. In an Israeli study, smoking cessation was associated with an increased risk of ulcerative colitis, but not of Crohn’s disease.67 In an elegant study by Cosnes et al.,68 current smoking was associated with later age of onset of ulcerative colitis and lower risk of need for immunosuppression in men but not women. By contrast, smoking was associated with early age of onset and more frequent need for immunosuppression in Crohn’s disease among women, but not men.68 Consistent with the direction of effect on incident disease, smoking is associated with a more-aggressive disease course in Crohn’s disease.69–72 Smokers are more likely to require immunosuppression and surgery, and have greater likelihood of recurrence after ileocecal resection. By contrast, in ulcerative colitis, smoking cessation is frequently a precipitant for disease flares within a year of cessation,69,73 and current smokers have a milder disease course, fewer surgeries and less need for immunosuppression. Several hypotheses have been proposed to explain the association between smoking and IBD though none have demonstrated convincingly the reason behind the divergent effect on Crohn’s disease and ulcerative colitis.72,73 Nicotine was long-believed to be the trigger; however, trials of nicotine replacement therapy in ulcerative colitis yielded equivocal results74 and no association was observed between oral tobacco use and Crohn’s disease,75 suggesting that other components of tobacco smoke might be important. Smoking could alter smooth muscle tone and influence endothelial function through nitric oxide production,76 or affect the integrity of the gut mucous barrier.77 The effect of smoking could also be

mediated by oxidative stress. Bergeron et al.78 found that mononuclear cells from smokers with Crohn’s disease but not ulcerative colitis were less sensitive to antiinflammatory protection against oxidative free radical stress because of reduced levels of synthesis of heat shock protein 70. Polymorphisms in genes contributing to nico­ tine metabolism and cellular oxidative response might modify susceptibility to smoke.79 Smoking also exerts an influence on the microbiota. Smoking cessation is associated with an early change in the microbiome, and this interaction with the immune response could underlie the effect of smoking cessation on ulcerative colitis.80–82

Appendectomy Similar to smoking, appendectomy demonstrates a divergent effect on Crohn’s disease and ulcerative colitis. In a large cohort of 212,963 patients who underwent appendectomy before the age of 50 years, the incidence of ulcerative colitis was markedly lower among those who underwent appendectomy for perforated or non­ perforated appendicitis and mesenteric lymphadenitis than for those with nonspecific abdominal pain, suggesting that inflammation of the appendix rather than the mere removal of the organ might be responsible for this protective association.83 This effect is limited to appendectomy before the age of 20 years. By contrast, the same cohort found an increased risk of Crohn’s disease for up to 20 years after the appendectomy;84 however, when patients were operated on below the age of 10 years, the risk of Crohn’s disease was reduced.84 The association between appendectomy and Crohn’s disease is more difficult to interpret as some of the inconsistency in findings between the different studies could reflect surgery for abdominal pain in Crohn’s disease before formal diagnosis, thereby leading to a spurious association of increased risk.85 Several studies have also evaluated whether appendectomy alters the natural history of these diseases.84,86–89 For Crohn’s disease, one study suggested a later diagnosis of Crohn’s disease in those who had undergone an appendectomy previously.88,89 As noted for incident disease, the reason for appendectomy seems to be important in determining outcomes. Appendectomy for perforating appendicitis was associated with increased risk of subsequent intestinal resection, whereas appendectomy for other causes was associated with a reduced risk of Crohn’s disease.84 For ulcerative colitis, prior appendectomy was associated with a greater risk of coexisting primary sclero­ sing cholangitis and pancolitis distribution of disease, and reduced need for immunosuppression, but had no clear effect on risk of colectomy.87–89 Hygiene The hygiene hypothesis was first proposed by Strachan et al.90 to explain the rising incidence of autoimmune diseases in the developed world. Indeed, several studies provided support for this hypothesis in the context of IBD. Number of siblings, larger family size, drinking un­p asteurized milk, living on a farm and exposures to pets (particularly early on in childhood) have been inversely associated with risk of Crohn’s disease or

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REVIEWS ulcerative colitis.16,52,91,92 However, most such studies have been case–control in design and could not rule out effect of recall bias or confounders. Other early life factors have been examined in the context of disease risk under the hypothesis of an early influence of such factors on the gut microbiota and development and maturation of immune responses. Although several studies have demonstrated a strong inverse association between a history of being breastfed and IBD, this finding is not consistent across all cohorts and is stronger for ulcerative colitis than for Crohn’s disease.93 Although mode of childbirth also has an important influence on the gut microbiota in infancy, the association with risk of IBD is less robust.94 In developing countries, measures of hygiene have not demonstrated the inverse association reported in the West, and have in fact been associated with an increased risk of ulcerative colitis.95

Infectious pathogens and antibiotics Infections A putative association between infectious pathogens and IBD has been of long-standing interest; generally speaking, the lack of transmissibility, excellent response to immunosuppression and poor response to antibiotics argues against a direct causal association. However, the importance of innate and adaptive immune responses, maintenance of barrier integrity, and host recognition and response to pathogens in disease pathogenesis suggests a more complex interaction of disease susceptibility with potential infectious triggers. Among the various pathogens, interest has been strongest for Mycobacterium avium subspecies paratuberculosis (MAP) responsible for Johne disease in cattle. A high frequency of MAP in patients with Crohn’s disease was found in some but not other studies,96–99 and a randomized controlled trial demonstrated no clinical benefit with antimycobacterial treatment.99 Cohort studies from Denmark suggested an association of IBD with Salmonella or Campylobacter infection,100 whereas others using data from the US military population101 as well as the UK primary care database102 have demonstrated an increase in risk of IBD after episodes of gastroenteritis without a firm bacterial or viral aetiology. This increased risk is strongest in the year immediately after the diagnosis of infection, suggesting that the reported association might at least in part be due to a detection bias.103 Interest in the potential role of viruses initially centred on a direct pathogenic link with the measles virus or vaccination, although rigorous studies refuted this link.104–106 Viruses could act as triggers in the setting of genetic susceptibility. In animal models, norovirus infection in mice with autophagy defects led to Paneth cell abnormalities and a Crohn’s-disease-like inflammatory reaction.107 This effect was dependent on TNF and IFN‑γ and was ameliorated by treatment with broad-spectrum antibiotics. The same result was not seen in mice without an autophagy defect, suggesting a complex interaction between viruses, bacteria and host genetics in disease pathogenesis. Infections are frequently triggers of relapse in those with established IBD. Of these, one of the most common 210  |  APRIL 2015  |  VOLUME 12

triggers is Clostridium difficile.108 This infection is frequently associated with relapses of disease, particularly in the hospitalized population, and is associated with a substantial burden of both mortality and morbidity with an effect that might last for over a year after the initial infection.108 Systemic infections could also act as triggers for relapse in those with established disease though the supporting data are less robust.109 Antibiotics The gut microbiota is diverse and unstable during early childhood.110 Perturbation of this microbiota in early childhood could influence the gut immune response and alter susceptibility to IBD. In a nested case–control analy­ sis from the University of Manitoba IBD cohort, 58% of paediatric patients with IBD received an antibiotic in their first year of life compared with only 39% of the controls.111 The association is greater for Crohn’s disease than ulcerative colitis,112 is observed with different classes of antibiotics113 and is stronger for exposure in the first year of life compared with later use.114 A dose-response relationship also exists with multiple courses of anti­ biotics contributing to a greater increase in disease risk than a single course.114 However, most of the association studies of antibiotics have been in Western populations who have low exposure to early life infectious pathogens or have good sanitation. In contrast to this prevailing data, antibiotic exposure demonstrated a protective association with both Crohn’s disease and ulcerative colitis in a large population-based study in Asia.45

Medications Other medications have been associated with IBD including aspirin,115 NSAIDs,116 oral contraceptives117,118 and postmenopausal hormone therapy.119 The association with NSAIDs was stronger with higher doses and longer duration of NSAID use and was similar for Crohn’s disease and ulcerative colitis.116 NSAIDs might trigger relapses in up to one-third of users. Their effect might be due to the nonselective inhibition of cyclo-oxygenase (COX) enzymes, as selective COX‑2 inhibitors are associated with a reduced rate of relapse.109 Oral contraceptive use confers an increased risk of Crohn’s disease but the magnitude of this effect decreases with cessation of use.117,118 Diet Fibre Most epidemiological studies of diet and IBD have focused on macronutrients and have relied on a case– control design susceptible to numerous limitations.120,121 Despite heterogeneity in design, the most consistent macronutrient association has been an inverse association with dietary fibre.122,123 Newly diagnosed paediatric patients with Crohn’s disease had markedly lower intake of fruits and vegetables than controls without IBD.122 In a prospective cohort study, women in the highest quintile of long-term fibre intake had a 40% reduction in risk of Crohn’s disease (OR 0.59, 95% CI 0.39–0.90);123 this inverse association was stronger for fibre from fruits and vegetables and not seen with whole grains



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REVIEWS or cereals. Several potential mechanisms could explain an inverse association with fibre. Soluble fibre (from fruits and vegetables) is metabolized by the intestinal bacteria to short-chain fatty acids that inhibit transcription of pro­inflammatory mediators.124 In addition, fibre helps maintain the integrity of the epithelial barrier and reduces translocation of E. coli across Peyer’s patches in vitro.125 Finally, the indole‑3-carbinol present in fruits and crucifer­ous vegetables activates the aryl hydrocarbon receptor and attenuates colitis in animal models.123 Dietary fat Dietary fat, particularly saturated fats, might also have a role in pathogenesis.120–122,126–131 In mice, a high-saturatedfat diet promotes expansion of a sulphite-reducing pathobiont, Bilophila wadsworthia, and was associated with an inflammatory response mediated by type 1 T helper cells and colitis in IL‑10-knockout mice.132 In humans, although saturated fats have been associated with risk of IBD in small case–control studies, prospective cohorts have not identified such an association, suggesting a more complex effect.120,122,126,130,133 High consumption of n‑6 polyunsaturated fatty acids (omega-6 PUFA) and low consumption of n‑3 PUFA (or a high n‑6:n‑3 ratio) has been associated with an increased risk of both ulcerative colitis and Crohn’s disease. This association might be modified by polymorphisms in fatty acid metabolism, particularly in the CYP4F3 and FADS2 enzymes.134 Inconsistent associations with IBD have been demonstrated with carbohydrate intake, refined sugars and animal protein.120,121,135,136 In contrast to the literature on diet and incident disease, few studies have examined the role of diet in established disease. Studies relying on self-reported diet suggest heterogeneity in ‘protective’ and ‘harmful’ foods.137 The marked interindividual variation in the gut microbiota confirms this expected h­eterogeneity in response to dietary i­nterventions in IBD. Vitamin D Few studies have examined an association of IBD with micronutrients but such a relationship is based on considerable biological plausibility from supporting laboratory studies. Emerging data suggest that vitamin D might have a role in the pathogenesis and course of IBD.138–140 In mice, deficiency of 1,25-dihydroxy vitamin D3 (1,25(OH)2D3) or knockout of vitamin D receptor is asso­ciated with an increased risk of colitis; administration of 1,25(OH)2D3 ameliorates this inflammation and suppresses expression of proinflammatory genes including TNF.141–144 Vitamin D might also suppress responsiveness of mononuclear cells to circulating antigens.138 Deficiency of vitamin D is common in patients with newly diagnosed IBD and more common than in healthy individuals.145 In a prospective cohort assessing predicted vitamin D status using a validated regression model, women in the highest quartile of predicted vitamin D status (median 32.2 ng/ml) had a significantly lower risk of Crohn’s disease than those in the lowest quartile (OR 0.54, 95% CI 0.30–0.99).146 Low levels of vitamin D (1 year were less likely to relapse and require steroids or immunosuppressive therapy than those who continued smoking. By contrast, nicotine supplementation in ulcerative colitis has yielded equivocal results in clinical trials,74,179 although case reports suggest efficacy in small series with refractory colitis.180 Given the inverse association between appendectomy and incidence of ulcerative colitis, therapeutic appendectomy for the management of refractory ulcerative colitis has been attempted. However, evidence is limited to a few case reports suggesting benefit.88,181,182 Few studies have intervened with dietary modifications and most such studies have been in the form of uncontrolled case series (Table 1). An elemental diet can restore diversity of gut microbiota and has been shown to be efficacious in inducing remission in paediatric IBD.183,184 The specific carbohydrate diet has also demonstrated limited clinical benefit in paediatric Crohn’s disease, but rigorous studies are lacking.185 Self-reported adherence to a gluten-free diet has been associated with clinical improvement, although it might not influence endoscopic activity.186 Jorgensen et al.187 randomly assigned 94 patients with quiescent Crohn’s disease to 1,200 IU of vitamin D or placebo daily and found reduced relapse in the vitamin D group (29% versus 13%, P = 0.06). In a small series, zinc supplementation reduced intestinal permeability and rate of relapse.151 In contrast to the epidemiological data supporting an association between n‑3 and n‑6 PUFA intake and IBD, randomized controlled trials of fish oil or n‑3 PUFA in patients with established Crohn’s disease have been unsuccessful in inducing or maintaining remission,188 whereas a small study of dietary modification to reduce n‑6:n‑3 PUFA intake in ulcerative colitis was e­ffective in maintaining remission.189 Few intervention studies have been published that have examined the effect of modifying stress.163,168,169 Psychological counselling was associated with reduced relapses in some, but not all, studies.190,191 In one small study, antidepressant use was associated with reduced rates of relapse in the year after initiation of therapy.192 As interventional studies are developed to evaluate the effect of environmental modifications, be it behavioural or dietary changes, one also needs to recognize that underlying host genetics could influence susceptibility to the effect of environmental modifications. Sex and ethnicity could also alter the likelihood of beneficial effect of smoking cessation (or nicotine replacement) in IBD,68 as might polymorphisms involved in nicotine and oxidative free radical clearance.79 Similarly, FADS2 and CYP4F3 mutations could influence any beneficial effect of an alteration in the n3:n6 PUFA ratio by altering plasma levels of PUFA metabolites.134

Exposome and continuous monitoring

The term ‘exposome’ was first coined in 2005 to include the entire life course of environmental exposures from the perinatal period onwards,193 which could be further subdivided into an ‘adductome’, encompassing chemical exposures leading to formation of DNA adducts contributing to carcinogenesis,194 and an ‘infectome’, measuring

Box 1 | Unanswered epidemiological questions in IBD When is the environmental exposure relevant to the pathogenesis of IBD? ■■ Early life and infancy? ■■ Recent exposure? ■■ Remote exposure? In whom are environmental exposures important? ■■ In those who are otherwise genetically susceptible to IBD? ■■ In those who have low genetic risk of IBD? ■■ In those with variants in metabolizing enzymes or other pathways that makes them susceptible to an environmental influence? Are the environmental influences that affect development of disease the same as those that influence natural history? What is the role of modifying environmental exposures in improving patient outcomes? ■■ Prevent disease in high-risk individuals? ■■ Avoid need for existing therapies or supplement existing agents? ■■ Induce remission in active disease? ■■ Maintain remission and prevent relapse in quiescent disease?

lifetime exposure to infections.195 Quantification of exposures encompassing various environmental factors could be useful in patients with IBD to predict natural history and might also be useful in those at risk (for example, first-degree relatives). Such exposures (including peri­ natal, early life and recent exposures) could be assessed in blood, stool or urine, each reflecting different routes of exposure. Electronic applications and wearable devices offer another attractive modality to monitor exposure, including physical activity, sleep, diet and stress. Biological measures such as sequencing the gut micro­ biome or quantifying epigenetic changes can supplement these passively collected or self-reported exposures and the genome can be used to determine susceptibility to the effect of various exposures. One could then intervene at the onset of environmental perturbations (for example, increased stress, reduced sleep or change in diet) before the development of gut inflammation and relapse.

Conclusions

IBD is a complex disease occurring at the intersection of genetics, the environment and the gut microbiota. Neither factor in itself is sufficient for development of disease. Increasing incidence and emergence in previously low-risk populations provide strong evidence supporting the effect of the environment for both Crohn’s disease and ulcerative colitis. Progress in genetic and microbiome analysis has demonstrated the key role of the interface between the immune response and the gut microbiota. Although a number of environmental associations have been identified, high-quality intervention studies are needed and several questions remain un­answered (Box 1). Existing and ongoing prospective cohorts such as the Genetics, Environmental, Microbial (GEM) Project in Canada studying those with Crohn’s

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REVIEWS disease and their healthy siblings,196 as well as paediatric initiatives for patients with newly diagnosed Crohn’s disease and ulcerative colitis (RISK197 and PROTECT198) will provide important insights into the interplay between genetics, the environment and microbiota in disease pathogenesis, natural history and response to treatment. Comprehensive management of patients with IBD will need to not just resolve existing inflammation and achieve mucosal healing, but also incorporate modification of the external environment to aid, achieve and maintain durable remission and improve patient outcomes. 1.

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Review criteria The MEDLINE database was searched for Englishlanguage reports using the search terms: “Crohn’s disease”; “ulcerative colitis”; “epidemiology”; “incidence”; “risk factors”; “smoking”; “environment”; “diet”; “stress”; “vitamin D”; and “lifestyle”. Nearly all the articles identified were within the past three decades, most within the past 10 years. The reference list of review articles identified as part of this search strategy was further searched for relevant articles not identified in the original search.

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