East Meets West: The Increasing Incidence of Inflammatory Bowel Disease in Asia as a Paradigm for Environmental Effects on the Pathogenesis of Immune-Mediated Disease

Abstract

Many diseases have increased dramatically in incidence over the past few decades in parallel with global industrialization. Diseases such as asthma, eosinophilic esophagitis and other atopic diseases, metabolic syndrome, obesity, and inflammatory bowel disease (IBD), to name a few, have become much more prevalent over the past 60 years beginning in Western societies, followed by Asian countries such as Japan and Korea, and now involving China and India. Using IBD as an example of a multifactorial disease with genetic and environmental elements involved in disease pathogenesis, it is clear that environmental factors are predominately responsible for the increasing incidence of these diseases. However, the exact nature of these environmental factors remains ill-defined. Given the fundamental role that the intestinal microbiota plays in immune regulation and the pathogenesis of IBD, it is reasonable to speculate that microbial and dietary alterations may be playing a central role in rising IBD prevalence. On April 7, 2016, the Chinese Society of Gastroenterology and the American Gastroenterological Association jointly sponsored a symposium in which experts from a diverse spectrum of disciplines met to compare and contrast Asian versus Western aspects of epidemiology and clinical phenotypes, as well as genetic and environmental factors as a first step toward understanding the factors that may be playing a role in the increasing incidence of IBD in Asia. Siew Ng opened the session by describing the changing epidemiology of IBD in Asia. The recent prospective ACCESS-IBD (Asia-Pacific Crohn's and Colitis Epidemiology Study) cohort provides, for the first time, detailed incidence and natural history data for IBD in East and Southeast Asia. The incidence of IBD across Asia was 1.37 per 100,000, with China having the highest incidence at 3.4 per 100,000 individuals. Across Asia, the incidence of IBD varies from 0.5 to 3.4 per 100,000 people, and seems to be greater in highly urbanized countries. Although lower than the West, the rapid increase in incidence over the past decade is consistently observed, particularly in Japan, Korea, Hong Kong, and mainland China. Ulcerative colitis (UC) appears first, followed by Crohn’s disease (CD). The UC to CD ratio is 2.0 in Asia, but this gap is narrowing over time. Complicated CD is as common in Asia as in the West and the evolution of disease phenotype over time is similar to that in the West. Ashwin Ananthakrishnan described the epidemiologic trends of IBD in the West. Population-based data from 1990 to 2000 from the Olmsted County cohort in the United States estimated the age-adjusted incidence of CD and UC to be 8 and 8.8 per 100,000, respectively. Similar estimates have been reported from population-based cohorts in North America, Europe, and New Zealand with some estimates of incidence of CD and UC being even higher at 15 and 14.5 per 100,000, respectively, from Manitoba, Canada. However, consistent across most population-based cohorts in the West, there has been a significant increase in incidence of IBD over the past 4 decades, with some studies suggesting a continued increase, while others demonstrate this continued increase only in the pediatric age groups. Within established high-incidence countries, north–south gradients in incidence with higher incidence in northern latitudes have been reported from Europe and North America. Variations in diet, lifestyle, and ultraviolet exposure may contribute to this gradient. However, even within a region, there may be significant small area variation influenced by rural–urban divide and ethnicity, among other factors. Immigrant populations may provide important insights into the relative contributions of genes and environment in the disease pathogenesis. Immigration to a high-incidence region from low-incidence countries is associated with an increase in risk of IBD in the second-generation offspring; however, this increase in risk many not be uniform across all ethnicities and countries of origin. The discussion at the conclusion of the session proposed reasons for the dramatic increase in the incidence in previously low-incidence countries, including a changing diet with adoption of a “Westernized” lifestyle, potential contribution of urbanization, environmental pollution, and changes in lifestyle. The second session compared the clinical characteristics and natural history of IBD in Eastern and Western populations. Professors Jiaming Qian and Kaichun Wu presented data about the phenotype and natural history of IBD from 2 large cohorts in China and Professor Dong Soo Han presented data from population-based cohorts in Korea. Ashwin Ananthakrishnan contrasted the observations in Asia with that observed in population-based cohorts describing the natural history of IBD in Western countries. Available national estimates suggest considerable burden of CD and UC in Asia, with an estimated 155,116 and 39,799 cases of UC and CD, respectively, in Japan and 32,026 UC and 18,242 and CD cases in Korea. The peak age of onset in Asia is in the third, fourth, and fifth decades of life, consistent with the pattern observed in Western countries. The distribution of disease location and behavior is similar between Asia and the West with an ileocolonic predominance affecting approximately 50% of cases. Perianal involvement was noted more commonly in Japan and Korea, affecting as many as 40% to 50% of CD patients, compared with the 26% rate of involvement at 20 years reported in cohorts from the West. Complicated disease at diagnosis is as common or more common in Asia with similar rates of progression from inflammatory behavior to fibrostenosing and penetrating complications. The greater frequency of complicated disease is also not explained by diagnostic delay, because the interval between onset of symptoms and establishment of diagnosis is similar in both regions. The extent of UC is comparable in both regions, although some studies from Asia have reported that as many as 68% of UC patients have left-sided colitis. Extraintestinal manifestations, particularly primary sclerosing cholangitis, are less common in Japan and Korea when compared with Western cohorts. The rates of CD-related surgery and recurrence postoperatively are comparable between the 2 regions. In contrast, UC in the East is characterized by a mild disease course and a less frequent need for immunosuppression and for surgery. The cumulative probability of colectomy at 10 years was 10% to 20% in Western cohorts compared with 7.8% in cohorts from Asia. Cohort studies have suggested a significantly lower proportion of patients on immunomodulators and biologic therapies in Asia compared with Western countries. Such differences could reflect a milder disease course in Asia (as suggested by lower rates of colectomy in UC), patient and provider hesitation regarding long-term immunosuppression particularly in the setting of competing infectious risks, and cost and access to therapies. It is important for future studies to determine if such variations reflect different disease biology or practice variation. Limited data exist about the comparative effectiveness of immunosuppressive or biologics in Asia compared with the West. Azathioprine is frequently maintained at a lower dose in Asia compared with the West, but is associated with similar long-term outcomes, with this difference potentially being due to more favorable pharmacokinetics. However, this is also associated with higher rates of leucopenia in Asia. Emerging data from North American and European cohorts demonstrate a secular reduction in the need for surgery in both CD and UC, suggesting that current treatment practices may be beneficially modifying the natural history of IBD. Whether a similar effect will emerge in Asia with growing use of newer therapies is unknown, but must be considered in ensuring access to such modalities. Judy Cho and Byong Duk Ye compared and contrasted the genetics of IBD in Western versus Asian societies. Epidemiologic studies have suggested that the development of IBD is strongly influenced by genetic predisposition. To overcome the limitations of linkage studies, “hypothesis-free” genome-wide association studies (GWAS), GWAS meta-analyses, and targeted genotyping array techniques have been performed during the past decades, and have broadened our understanding of the genetic basis of IBD. After the first GWAS in Japanese patients with CD, which revealed TNFSF15 as a CD-susceptible gene, subsequent GWAS and ImmunoChip studies showed that some risk loci for CD are shared between East Asians and European ancestry populations, although some seem to be unique to the East Asian populations. Studies on East Asian UC patients have shown a tendency toward more extensive genetic overlap with European ancestry populations than that seen in CD. The first transethnic association study of IBD increased the number of IBD risk loci to 200, with 231 independent single nucleotide polymorphisms, with the direction and effect size being consistent in the European and the non-European ancestry cohorts for the majority of the IBD risk loci. The observed genetic heterogeneity across divergent populations at several risk loci is by differences in risk allele frequency (NOD2) or effect size (TNFSF15-TNFSF8 and ATG16L1) or a combination of these factors (IL23R and IRGM), as previously reported. Because host genetic factors are suggested to play a role in shaping the gut microbiota in IBD patients as well as in healthy individuals, the different genetic architectures between Europeans and Asians may lead to differences in the gut microbial milieu, thereby contributing to different incidences and clinical characteristics of IBD across populations. Still, the number of genes/loci significantly associated with IBD risk in Asian populations is much fewer than that of European ancestry populations, at least partially resulting from the smaller cohorts studied thus far. Therefore, more genetic studies with larger cohorts are needed in Asia, combining analyses of genetic, microbiome, and environmental factors. Much of Asia has experienced rapid urbanization and transformation from low to middle income to urbanized, high-income countries, resulting in a massive transformation of health concerns from undernutrition to overnutrition. Data presented by Anthony Fodor and Penny Gordon-Larsen showed that dietary changes in China have occurred more rapidly than anywhere in the world, with 20-year increases in animal source foods (a key indicator of Western diet) and edible oils, declines in coarse grains and vegetables, and changes from steaming to frying and more away-from-home eating (indicators of diet Westernization). These diet changes have been accompanied by changes in body mass index over the past 20 years, with distributions that now closely mirror the United States: adult overweight prevalence nearly tripled from 1991 (11.7%) to 2009 (29.2%). Urbanization-related factors, such as decreases in physical activity, and socioeconomic factors and diet underlie some of the increase in obesity, and all of these changes are associated with increases in cardiometabolic risk. These same dietary alterations may also be factors in the pathogenesis of IBD in Asia; the increase in the incidence of IBD in Asia parallels rapid urbanization, suggesting that environmental factors, as opposed to underlying genetics, are driving the change. Immigration studies have further supported this hypothesis with data demonstrating that the children of immigrants adopt a risk of developing IBD that is similar to those native to the host country, and the age at which children immigrate may be of particular importance. Epidemiologic studies have reported the association between an increased risk of IBD and greater intake of “Western” dietary exposures such as total fats, polyunsaturated fatty acids, omega-6 fatty acids, and meat. Large epidemiologic studies such as the EPIC (European Investigation into Cancer and Nutrition) Study and the Nurses’ Health Study commonly measure dietary exposures using a food frequency questionnaire, which is limited in its ability to capture detailed dietary data, including data on food additives. Dale Lee and Minhu Chen discussed the efficacy of exclusive enteral nutritional therapy in treating active CD in both Asian and Western countries. In addition, studies involving a variety of exclusion diets have further suggested the potential therapeutic value of dietary modulation. Exclusive enteral nutritional and exclusion diets both eliminate certain commonly consumed foods, in particular more highly “processed” ones. Food additives are common in the Western diet, and animal and ex vivo studies have suggested a detrimental effect of certain food additives, including polysorbate-80, carboxymethylcellulose, maltodextrin, carrageenan, and microparticles. The capture of detailed dietary data in humans is challenging and the development of new methodologies, including biomarkers of food additives, will be necessary to better study which components of a Western diet may contribute to the pathogenesis of IBD. Toshifumi Hibi presented data about how dietary nutrients affect the function of the mucosal immune system. Several studies have suggested the importance of nutrients such as short-chain fatty acids, ligands for the aryl hydrocarbon receptor, amino acids, and vitamin D on modulating intestinal immune system function. For example, butyrate-producing Clostridium species regulate the development of intestinal regulatory T cells. His group has had a particular interest in the alteration of amino acid metabolism in IBD patients identified by plasma amino acid profiling and the role of histidine in preventing colitis. Finally, data were presented by Anthony Fodor indicating that accompanying urbanization in China are changes to the gut microbiome, including a decrease in diversity and an increase in taxa associated with diseases that are more prevalent in Western populations. Directly linking these changes to the microbiome to adverse health outcomes remains a key research challenge. Balfour Sartor discussed early life events shaping the intestinal microbiota. This is a highly relevant topic, given the increasing incidence of early onset IBD, epidemiologic evidence that repeated early childhood antibiotic exposure increases risk of CD, and that second-generation migrants acquire IBD incidence rates of their birth location. Mode of delivery, breast versus bottle feeding, diet, antibiotic exposure, and public health measures profoundly influence intestinal microbiota composition and metabolism. Enteric bacterial populations become more diverse and complex after weaning and are similar to adult profiles by 2 or 3 years of age. Early life (<3 years of age) microbiota are more easily altered than the more resilient microbiota of adult populations. These observations lay the foundation for early life interventions such as vaginal microbial transfer to Caesarean section infants and feeding human milk oligosaccharides to formula-fed infants. A key, unresolved issue is whether early life interventions will shape sustained adult microbiome function. Gary Wu summarized the extensive evidence of dysbiosis and abnormal luminal bacterial metabolism in IBD patients and the key role of diet in determining luminal bacterial composition and metabolism. The gut microbiota metabolize dietary fiber to short-chain fatty acids that provide primary energy for distal colonic epithelial cells and exert immunosuppressive activities. Western dietary components profoundly affect bacterial metabolism, which influences epithelial and immune function. Defined formula diets (both elemental and polymeric) treat active IBD with exclusive enteral diets more effectively than partial feeding, suggesting the detrimental effects of conventional diets. Moreover, artificial sweeteners and dietary emulsifiers adversely affect the gut microbiota and promote inflammatory responses, supporting the hypothesis that Western dietary components can promote IBD. Xin Wang compared gut bacteria and metabolic profiles in various world populations. Diets impact microbial community structure and metabolism, which in turn profoundly affect mucosal permeability and immune function. The microbiota of various Asian populations display Bacteroides/Bifidobacterium (BB) and Provotella (P) enterotypes, each associated with various diets. For example, the BB enterotype correlates with diets enriched in protein and animal fat, whereas the P-type enterotype correlates with carbohydrate-enriched diets. CD patients associated with the BB enterotype and exhibited low bacterial gene diversity profiles, whereas Ruminococcus and Provotella enterotypes were unusual. Interestingly, UC samples tracked more closely with normal specimens. Importantly, similar bacterial profiles were found in Chinese and Western CD patients. Zhanju Liu summarized accumulating evidence that specific resident bacterial species induce protective or effector immune responses that mediate intestinal inflammation versus homeostasis. Examples include segmented filamentous bacteria and Helicobacter hepaticus, which selectively activate aggressive T helper 17 cells and induce antigen-specific colitis, respectively. In contrast, Bacteroides fragilis, Faecalibacterium prausnitzii, and selected human Clostridium species activate regulatory T cells that prevent experimental colitis. Additionally, interferon-γ and interleukin-17–producing T cells from T-cell receptor transgenic mice stimulated by CBir1 flagellin-producing A4 Clostridium species induce colitis when transferred into Rag-1–deficient mice, in part by blocking protective T helper 2 immune responses. In total, elegant opportunities exist to selectively manipulate the dysregulated microbiota of IBD patients using nontoxic approaches that can be personalized based on an individual’s fecal microbiome profile. Iliyan Iliev presented exciting information regarding viral and fungal influences in the pathogenesis of IBD. The human mycobiome and virome (resident fungi and viruses) are now being identified by newly created molecular tools and data bases. Comprehensive metagenomics analyses indicate that eukaryotes (fungi) and viruses account for lower proportions of gut microbiota than do bacteria, but their numbers may be lowered artificially owing to inefficient fungal DNA isolation techniques and underdeveloped computational platforms and databases. One host fungal recognition receptors, Dectin-1/Clec7a, is protective in acute murine experimental colitis, and polymorphisms of the Clec7A human gene strongly associate with UC severity. Fungal mycobiome profiles change with acute experimental colitis, short-term fluconazole targeting of resident intestinal fungi ameliorates dextran sodium sulfate–induced colitis, fungal diversity is decreased in pediatric IBD samples, and Candida overgrowth is present. In contrast, Caudovirales bacteriophage diversity increases in CD samples, with a somewhat smaller increase in UC specimens. Dr Zhihua Ran summarized approaches to manipulate the gut microbiota therapeutically. Prebiotics (nondigestible, fermentable dietary components that selectively stimulate resident bacterial growth and metabolism) and traditional probiotic species have limited therapeutic benefit in CD, including preventing postoperative recurrence. In contrast, these agents have somewhat greater efficacy in UC and pouchitis, where combinations of multiple probiotic bacterial species may have greater effect than single agents. Although studies are limited, the combination of prebiotics and probiotics (symbiotic) seem to be beneficial for these indications, although without evidence of synergistic effects. In contrast, simple antibiotic regimens are more effective in CD than in UC, except for the specific complication of pouchitis, where impressive benefits are quite consistent, leading to antibiotics being the primary treatment of acute and chronic pouchitis. Areas of active investigation include using combinations of antibiotics and expanding the use of probiotics to include strains inducing regulatory T and B cells. Yunsheng Yang compared results of fecal microbial transplantation (FMT) in treating Chinese versus Western IBD patients. He traced fecal medicine and FMT to use the “golden juice” for infectious diseases in 10th century BC during the Western Zhou Dynasty and the “yellow soup” for intestinal diseases in humans in the 2nd century AD during the Eastern Han Dynasty. The 2 largest published studies from Canada and Finland of FMT for treating active UC showed borderline clinical response, but clearly demonstrated variable donor effects and an alteration of responding recipient’s fecal microbiota to resemble donor profile. A pilot uncontrolled study at Dr Yang’s institute demonstrated their ability to shift the recipient’s microbiota and induce clinical responses and remission in a refractory cohort of UC patients; however, randomized, placebo-controlled, multicenter studies are required for more definitive results. A preliminary report from an Australian study, recently presented at DDW 2016, raises the important questions of how frequently FMTs need to be administered and how long benefits persist. Mamoru Watanabe shared exciting developments in culturing primary intestinal stem cells to accelerate epithelial repair following injury. He described novel methods to culture primary small intestinal and colonic Lgr5+ epithelial stem cells. Proof-of-principle studies demonstrated successful transfer of fetal and adult intestinal stem cells to murine recipients and the ability of these transplanted cells to engraft and regenerate to repair experimental intestinal injury. Although early in its development and application, this technology has tremendous potential to restore the epithelial barrier after intestinal injury and inflammation. It is clear that epidemiologic trends document a dramatic increasing incidence of IBD in Asia, particularly in China, where there are very meaningful differences in the phenotypic expression of disease when compared with those in Western societies. This increasing incidence affords a unique opportunity to examine the multifactorial factors contributing to IBD. Although phenotypic differences may be in part a reflection of host genetics, it is very clear that there are many environmental influences, predominantly diet and the gut microbiota, that likely play a substantial role in the rising incidence of IBD in Asia. Evidence for their role comes not only from results in animal models, but also from the early evidence for efficacy of FMT in UC in China. There was consensus that further research to better define these environmental factors is of critical importance and could have a significant impact on our understanding of not only IBD, but also the pathogenesis of other immunologic diseases whose incidence is dramatically increasing in Asia paralleling industrialization. There are many gaps in our understanding of this area, and additional tools need to be developed to systematically phenotype patients with IBD in Asia as well as collect concurrent dietary information. Toward these ends, there was significant enthusiasm to accelerate collaborative endeavors between the Chinese Society of Gastroenterology and the American Gastroenterological Association with the hopes of identifying approaches to alter the environment of the gut to prevent and/or treat IBD.