IBD geographical variation between countries

The highest incidence rates of CD and UC have been reported in northern Europe, the UK and North America.8 ,10 Such high incidence rates in these countries may indicate common aetiological factors. Countries in the Pacific, including New Zealand and Australia, which share many possible environmental risk factors and similar genetic background as north-west Europe and North America have high incidence rates of IBD. For instance, population-based studies from Canterbury in New Zealand11 and Geelong in Australia showed that the incidence rates of both UC and CD were among the highest in the world.12 In countries that are becoming more westernised, including China, South Korea, India, Lebanon, Iran, Thailand, the French West Indies and north Africa, IBD appears to be emerging. In Africa and Central and South America, data are scarce or not available. Figures 1 and 2 illustrate the incidence rates of CD and UC worldwide.

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Figure 1

Global map of Crohn's disease incidence. This figure is only reproduced in colour in the online version.

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Figure 2

Global map of ulcerative colitis incidence. This figure is only reproduced in colour in the online version.

Within Europe marked differences in rates of IBD between centres have been reported. The highest incidence rates have been demonstrated in the islands of Iceland and the Faroe Islands in the north, and the islands of Crete and Sicily13 in the south of Europe. Within the UK, Germany and Spain, there are no direct comparisons of national variations. Higher incidence rates have been reported from studies in Ireland, Scotland and The Netherlands compared to the UK and western Germany.13 Many of these differences, however, might be explained by differences in the type of cohorts, methods of data collection and the organisation of healthcare. In the European Collaborative Study on IBD (EC-IBD), differences in incidence rates between northern and southern Europe were less than might have been expected.13 This may reflect an increase in the incidence rate of both diseases in southern Europe.14

Within eastern Europe, recent population-based studies from Hungary and Croatia have reported sharp increases in IBD incidence rates and prevalence, comparable to that of high-incidence areas in western European countries.15–17 In contrast, studies from other eastern European countries such as Romania and Poland still report relatively low incidence rates.18 ,19 As a result of methodological bias, the reported incidence rates may have been underestimated. The reasons for these changes could be increased awareness of the disease and differences in diagnostic practices, or they could reflect real differences, as a result of environmental influence. Changes in lifestyle in eastern Europe over the past two decades have resulted in a more ‘westernised‘ way of living.20 It will be of interest to follow the temporal trends for IBD in eastern Europe to monitor whether this increase continues over time.

The impact of increasing immigration to western societies is important. Earlier reports showed that the prevalence of UC among southern Asians who migrated to the UK was higher compared with the European UK population (17 cases per 100 000 persons vs seven per 100 000).5 ,6 A recent study showed that Spanish patients who emigrated within Europe, but not those who emigrated to Latin America, developed IBD more frequently than controls.7 Individuals who have emigrated to westernised countries and subsequently returned to their country of birth also continued to demonstrate an increased risk of developing IBD, especially UC, suggesting that environmental factors related to industrialisation play an important role in disease pathogenesis.7 The critical age of living within a high-incidence area remains to be established, but undoubtedly childhood years will prove to be important.

IBD geographical variation within countries

Within certain individual countries there is evidence of epidemiological variability, as has been reported in Norway,21 France,22 Canada23 ,24 and Scotland.25 Within France,22 ,26 Italy, Spain and Portugal,13 there is a north–south disease gradient. The incidence of CD increased by 23% over 12 years in northern France while that of UC decreased by 17% during the same period.27 Using a Bayesian approach to take into account differences in population sizes of geographical units and spatial autocorrelation, more recent data from a hospital-based nationwide registry continue to show higher incidence rates and prevalence rates for CD in the north compared to the south of France.22 Other geographical risk factors for CD in France include higher urbanisation in northern areas28 and areas with less in-home sanitation.29 Data on IBD multiplex families in northern France and Belgium showed clustering in space and time,22 suggesting that shared environmental factors may contribute to these clustering effects within a defined space. A study in Scotland has shown a higher incidence of paediatric CD from postal code areas of the north compared with those of the south.25 In Sweden (within the Uppsala healthcare region), the incidence of UC and CD has been reported to be higher in urban than rural areas.30

In Norway, similar incidence rates have been shown between the south-eastern, western and northern parts.21 ,31 ,32 The distribution was more homogeneous in the north compared to southeastern and western Norway.21 The north is characterised by a generally mixed urban and rural population, whereas south-eastern and western Norway have a more defined separation between urban and rural areas.21 Both the western and south-eastern areas showed a generally higher incidence rate in the scattered rural populations, contrary to previous international experience, in which urban areas have been considered to be areas at increased risk of IBD.33 In Norway, the counties with the most scattered and rural populations were also the areas with only one hospital, in contrast to the many recording hospitals and multidisciplinary doctors in the cities. This gave a variation in incidence rate between 17 per 100 000 in Oslo and 28 per 100 000 in the scattered populated area of Aust Agder, with one hospital in the only city of the county. These data may provide evidence for the importance of access to healthcare and awareness of the population under examination.

A key factor that might be related to higher rates in cities and urbanisation is improved sanitary conditions. An epidemiological study in the UK showed that having a fixed hot water supply in childhood before the age of 11 years was associated with an increased risk of CD.34 It may be that different risk factors are acting concomitantly within an area in addition to the existence of different risk factors between areas. Furthermore, variations in the accuracy, efficiency and quality of registration between areas cannot be ruled out as a contributing factor.

In the USA, a north–south gradient has been shown by hospital-based registrations,35 ,36 whereas in Canada, a nationwide comparison demonstrated an east–west disease gradient.37 Northern Canada is more sparsely populated than southern Canada, and its population is overrepresented by ethnic groups such as Canadian First Nations with low incidence rates of IBD,37 and thus there is a south–north gradient within Canada. The high rates in Canada and the northern USA relative to lower rates in southern USA, Mexico and Central America do suggest a north–south gradient in the western hemisphere. This gradient probably reflects differences in environmental exposure and not genetic factors.

Figure 3 shows a north-to-south disease gradient for UC in Spain and figure 4 shows an east-to-west disease gradient for CD within Canada.

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Figure 3

Variation of incidence rates for ulcerative colitis within Spain showing a north–south disease gradient (generated from data in supplementary appendix 1, available online only). This figure is only reproduced in colour in the online version.

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Figure 4

Variation of incidence rates for Crohn's disease within Canada showing an east–west disease gradient (generated from data in supplementary appendix 2, available online only). This figure is only reproduced in colour in the online version.

Changing epidemiology over time

The incidence of IBD is increasing with time and in different regions around the world. In the past 50 years, the incidence rate of UC first increased then stabilised or even decreased while that of CD has continued to increase. More recent data showed that the incidence rate of CD in adults in Europe has stabilised. However, temporal trends showed that the incidence of CD in Europe is still rising due to paediatric CD.38 For example, in northern France, the CD incidence rate has increased by 71% in the 10–19-year-old age group between 1988 and 2007.39

Traditionally considered an area of low incidence, Asia is witnessing a rise in incidence in parallel with rapid socioeconomic development.40–43 Recent data showed significantly higher rates in Asian populations, and time trend studies from Japan, Korea and Hong Kong have reported an increase in incidence rates of UC and a similar but lower rise in CD.4 In Japan, the prevalence of CD has risen rapidly from 2.9 cases per 100 000 persons in 1986 to 13.5 per 100 000 in 1998,44 whereas in South Korea the prevalence of UC has quadrupled from 7.6 per 100 000 in 1997 to 30.9 per 100 000 in 2005.2 In Hong Kong, the prevalence of UC almost tripled from 2.3 in 1997 to 6.3 per 100 000 over a 9-year period.45 In Singapore, the prevalence of CD increased from 1.3 in 1990 to 7.2 per 100 000 in 2004.46 In China, the number of cases of UC has increased by fourfold between 1981–90 and 1991–2000.47 There are no published studies comparing incidence rates or prevalence figures between different regions of the Asia-Pacific area. Challenges in the Asia-Pacific region include difficulty in defining catchment areas and the lack of uniform criteria for case ascertainment. Much of the aforementioned data are hospital based, and so there is a bias in terms of assessing only those populations that access the hospitals under study. Even within Asia incidence rates and prevalence of IBD vary according to geography and ethnic groups. The highest rates have been reported in India (particularly of UC), Japan and the Middle East, whereas overall rising trends of IBD are seen in east Asia. Rates of IBD appear to be higher in urban than in rural communities. In Turkey, the prevalence of UC was significantly lower in rural (2.2 per 100 000) than urban areas (5.9 per 100 000).48 Unlike Europe and North America, there are no data for a north–south or an east–west divide in the Asia-Pacific region. There is also a lack of population-based studies evaluating race or ethnicity in developing nations, although there is some suggestion that certain ethnic groups such as Indians are more susceptible to UC compared with Chinese or native Malay within the same country.49 ,50 The differences between ethnicities within one country may reflect differences in genetic susceptibility, living conditions and/or diet.51

In summary, there appears to be a north–south gradient of disease incidence in the Americas, with less of one in Europe in recent years. Some of the highest incidence rates of IBD occur in southern Australia and New Zealand.11 ,12 The east–west gradient that has evolved in Europe may be either a real phenomenon or simply a product of evolving healthcare systems and case ascertainment in eastern European countries; the reasons behind these regional differences are far from clear cut. Other data on intracontinental differences of IBD in general are few, and mostly based on results from a single country. Standardised population-based data of comparisons between the east and west of Europe as part of the European Crohn's and Colitis Organisation (EpiCOM (Epidemiologic Committee) Study) and between 10 countries within the Asia-Pacific region (Asia-Pacific Crohn's and Colitis Epidemiology Study) are in progress. Previously believed to occur less frequently among non-Caucasian compared with Caucasian populations, IBD is increasing in these populations, particularly in African Americans and Asians. Epidemiological data from migrant populations indicate that environmental factors contribute to the risk of IBD; first and second-generation migrants were at similar risk.5

Relationship between UC and CD

In addition to variations between countries and regions in the incidence and prevalence of IBD, the ratio between UC and CD also shows geographical variations. Compared to the rest of Europe,13 ,52 ,53 a higher incidence rate for UC than for CD has been reported in Nordic countries.14 ,21 ,54 The reason for this is not completely clear. In Canada and the USA,8 recent incidence rates suggest that CD is the more predominant disease, although in some North American studies the prevalence of UC is still greater than CD. The variation in ratios of UC and CD between countries and regions might reflect differences in environmental risk factors, but genetic predispositions may also play a role. In Europe, the incidence of NOD2 mutations appears to be highest in the middle part of Europe, which corresponds with regions where there is a higher CD to UC ratio.55 Interestingly, the CD to UC ratio is close to 1 : 1 in some of the eastern European countries with high IBD incidence; indeed, CD was even surpassing UC in some of the countries such as Croatia.16 ,17

In developing countries, the UC incidence increases first, followed by a rise in CD incidence.8 Reports from Asia have described a decrease in the ratio of UC to CD over time.4 In China the ratio of UC to CD has dropped from 41 to 15, whereas in Korea this has dropped from 6.8 to 2.3 in the past 20 years.56 This temporal trend suggests that CD and UC have both common and distinct risk factors. The former might explain the rise in both diseases with socioeconomic development, the latter might explain the time lag between increased incidence in UC followed by CD.

Smoking

In the west, smoking represents one of the most consistently reported risk factors for CD in case–control studies and in a meta-analysis.57–59 The magnitude of the risk (OR) for developing CD ranges between 1.5 and 2.0 in most studies. The association between smoking and IBD, however, may not be applicable to all ethnic groups or geographical regions for a number of reasons. First of all, smoking may not account for the worldwide trends in disease incidence. Of note, a possible explanation of this phenomenon may be at least partly the differences in the hygiene status and life expectancy. Conversely, countries with some of the lowest current smoking rates among adult male populations, such as Sweden and Canada, have among the highest incidence rates of CD. Approximately 20% of the adult male Swedish population are daily users of moist snuff (smokeless tobacco).60 In a large cohort study from Sweden, there was no significant association between the use of moist snuff and IBD.61 These data suggest that the link between smoking and IBD is mediated through airway exposure to non-nicotinic components of tobacco smoke. Second, in Israeli Jews who have a strong predisposition to IBD, smoking has not been associated with the development of CD.62 ,63 The smoking rates in the control Jewish population in Israel appeared lower than rates in other Caucasian studies (19.9–33% vs 30.9–56.2%),59 indicating that a high background smoking rate could not explain this lack of association. The disparity observed in the effects of smoking among Israeli Jews with CD compared to the non-Jewish white population may reflect a smaller role of smoking on the pathogenesis of CD in a population group with a strong genetic predisposition.59 It may be that smoking does not actually pose a risk for developing CD but modulates the disease, perhaps through a vascular effect, once the disease is present, facilitating the expression of disease. There are several studies that report that smokers have a more aggressive course of disease, including with earlier relapse rates of a medically or surgically induced remission.64

In CD, smoking may not play the same role in different ethnic groups as it does in western populations. One study in China was not able to demonstrate an association.65 In a cross-sectional observational study, there were fewer smokers among Chinese with CD in Hong Kong than Caucasians with CD in Melbourne, Australia.66 More studies are needed in Asia (a high smoking area) to determine the impact of smoking on the development and progression of CD and its association with disease phenotype. However, studies in Japan have shown a protective effect of smoking on UC,1 as has previously been shown in the west. One study showed that current smokers had a decreased risk of UC and former smokers had an increased risk.67 Similar findings have been reported in a case–control study from China.47

The effect of smoking in both UC and CD seems to be modulated by gender, with women being affected more disadvantageously than men.68 ,69 More recently, a time-dependent effect was also reported, suggesting that 4–5 years of smoke exposure may be associated with an altered risk of IBD.68 In contrast, the importance of smoking could not be confirmed in IBD patients with an elderly onset. Therefore, the effect of smoking in an individual may be the sum of the interplay of different host genetic and environmental factors (including smoking, non-steroidal anti-inflammatory drugs, or ultraviolet exposure from sunlight, etc). The mechanisms behind smoking and the onset of IBD remain unclear, but among siblings discordant for smoking, smokers had an increased risk of developing CD, whereas non-smokers tended to develop UC.70 This may suggest an interaction between smoking and genetic susceptibility or, as suggested above, that smoking is a modulating factor in those who present with the disease.

In summary, although tobacco smoking is the only environmental factor consistently predisposing to CD, there are no reliable data about the geographical distribution of tobacco smoking. It is likely that smoking does not cause CD but modulates the disease once present.

Meta-analyses confirmed that in Caucasian populations, smoking is an important environmental risk factor in IBD, with opposite effects on UC (OR 0.58) and CD (OR 1.76),59 whereas in other ethnic groups with different genetic susceptibility, smoking may play a lesser role. The reason why CD in Israeli Jews or Asians is not as sensitive to smoking as in other populations is not clear. Explanations might include differences in genetic and/or environmental factors (eg, type of tobacco, way of smoking or other dietary factors). Therefore, smoking may influence the course of CD but may not influence population trends of IBD. The biological mechanisms for the contrasting associations of smoking on UC and CD remain unknown, but microbial and immunological mechanisms are plausible, as smoking has immunosuppressive effects on T-lymphocyte function, which may lead to alterations in the gut microbiota. Smokeless tobacco has not been shown to increase the risk of CD, suggesting that the inhaled non-nicotinic components of cigarette smoke may be more important than nicotine itself in disease aetiology.

Appendectomy

The declining appendectomy rates in the past 15 years cannot account for the constant or decreasing incidence of UC in developed countries. In case–control and cohort studies from Europe and the Asia-Pacific region, appendectomy has been shown to be protective for the development of UC.71 ,72 In a large Swedish case–control study consisting of more than 200 000 patients who underwent appendectomy between 1964 and 1993, appendectomy before the age of 20 years for appendicitis or lymphadenitis (as opposed to abdominal pain or other causes) was associated with a lower risk of developing UC.71 In contrast, appendectomy without confirmed appendicitis was not associated with a protective effect.

Several studies from Asia have reported a similar protective effect of appendectomy against UC, with OR ranging from 0.11 to 0.38.47 ,73 ,74 In a Japanese multicentre study, UC patients diagnosed after appendectomy appeared to have more limited disease extent and fewer clinical relapses compared to patients with an intact appendix.73 Studies from France and Australia have demonstrated that UC patients who had undergone appendectomy before diagnosis were less likely to require immunosuppressive therapy75 or colectomy.75 ,76 In a meta-analysis of 13 case–control studies, appendectomy conferred a 69% risk reduction for the development of UC when smoking was controlled for.77

In contrast, the relationship between appendectomy and CD is less clear.78 Although several studies have demonstrated that appendectomy is a risk factor for the development of CD,11 ,79–83 others have either shown a protective effect75 or no association34 ,84–87 (table 1). A meta-analysis has demonstrated a significant risk of CD (relative risk (RR) 1.61) following an appendectomy, but heterogeneity was observed between studies.78 The risk was increased within the first year after surgery (RR 6.69), and at up to 4 years (RR 1.99), but after 5 years or more following an appendectomy, the risk dropped to baseline levels (RR 1.08).78 The increased risk of CD appeared to be higher in women than men, and in those with perforated appendicitis than non-perforated appendicitis.83 In a recent large Swedish–Danish population-based study, it appeared that diagnostic bias might account for the observed association between CD and appendectomy88 as the increased risk of CD within the first year after an appendectomy reduced significantly after 5 years, possibly reflecting a misdiagnosis of patients with incipient CD.78 There is currently no published study on the association of appendectomy and CD in Asia, Africa or eastern Europe.

In countries where there is an excess of CD compared with UC, such as France, it has been hypothesised that a high rate of appendectomies may account for this discrepancy.22 The appendectomy rate in France was at least three times higher than that observed in other European countries or in the USA.

In summary, despite some variation, the literature overall suggests a protective effect of previous appendectomy with confirmed appendicitis (reduction of 13–26%), particularly at a young age, and the development of UC across different geographical regions and populations, and a modest association with the development of CD. The inverse association with UC may be a causal one because it is not related to surgery for non-specific abdominal pain. The mechanism by which appendectomy protects against the development of UC but increases the risk of CD is not known; proposed hypotheses include alterations in mucosal immune responses that lead to appendicitis or, as a result of appendectomy, negatively impact on the pathogenetic mechanisms of UC.89–91 The appendix may act as a reservoir of enteric bacteria involved in antigen sampling that regulates the immunological response to host microflora.89 ,91 ,92 It would appear that this proposed mechanism may apply to worldwide populations.

Dietary influence on IBD

Global variation in dietary habits probably explains the differences in the risk of IBD across geographical regions and the increase in disease incidence in migrant and developing populations. However, the effect of diet on the risk and clinical course of IBD has not received as much research attention as is probably warranted. This is because the sheer numbers of possible dietary exposures, and their interactions with host factors such as genetics and the microbiome make the identification of dietary risk factors for IBD a challenging and formidable task. The foods we eat contain macronutrients, micronutrients, additives, pollutants and caloric content of variable concentration; and the water we drink varies in the amount of trace elements, microorganisms and organic and inorganic compounds.

The rates of IBD increased steadily in Europe and the USA from 1940 to 1960, and in Asia in the early 1990s. The rising rates coincided with the introduction and expansion of fast food chains, packaged food, increased use of antibiotics and aluminum foils. In an ecological study from Japan the increased incidence of CD correlated closely with the increased intake of animal protein and dietary fat, especially n-6 fatty acids and a decreased intake of n-3 fatty acids.93 With the absence of NOD2 mutations,94 the increasing incidence and prevalence of CD in Japan is likely to be accounted for by dietary changes. In a retrospective study from Japan performed within 3 years after diagnosis, a higher consumption of sweets was positively associated with UC risk, whereas the consumption of sugars, sweets, fats, oils, fish and shellfish was positively associated with CD risk.95

The difference in the incidence of CD in the north and south of France could also be accounted for by differences in exposure to dietary components.96 Individuals living in the south of France generally consume a diet that is richer in fruit, vegetables, fish, olive oil and wine (dietary factors that have been shown to be associated with a reduced risk of IBD), whereas those in the northern regions consume more butter, eggs, potatoes, sausage, ham and beer.97

In studies from Europe, the most consistent dietary association linked to the development of IBD, particularly for CD, is increased sugar intake98–102 (table 2). A population-based case–control study from The Netherlands showed that cola drinks and chocolate are potential risk factors for IBD.103 A second key dietary factor might be animal protein.104 ,105 The European Prospective Investigation into Cancer and Nutrition, consisting of more than 200 000 subjects across five European countries, showed that an increased intake of linoleic acid (n-6 fatty acid; particularly high in red meat, cooking oils and polyunsaturated margarine) more than doubled the risk of developing UC (OR 2.49).104 The time point at which dietary factors impacted on disease evolution, however, could not be derived from the study.104 In a large French prospective questionnaire cohort study of women aged 40–65 years, a high total protein intake, specifically animal protein, before disease onset was associated with an increased risk of IBD.105 These data are consistent with an earlier Swedish population-based case–control study showing that the consumption of ‘fast food‘ was associated with an increase in UC (OR 3.9) and CD (OR 3.4).106 Conversely, intake of dietary fibre, fruit and vegetables has been reported to be protective for both CD and UC,95 ,107 although results vary between studies.102 ,103 ,106 The main difficulty with dietary studies is understanding the timing of dietary intake in relation to disease. Is it more critical to assess childhood diet, or perhaps the diet taken within 5 years of diagnosis? Studies that survey subjects after diagnosis are confounded by recall bias issues and the probability that people will change their diets once symptoms have begun. Of patients not changing their diet, a high consumption of red meat and cheese was associated with CD, while a high consumption of margarine was associated with UC.108

One of the factors associated with westernisation of diet includes urbanisation. The incidence of UC appeared to rise rapidly in relation to urbanisation. This has been observed in several developing countries, while the number of patients with CD remained low or increased with a delay of 15 years compared to UC.109 It could well be that changes in lifestyle factors including diet affect UC risk more than CD, as reflected in increased incidence, years before CD risk is affected.

Using data from a population-based cohort in Norway and a registry of water quality, the risk of developing IBD was associated with high iron content. The RR of developing IBD increased by 21% when the iron content in the drinking water increased by 0.1 mg/l. A high iron concentration may work as a catalyst for oxidative stress, resulting in inflammation, or may stimulate the growth of bacteria, thus increasing the likelihood of inappropriate immune responses in genetically predisposed individuals.110

In summary, dietary antigens very likely play a role in the expression of IBD. Prospective studies suggest that a diet high in protein, particularly animal protein, is associated with a higher risk of IBD. Intake of the n-6 polyunsaturated fatty acid linoleic acid may confer risk, whereas n-3 polyunsaturated fatty acids may be protective for UC.111 No prospective data have been reported on risk related to the intake of fruits, vegetables or food microparticles on UC or CD development. However, despite an increasing number of studies examining the association between diet and IBD, no causal food item has been identified and no consensus has been reached, partly because results from studies remain difficult to interpret, and in some, findings were not reproducible. Methodology limitations include recall bias for presymptomatic food intake and the possibility of alteration of diet because of symptoms before a formal diagnosis of IBD. Based on epidemiological data and case–control series, the relationships between changes in food consumption would fit, in a timely manner, with changes in microbiota associated with IBD. With ongoing observation of existing cohorts and the development of population-based cohorts, more data on dietary risk factors may be expected during the coming years. Such data may benefit from considering interactions between the gut microbiota and any confirmed dietary factors.

Environmental effects on microbiota

Dysbiosis reported in IBD is likely to be a consequence of changes in environment including hygiene and food, resulting in an imbalance in the microbial–host relationship with mucosal barrier dysfunction and reduced microbial diversity.112 Dysbiosis with a decrease in beneficial bacteria, such as the Bifidobacteria, Lactobacilli, Bacteroides and Firmicutes,113 and an increase in pathogenic bacteria, such as adherent invasive Escherichia coli (AIEC)114–116 and Mycobacterium avium paratuberculosis ssp (MAP),117 ,118 have been reported in IBD. Little is known about how diet affects the microbiome. It has been postulated that dietary fructose, sucrose, animal fat and iron preferentially stimulate the growth of pathogenic bacteria, while poorly absorbed oligosaccharides promote the growth and metabolic profile of beneficial bacteria.

It remains controversial whether primary pathogens such as MAP, which causes Johne's disease in cattle,117 may be an aetiological factor for CD, but problems related to diagnosing the infection and having a biomarker of its presence remain a key obstacle to either moving this hypothesis forward or fully eliminating it. Clinical studies up to now have been inconclusive with regard to the impact of MAP in IBD. Several studies have detected a high prevalence of MAP in CD patients, and a meta-analysis of 28 case–control studies showed a positive association, both for enzyme-linked immunosorbent assays and PCR.118 A recent study,119 however, performed with highly sensitive methods in the intestinal mucosa, failed to detect the presence of MAP in newly diagnosed, treatment-naive cases, in contrast to many affected cases among hospitalised CD patients on treatment, within the same catchment area. MAP was not found among patients with long-standing UC. A study of seropositivity showed a high seroprevalence for Manitobans at approximately 35%, but failed to demonstrate a difference between CD, UC and controls.120 Furthermore, no interaction between the NOD2 genotype and MAP serology in relation to CD or UC has been identified.121 Whether seropositivity reflects past infection in humans is unknown. Based on these data, MAP is probably not an aetiological factor. It may be a bystander appearing during the course of disease, or it could be that MAP is a permissive infection (for instance, impacting on macrophage function) facilitating the pathogenicity of a second organism.122

The high prevalence of AIEC associated with ileal CD represents another potential primary pathogenic strain of bacteria.115 ,123 ,124 Colonisation leads to strong inflammatory responses in the gut suggesting that AIEC could play a role in CD immunopathogenesis. Furthermore, the presence of AIEC in the mucosa of patients with CD at initial diagnosis suggests that they may play a role in the early stages of disease onset.125 In France, it was found that AIEC reference strain LF82 was able to adhere to intestinal epithelial cells, to invade epithelial cells and to survive and replicate within macrophages,126 ,127 whereas in Canada other strains of AIEC including UM146 and UM147 that produce an increase in serine proteases have been reported.116 ,128 Much of the work on this organism, and its potential role in CD, has been undertaken in areas of high CD incidence. The significance of this pathogen in the pathogenesis of CD worldwide is currently unknown. It is not clear whether AIEC is a pathogen worldwide or is restricted to some countries. Characterising AIEC in low but increasing incidence, and high incidence countries and different ethnic populations may allow the identification of specific causal factors in the microbiota. These data can potentially provide an insight into the relevance and role of AIEC in the global epidemiology of CD.

The ‘hygiene hypothesis‘ postulates that individuals raised in a sanitary environment are more likely to develop IBD. This hypothesis implies that the increasing frequency of immunological disorders can be attributed to the lack of childhood exposure to enteric pathogens, or alternatively to the loss of saprophytic microorganisms that may impact on regulatory T-cell development. In support of the hygiene hypothesis are the generally negative associations with the epidemiology of Helicobacter pylori129 and the inverse association to the prevalence of helminthic colonisation.130 ,131 Although Canada has one of the highest rates of IBD in the world, the low rates of IBD among First Nations Manitobans could be explained by the hygiene hypothesis. Many of the Manitoban First Nations live in crowded and poor conditions, and are infected with pinworms, hepatitis A and H pylori.

The suggested ‘cold chain hypothesis‘ represents a more direct explanation of a causal relationship between specific bacteria and the immunocompromised host, and originated from a molecular perspective postulating that CD is a result of a defect in the host recognition of pathogenic bacterial components that usually escape the immune response leading to an excessive host response to bacteria, such as Yersinia spp and Listeria spp, which can survive refrigerator temperatures.132 The definition relies on the introduction of refrigeration in society, which was related to the time of the rising incidence of CD. Case–control studies have supported this hypothesis, in combination with other socioeconomic risk factors.133 ,134

As IBD is most common in the northern hemisphere, most studies with regard to microbial risk factors have been performed in this region. While one might speculate that an improvement in sanitary conditions is responsible for reduced microbial diversity, industrial pollution in society might serve as another explanation for a changed environment. It is unlikely that the exogenous predisposition to IBD can be explained by one single environmental factor. At the moment, our knowledge regarding possible risk factors derived from industrialisation must be divided mainly into primary direct effects of endogenous dysbiosis as some risk factors may act earlier than dysbiosis and secondary effects on this microbial imbalance. The latter explanation will include all the risk factors that will either increase the microbial instability or increase the vulnerability of the host organism.

Infectious agents causing an episode of infectious gastroenteritis may play a role in the initiation and/or exacerbation of IBD. Several studies have shown that acute gastrointestinal infections135–137 are associated with the development of IBD, especially with Campylobacter and Salmonella, with an OR of 4.1 in the first year after infection when compared with unexposed controls. The risk of developing IBD was significantly higher among 13 148 patients exposed to Salmonella or Campylobacter gastroenteritis than among 26 216 control patients.137 In a study assessing the incidence of positive and negative stool tests among patients already diagnosed with IBD, the findings of high incidence rate ratios (IRR) for IBD the first year after both positive (IRR 5.4–9.8) and negative (IRR 53.2–57.5) stool tests suggest that increased rates of stool testing of patients with unclear gastrointestinal symptoms may lead to detection bias.138 In a study from Maryland using a military database, an episode of gastroenteritis increased the risk of IBD with an OR of 1.40. The risk was slightly higher for CD compared with UC.135

No evidence for causation of IBD by a single agent has been identified, whereas a number of microbes have been strongly associated with the presence of disease. Many of the features of a modern lifestyle observed in developing countries, including changes in domestic hygiene, family size, birth order, antibiotic usage, crowding and parasitism may be proxy markers of microbial exposure during childhood.130 Alterations in the gut microbiota could also be linked with a westernisation of diet, increased stress levels and obesity.3 New emphasis has also been placed on common viral infections as important environmental factors in the pathogenesis of IBD, and studies investigating the host interactions with the human virome in IBD are warranted.139