Rising Incidence of Inflammatory Bowel Disease in the Asian Subcontinent—An Exploration of Causative Factors

: Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC) and Crohn’s disease (CD), is a global health problem with a worldwide increase in incidence. While previously it was more prevalent in Western countries, especially in North America and Europe, there has been a recent sizeable increase in the incidence of IBD in Asia. This article is a brief overview of the causative factors that contribute to this rise in IBD cases in Asian countries. There is a notable disparity between the Asian IBD population and the Western one in terms of age distribution and gender predilection, and genetic studies reveal both shared and unique susceptibility loci. Changes in environmental factors, including alterations in diet, hygiene, and lifestyle, are thought to play a key role in the epidemiological transition observed in Asia. It is crucial to comprehend how genetic predisposition interacts with environmental factors in order to understand the causes of IBD in the Asian population and develop precise interventions to alleviate its impact.


Introduction
Ulcerative colitis (UC) and Crohn's disease (CD) are chronic conditions characterized by the inflammation of the gastrointestinal (GI) tract, which tends to recur over time.Inflammatory bowel disease (IBD) impacts over 0.3% of the world population, thereby emerging as a significant global health problem [1].The prevalence of IBD is notably elevated in regions such as North America, Europe, the UK, Canada, and Scandinavia in comparison to developing nations [2][3][4].As per a systematic review, the annual incidence rates of UC and CD in Europe are approximately 24.3 and 12.7 per 100,000 individuals per year, respectively.The annual incidence rates for UC and CD were reported as 19.2 and 20.2 per 100,000 individuals per year, respectively, in North America [5].Over the past two decades, there has been a notable change in the epidemiology of IBD.While the occurrence of IBD has stabilized in Western countries, Asia presents a worrisome trend with a rising incidence, evolving into a considerable health concern.In Asia, the incidence of IBD ranges from 0.5 to 3.4 per 100,000 individuals, highlighting the dynamic nature of this emerging health issue in the region [6].In the last 10-15 years, the incidence of IBD has increased in Korea, Japan, China, Hong Kong, and India [6][7][8].This rise in IBD incidence has been more pronounced in countries that embrace a Western industrialized lifestyle.This results in alterations in environmental factors, including better hygiene standards, changes in nutritional patterns, and modifications in food products.Also, individuals who migrate from areas with lower prevalence to areas with high prevalence appear to acquire a similar risk of developing IBD as the local population.This finding underscores the impact of environmental changes on the development of IBD, especially in those who are genetically predisposed [9].The correlation between "westernization" and elevated consumption of total fat (especially animal fats, ω-6 polyunsaturated fatty acids (PUFAs), and milk fats), refined sugars, and meat, alongside reduced intake of fruits and vegetables, suggests a potential link between diet and the increased susceptibility to developing inflammatory bowel disease (IBD).Diet could impact intestinal inflammation through various biologically plausible mechanisms, such as dietary antigen presentation, changes in the gut microbiome, modulation of the mucosal immune system, and alteration of epithelial barrier function, among other factors [10].
Several lifestyle elements, such as physical activity levels, obesity, stress, sleep patterns, and smoking habits, have the potential to alter the likelihood of developing inflammatory bowel disease (IBD).Among individuals already diagnosed with IBD, these lifestyle factors can substantially influence disease progression and clinical outcomes.Engaging in recreational exercise has shown to lower the risk of flare-ups and fatigue in IBD patients.Conversely, obesity heightens the risk of relapse and is linked to increased levels of anxiety, depression, fatigue, and pain, as well as greater healthcare utilization [11].
Previously, the Indian population was thought to have a low risk of IBD.However, recent published data indicate a notable rise in incidence.Two studies conducted in northern India have reported a population prevalence of 42 per 100,000 individuals and a crude incidence of 6.02 per 100,000 populations for UC [12,13].Additionally, CD, which was earlier thought to be more prevalent in Western countries, has been increasingly reported in India [14,15].While there is a lack of population-based studies for CD in India, a multicentric hospital-based study from the northern and eastern states of the Indian subcontinent indicated a fourfold increase in referrals for CD from the late 1990s onwards, alongside a higher frequency observed in the southern states of India [16].
As the majority of individuals opt to reside in urban areas, access to improved sanitation, hygiene, and overall healthcare infrastructure has increased.However, this type of urban lifestyle also exposes them to poor air quality, sedentary lifestyles, and diets rich in saturated fats [17].There is also familial clustering of IBD that is frequently observed, indicating a genetic predisposition.Although approximately 163 genetic loci have been associated with IBD, it is well known that genetic factors alone cannot trigger disease manifestation.The development of IBD arises from a multifaceted interaction involving genetic susceptibility and environmental factors, notably those impacting the composition of the normal intestinal microbiota, which triggers an abnormal mucosal immune response.Despite the exploration of various environmental risk factors, no singular factor has been identified as the sole cause of IBD [9].This review article explores the causative factors responsible for the rising incidence of IBD in Asian countries.

Causative Factors
Age: The median range of onset of IBD is 31-34 years in Western Europe, North America, and Oceania.For both CD and UC, there is a peak in incidence noted between 20 and 30 years of age, with a second peak between the ages of 60 and 79 in patients with UC.In Asia, the median age at diagnosis for CD and UC is 34 and 42 years, respectively.In contrast to the West, the majority of Asians demonstrate a single peak distribution in UC cases, whereas a bimodal distribution is observed in CD cases, with peaks occurring in the age ranges of 20-24 years and 40-44 years, respectively.Recent studies from Japan have indicated a rising trend of elderly onset UC, with a trimodal distribution reported in UC cases that peak at 10-20 years, 40-44 years, and 50-60 years, respectively [18].
The mean age at diagnosis for UC and CD was 38.5 and 35.9 years, respectively, in a nationwide survey that was conducted in India.Notably, no second peak in age distribution was observed [19].Likewise, in a study conducted across three centers, the average age of symptom onset for CD was found to be 34.5 years [14].
Results from the ACCESS study revealed that the median age at diagnosis for UC and CD was 42 and 34 years, respectively.This study also noted a secondary, smaller peak in the age range of 40-44 years among CD patients, whereas UC patients exhibited a single peak.
While the age of onset for IBD in India aligns with that observed in the West, with CD typically occurring at a younger age than UC, the bimodal peak characteristic of Western populations is notably absent in India and other Asian countries [20].
Gender distribution: The incidence of UC across Europe, North America, and Oceania is unaffected by gender.However, the data regarding gender predominance in CD patients are less consistent.Some of the studies show a higher predilection of CD among females, while some show no gender disparity.In an analysis where data from various Western studies were pooled, it was found that females were more likely to have CD from adolescence to middle age.On the other hand, males aged 45 years and above exhibited a higher propensity to develop UC.In contrast, studies in Asia have shown male dominance for both CD and UC.One such example is that observed in mainland China, where the risk ratio of CD and UC in males compared with females is 1.15:1 and 2.4:1, respectively.Similar research conducted in Korea also revealed an increased risk of UC among males.A comprehensive pooled analysis further supports these observations, indicating a consistent correlation between male gender in Asian populations and a heightened vulnerability to both CD and UC, particularly among individuals aged 10-50 years [18].
Studies from India indicate that there is a slight male preponderance in patients with UC and a ratio of male/female of >1 in patients with CD.The IBD survey noted a maleto-female ratio of 1.4 for UC and 1.3 for CD.Similarly, the multicenter study reported a male-to-female ratio of 1.8 for CD.This observed predominance of males within the Indian cohort could be attributed to either a comparatively lower incidence compared with Western populations or reflect socio-referral biases.This bias could manifest as women and girls being underrepresented in seeking medical attention, thus skewing the gender distribution [20].Table 1 summarizes the data between the West and Asia.
The genetic components of IBD involve polymorphisms in genes usually associated with facilitating interactions between the commensal microbial flora and the gut immune system.A total of 163 loci have been associated with inflammatory bowel disease (IBD) in a meta-analysis that integrated genome-wide association studies (GWAS) with immunochip data.Of these, 110 were common to both CD and UC, while 30 were specific to CD and 23 were specific to UC [21].Initially, data from genome-wide association studies were primarily from European populations, but there has been an increasing number of publications from Asia, particularly from countries like Japan, Korea, and India.These studies have revealed both the similarities and the differences in the genetic architecture of IBD between Caucasians and non-Caucasians.NOD2 polymorphism has exhibited the strongest association with IBD, particularly CD.Recent investigations evaluating NOD2 polymorphisms in Indian populations have failed to establish such an association.Three common CD-associated NOD2 polymorphisms were found to be absent in Indian patients [22][23][24].A weak association of rs2066842 (Pro268Ser) with ulcerative colitis (UC) was identified in two of the studies [22,24].In a study conducted by Juyal et al. [25], the researchers explored the correlation of UC/CD-specific genetic loci identified through a meta-analysis in a European population within a North Indian population.They examined 53 such loci and discovered that 25 single nucleotide polymorphisms (SNPs) displayed associations with inflammatory bowel disease (IBD) in Indians.However, after applying the Bonferroni correction, only five SNPs remained statistically significant: rs2395185 (HLA-DRA), rs3024505 (IL10), rs6426833 (RNF186), rs3763313 (BTNL2), and rs2066843 (NOD2).A protective association with TNFSF15 (tumor necrosis factor superfamily 15) gene polymorphisms and IBD within the Indian population was highlighted in another Indian study [26].TNFSF15 gene polymorphisms have been implicated in IBD risk not only in studies conducted in Japan but also in the UK [27,28].However, the same group reported an association between the IRGM gene (an autophagy-related gene), which has previously shown a positive association with Crohn's disease (CD) in multiple European studies, and CD in the Indian population [29].
An association of three single nucleotide polymorphisms (SNPs) that resulted in significant mutations within the ATP and Mg 2+ -binding domains of Exon 6 of the NOD1 gene was shown in a study conducted in Northern India.These mutations potentially impair the protein's oligomerization process, resulting in a "loss of function" scenario.Consequently, the protein may fail to recognize muramyl dipeptide, essential for activating NF-κB [30].In another study from Northern India, an association between the TLR4 D299G polymorphism and both ulcerative colitis (UC) and Crohn's disease (CD) was identified, while the T399I polymorphism was associated specifically with UC [31].These polymorphisms result in an aberrant immune response.In another study, the association of TLR5 variants R392X and N592S with UC was established [32].Apart from NOD2, the protective allele of the IL23 gene (R381Q) did not exhibit an association with Crohn's disease (CD) within the Indian population [20].Research conducted in Japan [33,34] has corroborated the absence of NOD2 polymorphisms in Asian populations.Furthermore, these studies did not find an association between another autophagy-related gene, ATG16L1, and inflammatory bowel disease (IBD) in Asian populations.Thirty-eight novel disease susceptibility loci associated with IBD [35] were identified in a trans-ethnic study encompassing East Asians, Indians, Iranians, and Caucasians.
Microbiome: Although specific bacterial agents triggering intestinal inflammation have not been pinpointed, the potential involvement of pathogenic bacteria cannot be discounted.Studies have demonstrated that anaerobic bacteria like Escherichia coli mpk can induce colitis, while Bacteroides vulgatus mpk has exhibited a protective effect in several animal models of IBD.Alterations in the relative proportions of phylogenetic groups such as Bacteroides, Eubacterium, and Lactobacillus spp.have been observed during both active phases and remission stages of ulcerative colitis (UC) [36].An aberrant immune response to intestinal microbiota, particularly in individuals with genetic predispositions, is likely to cause IBD [37].Research has revealed that patients with IBD exhibit a decrease in bacterial population diversity, particularly within the Firmicutes phylum [38].Research conducted in northern India unveiled a noteworthy reduction in the populations of Bacteroides, Lactobacillus, Ruminococcus, and Bifidobacterium bacteria among patients diagnosed with both UC and CD [36].This is similar to the findings in the West [20].Likewise, researchers have examined fecal samples from patients with UC and those from healthy individuals to explore the connection between butyrate concentration and butyrate-producing bacteria [39].The investigation unveiled a significant decline in the Clostridium coccoides and Clostridium leptum clusters in the fecal samples of UC patients.Additionally, reduced concentrations of fecal short-chain fatty acids (SCFAs), notably n-butyrate, iso-butyrate, and acetate, were observed in UC patients.These findings parallel previous studies that have reported similar observations [40].The microbiome profile identified in the Indian IBD pop-ulation closely mirrors that of patients in the West, indicating a potential consistency in the key factors contributing to IBD pathogenesis across both Western and Eastern populations.
Smoking: Smoking has been identified as a risk factor for the development of CD in the West, and it has been shown to adversely affect the natural course; however, studies conducted in Asia have not replicated these results [41].A Chinese study has revealed no association between smoking and the severity of IBD.Similar findings were seen in a study from Northern India, which showed no disparity in the disease phenotype of CD between smokers, oral tobacco users, and non-smokers, nor did smoking or tobacco use influence the long-term outcomes of CD patients.The rates of surgery and the need for biologics, immunomodulators, and steroids were comparable among smokers, oral tobacco users, non-smokers, and tobacco non-users [20].A possible theory for this discrepancy is the constituents of tobacco products in different parts of the world, but there are no data to support this theory.
Hygiene Hypothesis: The hygiene hypothesis proposes that excessive protection of children from common environmental infectious agents due to improved hygiene practices might occur.In instances where a child encounters a pathogenic infectious agent later in life, after prolonged protection (delayed exposure), there is a potential for an inappropriate immunological response to be elicited.This could result in the initiation of an abnormal or ineffective inflammatory process, potentially leading to the development of inflammatory bowel disease (IBD) [42].In the ACCESS study, several factors were identified as protective against both UC and CD.Those included being breastfed for more than 12 months, use of antibiotics, and consumption of tea or coffee daily.Also, having dogs and doing physical activity every day were found to be specifically protective against CD.The use of a hot water tap and flush toilets during childhood was solely protective against UC [43].In another study from Southern India that included 200 CD patients, the correlation between environmental and dietary factors and CD diagnosis was studied [44].Univariate analysis revealed a positive association between CD and urban residence (during childhood and currently), access to protected drinking water (during childhood and currently), availability of piped water in the house (during childhood and currently), and strict vegetarian diet patterns.On the contrary, regular consumption of fish and the presence of cattle in the house were negatively associated with CD.Although only regular fish consumption and the presence of cattle in the house showed protective associations on multivariate analysis, the use of safe drinking water was positively associated with CD.In another study from Northern India, better toilet facilities and having a private bed showed an inverse association with ulcerative colitis (UC), whereas having a pet and experiencing stressful life events were linked to a higher risk of UC [45].Due to the varied literature that is available on the hygiene hypothesis, both within India and across other Asian countries, the concept of the hygiene hypothesis is challenging to quantify and evaluate.

1.
North-South Gradient: Studies from the USA and Europe have noted a regional disparity, where the prevalence of IBD is greater in the northern regions compared with the southern ones.However, this pattern does not appear to be consistent with findings from studies conducted in India [20].A survey on IBD published in 2012 revealed that cases of IBD were observed in both northern and southern regions of India [19].The difference in exposure to sunlight, and thus to vitamin D, which has anti-inflammatory and immunomodulatory effects, could account for the North-South gradient observed in Western regions [46].As India is a tropical country, this gradient in sunlight exposure may not be as pronounced.The precise reason as to why Crohn's disease (CD) is more prevalent in Southern India compared with Northern India remains unclear [20].

2.
Role of Migration: Studying the epidemiology of IBD among Asian populations who have relocated to Western countries, particularly those transitioning from lowincidence to high-incidence areas, offers insights into the influence of environmental factors on disease development.A retrospective epidemiological study that was conducted in the early 1990s revealed that the standardized incidence of ulcerative colitis (UC) among South Asians residing in Leicestershire, UK, was higher than that of the local population (10.8/100,000 vs. 5.3/100,000).Among South Asians, the Sikh population exhibited the highest incidence (16.5/100,000), followed by the Hindus (10.8/100,000) [47].However, the same group also observed that while the incidence of Crohn's disease (CD) had increased over time in both Europeans and South Asians, it remained significantly lower in South Asians when compared to the Europeans [48].
Early-life exposure, particularly to the environment of high-incidence areas, may play a pivotal role in predisposing individuals to develop inflammatory bowel disease (IBD) [20].

Conclusions
IBD is a global health challenge, with a significant increase in its incidence that has been observed worldwide.While originally, it was more common in the West, the epidemiology of IBD has been evolving, with Asian countries now experiencing an increase in the incidence of the disease.This shift has been attributed to various factors, such as changes in lifestyle, dietary habits, and environmental factors.
The age at diagnosis of IBD in Asia differs slightly from the West, with unimodal distribution of UC cases and a bimodal distribution of CD cases, which indicates a significant difference in disease pathogenesis.Additionally, gender disparities in IBD incidence have also been noted, with Asian populations showing a higher risk among males when compared to females, contrary to findings in Western countries, where females are at a higher risk.
Genetic factors are known to play a significant role in IBD susceptibility, with several loci that have been identified to be associated with the disease.However, variations in genetic associations between Caucasian and non-Caucasian populations highlight the complexity of IBD etiology.Furthermore, studies on the microbiome have revealed alterations in bacterial populations in IBD patients, with consistency observed between Western and Indian populations.
Environmental factors, like smoking and hygiene practices, are also known to influence the development of IBD, although these findings vary across populations.The hygiene hypothesis, which suggests a link between reduced exposure to infectious agents and increased autoimmune diseases, presents a challenging concept to quantify and evaluate in the context of IBD.
The epidemiology of IBD in India does not follow the North-South divide that is observed in the West, thereby highlighting the need for further research to understand regional variations.Studies on Asian migrants in Western countries offer insights into the interaction between genetic predisposition and environmental factors in IBD pathogenesis.
To conclude, the rising incidence of IBD in Asia emphasizes an interesting epidemiology.In the future, multidisciplinary research involving genetics, microbiology, and epidemiology will be necessary to unbox the complex mechanisms involved in IBD in Asian populations, thereby developing targeted therapy for this global health problem.Understanding the link between genetic susceptibility, environmental factors, and lifestyle changes is crucial to developing effective IBD preventive and management strategies in diverse populations.

Table 1 .
Summary of data between the West and Asia.