Introduction

Inflammatory bowel disease (IBD) is a chronic inflammatory disease affecting the gastrointestinal tract, and includes ulcerative colitis and Crohn’s disease. While the exact etiology of the disease is unknown, it is thought to arise from a dysregulated immune system resulting in chronic mucosal inflammation. This is contributed by both genetic and environmental factors. The heritability of Crohn’s disease is thought to be around 50 % [1], with a lower estimate for ulcerative colitis [2]. Recent genome-wide association studies (GWAS) have identified numerous genetic variants associated with ulcerative colitis [3•, 4] and Crohn’s disease [5•, 6]. These genetic factors together can only explain a small proportion of the heritability and disease susceptibility [7]. Genetic mutations of IBD in non-Caucasians differ from that of Caucasians [8•]. While more genetic variants remain to be identified, it is likely that environmental factors play an important role in the pathogenesis of IBD. In support of this hypothesis is the striking observation that IBD emerges when a society makes the transition from a ‘developing’ to a ‘developed’ status. This epidemiologic change cannot be explained by genetic changes alone, particularly in the absence of a large background genetic shift, and is likely to be contributed by changes in the environment. Some may regard IBD as a "disorder of modern lifestyle" or even a "disease of the affluence". The present paper aims to describe important observations in developing countries that provide clues to our understanding of IBD. Developing nations have two-thirds of the world's population. Major changes over the past two decades in these populations, including but not limited to changes in dietary patterns, improved socioeconomic status, improved sanitation and altered microbial exposures, have been implicated as potential environmental risk factors for IBD.

Epidemiology

Incidence and Prevalence

The incidence and prevalence of IBD varies greatly around the globe. Traditionally, higher rates are seen in developed countries in the west. The estimated incidence and prevalence for IBD are up to 15 per 105 and 200 per 105 person-years, respectively in some populations [9•]; with the highest rates reported in northern Europe and North America.

Despite a lower incidence and prevalence, epidemiological studies showed that IBD is not uncommon among non-Caucasians. In East Asia, the prevalence of ulcerative colitis ranges between 7.0 per 105 persons in Hong Kong [10] to 30.9 per 105 persons in South Korea [11], whereas for Crohn’s disease it is between 2.9 per 105 persons in Singapore [12] to 13.5 per 105 persons in Japan [13]. The age- and sex-adjusted incidence rate for IBD ranges between 0.4 per 105 person-years in Hong Kong [10] and 3.6 per 105 person-years in South Korea [11].

Higher prevalence and incidence rates were observed in other parts of Asia. In a house-to-house survey in north India [14], the prevalence and incidence rate of ulcerative colitis among the Punjabi population were 44.3 per 105 and 6.0 per 105 person-years. This incidence rate is one of the highest reported in Asia. As for the Middle East, the prevalence of ulcerative colitis ranges between 41.7 per 105 persons in Kuwait [15] and 167.2 per 105 persons in Israel [16], while for Crohn’s disease it is between 53.1 per 105 persons in Lebanon [17] and 65.1 per 105 persons in Israel [18]. The incidence rate here ranges between 1.4 and 5.0 per 105 person-years; these figures appear higher than that of data from East Asia.

There is a paucity of descriptive population-based epidemiological data from developing countries. Two studies, conducted in different regions of Puerto Rico, have reported a greatly divergent prevalence of 12.5 per 105 persons in rural area [19] versus 62.2 per 105 persons in urban area [20] for ulcerative colitis. The prevalence of Crohn’s disease is 5.9 per 105 persons in rural areas and 41.4 per 105 persons in urban areas. Within Asia, Japan is only country that has a national IBD registry. The total number of affected persons with IBD is thought to be more than 100,000 from data from the Japanese Ministry of Health, Labor and Welfare. Data from other countries in Asia were derived mostly from hospital cohorts or physician-based surveys. Accurate epidemiologic data in some developing countries are affected by limited access to health-care, poor physician awareness, and lack of diagnostic equipments. Thus, data available in the literature may have only captured the tip of the iceberg of the population with the best healthcare access, and is unlikely to reflect the true disease burden, especially in developing countries in Asia, Africa and South America.

Temporal Trends

Despite the lack of national registries or population-wide epidemiological studies in developing countries, time-trend studies have suggested that IBD is not uncommon and is on a rising trend among many non-Caucasian populations. The prevalence of ulcerative colitis rose from 7.6 per 105 in 1997 to 30.9 per 105 persons in 2005 in South Korea [11], and from 2.3 per 105 to 6.3 per 105 persons in Hong Kong within a decade [10]. A review from a national registry published in 2008 revealed a greater than threefold rise of Crohn’s disease in Japan, from a prevalence of 2.9 per 105 in 1986 to 13.6 per 105 persons in 1998 [13]. A collective analysis on 10,218 ulcerative colitis patients in China also showed a threefold rise in disease diagnosis from the 1980s to 1990s [21]. Although this article is not a formal epidemiological study and hence cannot infer a true temporal increase in incidence, it suggests that ulcerative colitis is not uncommon and may be on the rise in many developing countries. In support of this is the observation that, when IBD emerges in a country, ulcerative colitis appears first, followed after a variable interval by Crohn’s disease. This worldwide trend is evident in developing countries, in under-developed sectors of society such as aboriginals living in New Zealand and Canada, and also amongst migrants from developing to developed countries. It could well be that changes in life-style factors including diet affect ulcerative colitis risk more than Crohn's disease, as reflected in increased incidence occurring some years before Crohn's disease risk is affected.

An increasing disease trend has also been reported in other countries outside East Asia. A study based on a community survey of physicians in Israel in the period 1987−1997 reported an incidence rate of 5.0 per 105 person-years for Crohn’s disease, with a greater than two-fold increase from 2–3 per 105 person-years in an earlier period of 1967−1986 [16]. Although the incidence rate of ulcerative colitis appeared relatively stable at about 5.0 per 105 person-years [18], the authors reported a rise in prevalence of both ulcerative colitis and Crohn’s disease, from 121.0 per 105 and 25.5 per 105 persons in 1987 to 167.2 per 105 and 65.1 per 105 persons in 1997, respectively. In Puerto Rico, the incidence of ulcerative colitis rose from 1.96 to 3.32 per 105 person-years from 1996 to 2000 [19]. A fourfold rise in incidence rate of Crohn’s disease from 0.49 to 1.96 per 105 person-years was observed. In a recent systematic review consisting of more than 100 studies, the incidence and prevalence of IBD are increasing with time and in different regions around the world, indicating its emergence as a global disease [22].

Clinical Characteristics

The distribution of IBD is characterized by a bimodal distribution in many western countries. The diagnosis of Crohn’s disease and ulcerative colitis usually peaks at age 20−30 and age 30−40 years, respectively, both followed by a smaller peak at an older age of 60−70 [23]. Although previous studies in Asia have reported a similar peak age of onset for both diseases, they have not consistently observed the second smaller peak at the older age [11, 14–16, 18, 21, 24–26].

Previous studies suggest a slight female preponderance for Crohn’s disease, and an equal or slight male preponderance for ulcerative colitis in western populations [27, 28]. Most Asian studies suggest a similar gender distribution for ulcerative colitis, whereas for Crohn’s disease, in contrast to western populations, there appeared to be a male predominance, with a male-to-female ratio ranging between 1.67 and 2.9 to 1 [11, 13, 24, 29]. A slight female preponderance was seen in the Hispanic population for IBD [19, 20, 30, 31].

The clinical course of ulcerative colitis in Asia is generally regarded as similar to the western populations [32, 33], although isolated studies suggest a milder disease severity [15, 26]. Fulminant disease appeared to be rare in the Chinese population [21, 26]. Previous data from a western population suggest that 37 % of patients have pan-colitis at diagnosis [34], and in Asia, 21−45 % of patients have pan-colitis at diagnosis [10, 26, 29, 35•, 36–42]. The two hospital-based studies in Puerto Rico showed largely divergent results of 15 versus 80 % [30, 31].

In contrast to ileal disease, which is more common in the west, several studies from East Asia showed ileo-colonic predominance for Crohn’s disease, with 66.7 % in South Korea [11], 65.8 % in Japan [43] and 50.5 % in Hong Kong [44], similar to the finding of 52.3 % in the Hispanic population [31]. More heterogeneous results have been obtained in other parts of Asia [26, 38, 45] and the Middle East [17, 18, 46, 47] with ileo-colonic involvement ranging between 12.5 and 40.9 %. Such heterogeneity has also been observed in western studies [48–50], with an evidence of phenotypic evolution over time [44, 51–53].

The frequencies of extraintestinal manifestation for both types of IBDs in developing countries appeared to be lower than the reported figures of 21−41 % for the Caucasian populations [54–56]. The frequency appeared to be lowest for ulcerative colitis in East or Southeast Asia, ranging between 5.7 and 13.6 % [29, 41, 57], whereas the frequency for Crohn’s disease ranges around 6.4−23 % [26, 29, 38, 41, 58]. Higher rates ranging up to 40.0 % have been reported in studies from the Middle East and South Asia [36, 46].

The incidence of colorectal cancer among ulcerative colitis patients in Asia [17, 29, 46, 57, 59, 60••] appeared to be lower than those in the west [61]. A study from India estimated the colorectal cancer risk in ulcerative colitis patients to be 2.3 % at 10 years [62], lower than the estimate of 8.3 % for western populations [63]. However, this is likely to be a reflection of the low disease prevalence, and colorectal cancer may increase over time as the disease become more prevalent in developing countries.

Migrant Populations

Studies of migrant populations can potentially help dissect the etiologic importance of genetic and environmental factors in causing a disease. Studies in first- and second-generation South Asians in Leicester in the United Kingdom showed a high rate of ulcerative colitis compared with the local populations, suggesting that the disease pattern follows that of the indigenous population after only one generation [64, 65, 66••]. Given the relative constant genetic composition within a few decades, such drastic changes in disease epidemiology in the migrant populations are likely to be accounted for by environmental factors. Together with other migrant studies in North America [67–69], this suggests that environmental factors may be more important than genetic factors in the etiology of IBD. This is also consistent with findings from twin studies [2, 70, 71, 72••]. In monozygotic twins, the concordance rates for Crohn’s disease range between 20 and 50 %, whereas the concordance rates for ulcerative colitis are even lower. Several lessons can be learnt from migration studies. It is clear that immigrants have a genetic predisposition, and that there must be an environmental factor triggering disease expression, and it seems that environmental exposure during childhood is critical.

In the following section, we discuss what we perceive as the most important environmental factors in developing countries that may account for the changing epidemiology of IBD. These factors include an adoption of a western diet [73], improved hygiene and sanitation [74•] and socioeconomic growth. Although no single agent has been found to be causative, some of these factors, together or in isolation, have been shown to influence the disease risk and natural course of IBD.

Environmental Factors

Diet

Global variation in dietary habits is by far one of the most likely explanations for the differences in risk of IBD across different geography and the increase in disease incidence in migrant and developing populations. The rising rates of IBD in Asia coincide with the introduction and expansion of packaged food, fast food chains, and increased use of antibiotics and aluminum foils. Rapid industrialization in developing countries has been accompanied by westernization of diet, such as increased consumption of refined sugar, fatty acids, cereals, and meat and reduced consumption of fruit and vegetables [75, 76]. In China, meat, edible oil, and fat intake have increased in both rural and urban areas over the last 20 years [77]. In Japan, the consumption of sugar, animal protein, and ω-6 fatty acid correlates with the rising incidence of ulcerative colitis and Crohn’s disease [78, 79]. Increased intake of dairy products and meat has also paralleled the rising trend of ulcerative colitis in Japan [37]. Children with Crohn’s disease in Canada were found to have lower dietary fiber and ω-3 fatty acid [80].

The largest population-based dietary study, conducted by the European Prospective Investigation into Cancer and Nutrition (EPIC) group, has reported a correlation between increased intake of linoleic acid, a ω-6 fatty acid, and the risk of ulcerative colitis. Linoleic acid is present in many food substances including red meat, cooking oils, and certain margarines, and represents a major ingredient in the diet in developing countries. Linoleic acid undergoes metabolic conversion to arachidonic acid and can be converted to eicosanoids which are present in excess in mucosa of ulcerative colitis patients and inhibited by 5-aminosalicylic acid [81, 82].

Based on epidemiological data and case−control series, the relationships between changes in food consumption would fit, in a timely manner, with changes in intestinal microbiota associated with IBD. Population-based and prospective data assessing dietary risk factors in IBD may benefit from investigations of the interactions between the gut microbiota and any confirmed dietary factors. This is particularly important in developing nations in which westernization of diet is evident. The observation that the timing of introduction of certain foods or chemicals to infants affects the risk of developing celiac disease and diabetic autoimmunity is also likely to be relevant to IBD.

Gut Microbiota

The human gut is colonized by up to 1014 bacterial cells and constitutes the largest microbial community within the human body [83]. In normal individuals, the intestinal microbiota have a symbiotic relationship with the host to carry out important metabolic and immunomodulatory function. Recent studies have found a different microbial composition in IBD patients, with decreased prevalence of commensal bacteria and a concomitant increase in others, leading to the hypothesis that IBD may have resulted from immune dysregulation secondary to a host−microbiota symbiosis breakdown. The importance of such a mutualistic relationship is also supported by recent GWAS which implicate genes involved in immunity and autophagy in the susceptibility to IBD. These biological pathways are important in sensing and mounting immune response against different micro-organisms.

Several studies have shown that IBD patients have a reduced abundance of dominant commensal bacteria in the gut. Mucosal biopsies taken from IBD patients were found to be depleted in commensal bacteria, notably Bacteroidetes and Firmicutes, with a concomitant over-representation of Actinobacteria and Proteobacteria [84••]. These findings are consistent with several other studies, which also observed a decreased Clostridium abundance [85, 86]. Such a distinct microbiota composition was confirmed in a subsequent metagenomic sequencing experiment [87••]. The different microbiota composition exists not only between healthy individuals and IBD patients but also between different ethnic groups. A recent study showed remarkable differences in the gut microbiota composition between Malawian and Finnish infants, with a greater proportion of Bifidobacterium, Bacteroides-Prevotella and Clostridium [88]. Nonetheless, it is unknown how this difference may alter the intestinal physiology in the disease process. Despite speculations that several micro-organisms are the culprits in Crohn's disease, such as Mycobacterium avium paracellulare [89, 90], Listeria [91] or the measles virus [92, 93]; these findings have not been consistently replicated [94]. There is no concrete evidence that a single pathogen is the cause of the disease. Many of the features of a modern lifestyle observed in developing countries, including changes in domestic hygiene, smaller family size, antibiotic usage, crowding, and reduced parasitism may be proxy markers of microbial exposure during childhood [95]. Alterations in the gut microbiota could also be linked with many features of developing societies including westernization of diet, increased stress level, and obesity [96].

Recent observational studies have demonstrated an association between antibiotic use either taken in childhood or at any time before IBD diagnosis and the subsequent diagnosis of IBD [97, 98]. Although these studies have methodological limitations, and causality or biological mechanisms cannot be inferred, antibiotic use can rapidly change the spectrum of the intestinal bacterial composition and thus explain rapid changes in disease incidence in the pediatric population or in developing nations. Studies investigating antibiotic use in developing countries are important to explore whether this is a contributing factor to the increasing incidence.

Hygiene Theory

The hygiene hypothesis suggests that the rise of certain allergic and autoimmune diseases is related to the improvement in sanitation and hygiene, which has led to a decrease of infectious diseases. This hypothesis was first proposed by Strachan, who observed an inverse correlation between hay fever and the number of older sibling when following more than 17,000 British children in the 1958 birth cohort [99••]. This hypothesis gained support from epidemiological studies showing increased incidence of atopic [100–102] and other autoimmune diseases in developed countries [103–106]. Such an increase parallels improvements in socioeconomic status and gross national product of the countries, along with industrialization and urbanization, with concomitant falls in family size and incidence of infectious diseases [106]. It has been hypothesized that exposure to certain infectious agents early in life induces tolerance and immune-regulation to protect against allergic and autoimmune diseases.

The global epidemiology of IBD is consistent with the hygiene hypothesis. In China, the increase in IBD appears to parallel a reduction in the incidence of several infectious diseases as the government implements nationwide vaccination programmes and vigilant control measures [107]. Although Canada has one of the highest rates of IBD in the world, the low rates of IBD among First Nations Manitobans and British Columbians could also be explained by the hygiene hypothesis. Many of the Manitoban First Nations live in crowded and poor conditions, and are infected with hepatitis A, Helicobacter pylori, and pinworms. A population-based study from Israel showed that surrogate markers of enhanced childhood hygiene were associated with the risk for IBD, including living in an urban environment (OR 1.38), small number of siblings in the family (for 1 sibling vs. 5 or more, OR 2.63), and higher birth order (for birth order of 5 or higher vs. 1, OR 2.35) [108]. A case−control study from South India showed that urban residence (OR 1.70) and piped water (OR 1.59), which were indicators of better hygiene, increased the risk of Crohn's disease, whereas exposure to cattle (OR 0.57) was protective for Crohn's disease [109]. While one might speculate that better sanitary conditions is responsible for reduced microbial diversity, industrial pollution in a society might serve as another explanation for a changed environment. It is unlikely that the exogenous predisposition for IBD can be explained by one single environmental factor.

Smoking

Smoking is one of the most thoroughly studied environmental factors, and has been consistently shown to be associated with the risk, the natural course, and outcome of both ulcerative colitis and Crohn’s disease. It has been well recognized that smoking decreases the risk of ulcerative colitis [odds ratio(OR), 0.58; 95 % CI = 0.45−0.67) but increases that of Crohn’s disease (OR, 1.76; 95 % CI = 1.40−2.22) [110••]. The effect of smoking in ulcerative colitis is consistent in other populations, including Japan [111], China [112], and Iran [113], although the effect on Crohn’s disease in the west has not been replicated in South Korea, Hong Kong, and Israel [24, 114–117].

The association between smoking and IBD, however, may not be applicable to all geographic areas or ethnic groups. Smoking alone cannot account for the worldwide trends of IBD incidence and is unlikely to be the cause of the rising incidence in developing countries. 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 Crohn's disease, whereas in Asia and South Africa where more than 50 % of the adult male populations smokes, the incidence of Crohn's disease remains low. It is likely that smoking does not cause Crohn's disease but modulates the disease once present.

Summary

The epidemiology of a disease often gives clues to etiologic agents. Although our understanding of the etiology of IBD is far from complete, important information and clues can be derived from emerging data in developing countries. It stands to reason that the driving forces behind the rise of IBD in developing nations are environmental factors, as these nations have undergone enormous social and economic growth over the past two decades. The two most well-established risk factors for IBD, smoking and appendectomy, cannot fully account for all variations in IBD incidence and prevalence. By far the most topical and likely factors that may explain geographic variability and the rising incidence in developing countries and urban areas are changes in diet and improved hygiene with downstream effects on the intestinal microbiota. Nevertheless, given the myriad of lifestyle changes associated with industrialization, it is difficult to dissect independent risk factors as likely etiologic agents. It is likely that these environmental factors act both independently and synergistically to affect the disease risk. There is evidence that gene−environment interactions are important in IBD [118].

Further support for the importance of environmental factors is obtained from the migrant studies of the South Asian populations [64, 65, 66••]. The fact that the disease pattern follows that of the indigenous population after only one generation points to something that happens early in life. The major event that differentiates the first and the second generation of migrant is the life experience during infancy, childhood, or early adolescence. The hygiene theory that early infections in life protect against allergy or autoimmune disease fits perfectly into this observation.

Moreover, it is possible that the weights of genetic and environmental factors differ between ethnic groups. For example, some NOD2 variants have not been detected in the Han Chinese [119, 120], Japanese [121, 122], Korean [123], Indian [124], and Malaysian [125] populations. Genetic mutations of IBD in Asians have also been found to be different from Caucasians, with a lack of significant association with ATG16L1 in East Asians [8•]. These findings suggest that genetics may play a different role in the pathogenesis of IBD in non-Caucasian populations. The highly variable allele frequencies of NOD2 and other variants are not unexpected, given that disease modifying variants are commonly under the pressure of natural selection and show high degree of population differentiation [126, 127]. Such genetic heterogeneity may also explain the considerable lower rates of familial aggregation [21, 24, 26, 45, 69, 128–131] and the male predominance in Crohn’s disease in Asia [11, 13, 24, 29].

Recent advances in sequencing technologies have allowed the gut microbiota to be studied using a metagenomic approach. While it may not identify a single etiologic agent, it would undoubtedly inform us, with an unprecedented depth, on the relationship between the microbial composition, the disease status, and the host genetics which is largely related to the ethnic origin, as in the recent metagenome-wide association study of gut microbiota in type 2 diabetes [132].

Lastly, epidemiological studies in developing countries are limited by the lack of population-wide registries. An ideal study should be conducted in an area with universal access to health care, standardized case definition, and a well-maintained registry. This is often difficult, given limitations in resources in many developing countries. Large collaborative efforts should be encouraged to build a platform for research in this field, which will not only inform the scale of disease burden but also help dissect the etiology of this impending IBD epidemic.