Environmental pollutants and the rising burden of inflammatory bowel disease in East Asia: a narrative review
Article information
Abstract
Inflammatory bowel disease (IBD) is rising at an alarming rate in parallel with rapid urbanization in newly industrialized parts of the world, including East Asia. Simultaneously, environmental pollutants are also an escalating problem in these regions. Recent studies have reported on associations between environmental pollutants and IBD, however, data on this topic specific to East Asia are limited. In this review, we summarize available data on environmental pollutants and related exposures in East Asia and their relationship with IBD. Motor vehicle emissions and industrial wastes are key sources of air pollution, while drinking water, seafood and vegetable produce constitute main sources of heavy metal and pesticide exposure. Microplastics are even more ubiquitous and pervasive toxicants. Mechanistic data suggest that environmental pollutants may influence IBD risk and outcomes through microbial dysbiosis and intestinal barrier disruption, ultimately leading to intestinal inflammation. Understanding the impact of environmental exposures and outcomes is key to potentially identify modifiable factors and inform strategies to predict, prevent and mitigate the rising burden of IBD in East Asia.
BACKGROUND
The incidence of inflammatory bowel disease (IBD), an immune-mediated disease of the gastrointestinal tract, is rising globally at an alarming rate [1,2]. Once considered a disease of Western countries, newly industrialized parts of the world, such as East Asia, are experiencing a surge in the IBD incidence and prevalence [3]. This rise in disease burden is associated with increased direct and indirect healthcare costs and disability in these regions [4,5]. While IBD etiology remains to be fully understood, increasing data implicate environmental shifts, including diverse pollutants and toxicants, in IBD risk. Further, regionspecific environmental risk factors may drive the epidemiological differences in IBD and an understanding of these risk factors is crucial towards targeted prediction and prevention strategies. In this review, we discuss environmental risk factors, particularly pollutants, implicated in intestinal inflammation and IBD in East Asia, including China, Hong Kong, Japan, Mongolia, Korea, and Taiwan. We provide added context through animal models and in vitro studies from this region, and highlight knowledge gaps. We also address the concept of IBD prevention and steps towards developing such strategies in East Asia.
STUDY SEARCH AND SELECTION
We conducted a structured search of PubMed for studies on IBD, intestinal inflammation, microbial dysbiosis, and environmental pollutants, including air pollutants, heavy metals, microplastics, and pesticides and organophosphorus compounds, with a focus on East Asia. Relevant animal model studies were included to provide mechanistic insights. Reference lists of selected articles were reviewed to ensure completeness, and pertinent studies from Western populations were incorporated for contextual comparison.
ENVIRONMENTAL POLLUTANTS IN EAST ASIA
1. Air Pollutants
Air pollutants include diverse gases and volatile compounds from sources such as motor vehicle emissions, industrial and agricultural wastes [6]. Air pollutants, including particulate matter (PM2.5 and PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), ozone (O3), and carbon monoxide (CO) have been linked with increased risk of IBD in studies from the United Kingdom, the Netherlands, Italy, Ukraine, and Canada [7-13].
With respect to data from East Asia, a survey study reported on long-term effects of air pollution on gastrointestinal outcomes, including IBD, in 13,298 individuals between 2011 and 2020 across 28 provinces in China. In this study, the hazards for development of gastrointestinal diseases were increased with exposure to PM2.5 and lower with exposure to ozone. Exposures were measured using artificial intelligence algorithms integrating simulation models, surface measurements, remote sensing data and atmospheric reanalysis. Urban-rural differences in associations were also reported, with stronger associations between PM2.5 and sulfur dioxide with IBD in urban areas compared to rural areas [14]. In another study of 17,566 individuals in China between 2018 and 2022, exposure to multiple air pollutants, including PM2.5, nitrogen dioxide, ozone, nitrate, ammonium, organic matter, black carbon, chloride, and sulfate (hazard ratio, 1.34; 95% confidence interval, 1.16–1.55) was associated with an increased IBD risk [15].
Mechanisms underlying these findings include gut microbiome perturbations: in a Chinese study using stool samples from 1,583 participants, long-term exposure to PM2.5 was associated with a lower gut microbiome diversity [16]. In a mouse model study in China, exposure to concentrated PM2.5 induced proliferation of 5 non-gastric Helicobacter species and depletion of Eubacterium rectale, Clostridium, Lactobacillus intestinalis, and Lactobacillus species, bacterial strains which have been linked with protective effects against IBD [17]. Other studies have demonstrated consistent findings; mice exposed to concentrated PM2.5 to mimic highly polluted urban areas of China showed increased inflammatory cell infiltration in the ileum, decreased intestinal mucus thickness and mucus secretion, and reduced numbers of goblet cells and ileal villi. Similarly, other data have demonstrated reduced expression of tight junction proteins such as occludin with PM2.5 exposure [18]. Chronic PM2.5 exposure is also linked to colonic inflammation and increased oxidative stress in mice with a positive correlation between serum interleukin 8 (IL-8) and anthropogenic pollutant levels in serum samples from 47 individuals from a residential region in Taiwan, a study using a combined in vitro and in vivo model (r=0.30, P=0.065) [19].
In summary, air pollutants may exert a pathogenic role in IBD development beginning in the preclinical phase through effects on intestinal permeability and microbial response, and continue to drive the process through colonic inflammation.
2. Heavy Metals or Transition Metals
Heavy or transition metals are also present in diverse sources, including soil and drinking water [20,21]. Metal exposure can be associated with different outcomes; while many are essential for biological metabolism, in excess doses, they can lead to cytotoxicity and carcinogenesis [22]. Conversely, other metals such as cadmium are consistently linked with adverse health outcomes [23-26]. For example, in the context of IBD, metals such as lead, copper, and iron are implicated in intestinal inflammation [20,24]. On the other hand, zinc exposure may be associated with a lower risk of IBD [27,28].
A prospective study in China explored the association between heavy metals in tap water and IBD [29]. Of 22,824 participants in this study, who were followed between 2016 and 2022, 46 patients developed IBD. While higher levels of mercury, manganese, selenium, sulfur tetroxide, chlorine, and nitrate nitrogen in tap water were associated with IBD, zinc and fluorine demonstrated inverse associations with IBD. A study of 259 children (98 Crohn’s disease [CD], 118 ulcerative colitis [UC], and 43 normal controls) in Japan found that 40.2% of the children with IBD had subnormal zinc levels. Selenium deficiency was significantly more prevalent in CD (15.3%) than in UC (5.9%; P<0.05) and healthy controls (0%; P<0.01) [30].
Mouse model studies from East Asia demonstrate the role of these metals in driving microbial dysbiosis, immune activation, and intestinal injury. In a mouse model study, chronic lead exposure was associated with reduced occludin, colonic zonula occludens expression, and intestinal dysbiosis in a dose-dependent manner [31]. Similarly, in another study, chronic exposure to cadmium in mice was associated with intestinal villi thinning and shedding, decreased messenger RNA (mRNA) levels of occludin and claudin-1 in the small bowel, and increased expression of tumor necrosis factor alpha (TNF-α). Chronic cadmium exposure was associated with microbial dysbiosis characterized by reduced abundance of short-chain fatty acid producing bacteria such as Lachnospiraceae and Ruminococcaceae [32]. Arsenic was found to have a similarly detrimental impact in Cyprinus carpio, a common edible fish, with shortening of villi and inflammatory cell infiltration with higher levels of arsenic, as well as altered intestinal microbial taxa such as increase in Proteobacteria, Fusobacteriota, Bacteroidota (formerly Bacteroidetes), and Verrucomicrobiota (formerly Verrucomicrobia) (P<0.05) and decrease in Cyanobacteriota (formerly Cyanobacteria), Actinobacteriota (formerly Actinobacteria), Planctomycetota (formerly Planctomycetes), and Bacillota (formerly Firmicutes) [33]. In another study, exposure to copper in mice induced a significant decrease in gut microbial diversity, characterized by decreased relative abundances of Tenericutes, Actinobacteria, and Verrucomicrobia [34].
3. Micro and Nano Plastics
Microplastics and nanoplastics are derivatives of polymeric materials, ubiquitous in our modern environment, and pollutants of increasing concern. Exposure to microplastics primarily occurs through ingestion and inhalation [35]. Microplastics can cross the intestinal barrier and accumulate in the small intestine and other organs [36]. Preliminary studies, including those from East Asia, suggest an association between microplastics, nanoplastics, and IBD.
In a Chinese study, microplastics were measured in stool samples from individuals with and without IBD (n =52 and n=50, respectively). Individuals with IBD (41.8 items/g of dry matter) had significantly higher levels of microplastics compared to healthy controls (28.0 items/g of dry matter). Individuals with IBD reported a higher intake of food and water packaged in plastic in this study [37]. Microplastics were detected in 95% of participants, with polyethylene terephthalate and polystyrene being the most prevalent types in a pilot study of 69 school children in China. Children with higher microplastic exposure exhibited significantly reduced microbial alpha diversity (P<0.05) [38]. In a Chinese cohort of 10 patients that underwent surgical resection for complications of CD, microplastic levels positively correlated with increased inflammatory gene expression and greater fibrosis in the ileum [39].
Potential mechanisms underlying these associations have been explored in mouse model studies in East Asia. In a Chinese study, mice fed with diets prepared using polypropylene cutting boards were compared to mice fed with diet prepared using wooden cutting boards. The former showed decreased relative expression of occludin, zonulin-1 in the ileum and colon and claudin-4 in the ileum, increased expression of the Muc2 gene in the ileum and colon and an increased concentration of secretory immunoglobulin A in the colon. Relative abundance of beneficial bacteria such as Lactobacillus, Faecalibaculum, and Bifidobacterium were lower in the polystyrene exposed mice [40]. In another study, oral exposure to microplastics by gavage led to accumulation of polystyrene microplastics in murine intestine and microbiome disruptions. Microplastic exposure also reduced the levels of secretory immunoglobulin A in the intestine and the differentiation of CD4+ and CD8+ T cells in mesenteric lymph nodes. Disruption of the intestinal epithelium, shorter and disorganized intestinal villi, intestinal crypt dysplasia, vacuolation in the intestine, thinning of basal lamina and lymphocyte aggregation were seen in the microplastic exposed group [41]. In a Japanese study investigating the effects of microplastic exposure from polyethylene terephthalate on mice intestinal cells, microplastics impacted the transcriptome in gut immune cells and their metabolisms, and gut microbial composition [42]. In another Chinese study, mice treated with polystyrene microplastics for 5 weeks showed decreased mucin production and decreased abundance of Bacillota and α-Proteobacteria in the feces [43]. In a Chinese study, male mice exposed to 5 μm pristine and fluorescent polystyrene microplastics for 6 weeks showed reduced mucin production with relative decrease in mRNA levels of Muc1, Muc2, Muc3, Klf4, Meprin-β, and Retnlb genes [44]. Rats exposed to polystyrene microplastics for 90 days showed decreased goblet cells, disordered muscular layer arrangements and crypt structure disruptions. Investigators found elevated levels of IL-1β, IL-6, and TNF-α in rats exposed to polystyrene microplastics [45]. In a Chinese study, Crohn’s-like ileitis characterized by ileal structural impairment, the release of inflammatory cytokines and necroptosis was seen in mice exposed to nanoplastics [46]. Exposure of rats to Bisphenol A, a chemical used in plastic manufacture, in a Chinese study induced intestinal damage in the jejunum characterized by shortening and reduction in number of villi and widening of inter-villous spaces. Bisphenol A exposure also induced oxidative stress, immune activation, and microbiota disruption [47].
Interpretation of existing studies is limited by the lack of standardized methodologies for microplastic measurement, with variability in sampling and detection methods, reporting units, and particle size thresholds.
4. Pesticides and Organophosphorus Compounds
In the preliminary results of a Japanese study of 38 healthy individuals investigating the effect of pesticides on fecal short-chain fatty acids, urinary organophosphate levels negatively correlated with fecal acetate and lactate (r=−0.345 and r=−0.391; P<0.05), implicating an altered microbial metabolism with pesticide exposure [48]. In another study exploring the effects of polycyclic aromatic hydrocarbon (PAH) exposure on intestinal immunity in electronic waste areas of China, PAH pollutants were associated with intestinal inflammation and intestinal epithelial changes in children. Exposure was also associated with transformation of microfold (M) cells. Higher hydroxylated PAH concentrations in electronic-waste-exposed children were associated with higher sialyl Lewis A level, absolute lymphocyte and monocyte counts, decreased percentage of CD4+ T cells, and had a higher risk of diarrhea [49].
A Chinese study examined the underlying mechanism of colitis in mice exposed to tebuconazole, a triazole fungicide used in agriculture. Mice exposed to tebuconazole showed gut microbial dysregulation, structural damage, inflammatory cell infiltration and disruption of intestinal barrier (P<0.05) [50]. Another Chinese study examining the effects of imazalil, a broad-spectrum fungicide, showed microbial dysbiosis characterized by reduced abundance of Bacteroidota, Bacillota and Actinobacteriota in the cecum of imazalil-exposed mice. Inflammatory cell infiltration, increased fecal Lcn-2 and increased TNF-α, IL-1β, IL-22, and IFN-γ mRNA levels were also observed in the colon of imazalil-exposed mice [51]. Carbendazim is a systemic broad-spectrum fungicide and a food preservative. A Chinese study reported increased serum concentrations of IL-1β and IL-6 in mice orally exposed to carbendazim. Carbendazim exposure also caused decrease in Bacteroides and an increase in Bacillota and Actinobacteriota [52]. In a Chinese study examining the effect of chlorpyrifos on microbiota using rats fed with normal- and high-fat diets, chlorpyrifos-induced microbial response was diet-dependent with a greater number of perturbed genera in high-fat diet fed rats [53]. In another Chinese study using zebra fish, chlorpyrifos exposure promoted oxidative stress characterized by increase in malondialdehyde and decrease in glutathione levels in the gut along with changes in gut microbiota [54]. In another Chinese study, chronic exposure of p, p’-dichlorodiphenyldichloroethylene (p, p’-DDE) and β-hexachlorocyclohexane (β-HCH), 2 predominant metabolites of organochloride pesticides in mice, was associated with increase in Bacillota and Proteobacteria, and decrease in Bacteroidota, Verrucomicrobiota, Actinobacteriota (P<0.05), and Candidatus Saccharibacteria [55]. In a Chinese study, oral administration of imazalil, a fungicide used in plants and animals, affected intestinal barrier function in mice, reducing mucus secretion, decreasing the expression of cystic fibrosis transmembrane conductance regulator-related genes in both the ileum and colon [56].
A study from China showed that antibiotic use can alter intestinal microbial structure in mice and alleviate hepatotoxicity and nephrotoxicity induced by pesticide chlorpyrifos [57]. Another Chinese study reported increased bioavailability of triazine herbicides in mice treated with ampicillin for 3 days [58].
PRENATAL AND EARLY LIFE EXPOSURE
The early life period, which extends from the prenatal period to early childhood, is a critical window for immune development and microbiome establishment; exposures during this period confer long-lasting effects on the offspring [59]. Gut microbiome is acquired from the mother at birth, with gradual diversification upon interaction of the offspring with their environment [60]. Below, we summarize data from East Asia relating to the early life period on intestinal inflammation and the microbiome.
A study of 37 mother-infant dyads in China examined the effects of time-varying ambient air pollution exposure including PM2.5, PM10, and nitrogen dioxide on the gut microbiome of infants during their first 2 years of life. Higher cumulative exposure to PM2.5 and nitrogen dioxide during the first 6 months of life was associated with reduced alpha diversity (P<0.01) and altered beta diversity (P=0.003) of the infant gut microbiome. Exposure to ambient air pollutants was associated with decreased abundance of Bifidobacterium and Lactobacillus, and increase in Proteobacteria with more pronounced effects during first year of life [60]. In another study of 62 pregnant women, increased ozone exposure during the second and third trimesters was significantly associated with reduced microbial alpha diversity in neonates (β=–0.21; P<0.01), with more pronounced effects in male infants and those delivered vaginally [61]. Another study examined the impact of PM1 exposure, specifically particles with a diameter ≤1 μm, particles more biologically invasive than the more commonly studied PM2.5 during pregnancy in 62 mother-infant dyads, PM1-induced microbial alterations in mothers were partially replicated in their neonates, with both groups showing reduced microbial alpha diversity [62].
In a Chinese study of 304 infants investigating the impact of early-life exposure to chemical pollutants on gut microbiota composition in hospitalized infants, high pollutant exposure was significantly associated with lowered alpha diversity (Shannon index, P=0.02) compared to those with minimal exposure [63]. In another Chinese study investigating the association between per- and polyfluoroalkyl substances exposure on microbial diversity and neurocognitive development in 789 pregnant mothers, higher exposure to per- and polyfluoroalkyl substances was significantly associated with higher relative abundances of Enterococcus spp. but lower relative abundances of several short-chain fatty acid-producing genera [64].
DISCUSSION
In this comprehensive review focusing on the role of environmental pollutants and other distinct environmental factors on intestinal inflammation, microbiome perturbations, and IBD in East Asia, we highlight important findings and recapitulate those from studies across other regions. There is a substantial burden of environmental pollutants in East Asia linked to ongoing urbanization [65,66]. Heavily populated urban areas are disproportionately affected by air pollution driven by industrial and motor vehicular emissions. Drinking water and seafood are key sources of heavy metals. Pesticides and other organophosphate compounds are present mainly in drinking water and fresh produce. In contrast, microplastics and per- and polyfluoroalkyl substances are present in a wide array of sources ranging from diet to household dust. These various classes of environmental pollutants are implicated in intestinal inflammation through disruption of gut microbiome and intestinal barrier integrity. Emerging evidence suggests exposure to air pollutants and microplastics, especially in early life, may trigger alterations in gut microbial flora (Fig. 1).
Environmental exposures and their potential effects on inflammatory bowel disease in East Asia. BPA, bisphenol A; PFAS, per- and polyfluoroalkyl substances.
Air pollution in East Asia, particularly in densely populated urban areas, has been linked to several gastrointestinal diseases including IBD [15]. Simultaneous exposure to multiple air pollutants and the duration of exposure may intensify detrimental effects [16,17]. Recent studies examining the effects of prenatal and infant exposure add further nuances based on timing of exposure [60,61]. These data are consistent with studies from Europe and Canada that implicate air pollution in IBD risk [7,9,10,13]. Pollutants such as PM2.5, PM10, nitrogen dioxide and nitric oxide have been linked with both CD and UC incidence in the United Kingdom [7,13]. Similarly, early life exposure to air pollutants in Canada is associated with IBD development [10]. Distinguishing the impact of environmental exposures based on IBD phenotype, demographics and importantly on timing of exposure—early life versus later in life—can help define epidemiological differences as well as help implement focused preventive strategies during strategic windows of opportunity [59,67]. Animal models reveal key mechanistic pathways including gut microbial dysbiosis, intestinal barrier disruption, increased cytokine production and genetic alterations ultimately leading to intestinal inflammation [17-19]. With these provocative data, large epidemiological studies with quantitative measurement of diverse toxicants in biological samples, environmental mixture analyses, and long-term follow-up will be informative. Further, data on the impact of pollutants on outcomes such as disease course, medication use, hospitalization, and surgery following IBD diagnosis are limited and represent an important knowledge gap [68].
Next, essential and non-essential metals have been implicated in IBD in studies from East Asia. High concentrations of non-essential metals such as mercury, manganese and selenium in drinking water are associated with an increase in IBD risk, whereas zinc may have a protective role [29]. Another study also found lower levels of zinc in individuals who later developed IBD, supporting a protective association [69]. These data are consistent with studies from other parts of the world on the relationship of metals with IBD, with a protective association with zinc [27,70-72]. Both UC and CD patients had higher odds of residing in areas where lead or arsenic were above maximum contaminant level, but lower odds of residing in areas with elevated aluminum or cadmium, compared with controls in the United States [71]. In a study of asymptomatic patients with incidentally diagnosed IBD in Spain, higher boron and lower zinc levels were reported among individuals with IBD compared to controls [27]. Similarly, a Greek study reported lower zinc and selenium levels in CD. Chromium was negatively associated with serum IL-6, and cesium with fecal calprotectin and serum IL-10 in this study [72]. In addition to drinking water, soil and seafood are major sources of non-essential metal exposure in East Asia; studies assessing the impact of metal exposure via these sources would be informative. Preclinical studies suggest that heavy metals may induce gut inflammation, alter gut microbiome features and impact on macronutrient and trace element metabolism in tissue [31]. Geographic and occupational differences in metal concentrations in mining and farming soil are additional considerations [73]. Further, dietary factors and gastric acid secretion, which can also vary across geography and cultures, may influence bioavailability of heavy metals [73,74]. Therefore, the effects of heavy metals in East Asia is likely to be influenced by multiple factors, highlighting the complex interplay of the exposome and downstream events and the importance of geographical heterogeneity.
Another pollutant of environmental importance is microplastics. A study reported increased fecal concentration of microplastics in patients with IBD compared to controls in China with the former reporting higher intake of food and water packaged in plastic [37]. In another study, microplastics were detected in fecal samples of 95% of the children in China [38]. This study reported microbial disruptions in children exposed to higher levels of microplastics. Polypropylene and polyethylene microplastic contamination in manure and feeds from farms has been reported in China recognizing a pathway for contamination of agricultural soil [75]. In a pilot study of 15 participants in the United States, microplastics detected in stool samples originated from a range of consumer and food-related products, including packaging materials (polyethylene, polypropylene, polyethylene terephthalate, polystyrene), textiles (polyamide/nylon), and other sources such as dental materials (polymethyl methacrylate), coffee machines (polyoxymethylene), and household or food-contact applications (polyurethane) [76]. Therefore, sources of microplastics are numerous, spanning from foodstuffs and packaging, household dust to agricultural manure. While human studies related to underlying mechanisms are limited, microplastics are linked to increased fibrosis and inflammation in pathology samples in patients with CD [39]. In mouse models, however, Crohn’s-like ileitis characterized by ileal structural impairment, release of inflammatory cytokines and necroptosis have been reported in mice exposed to nanoplastics [46]. Data from mouse models also show an association between microplastics and microbial dysbiosis, intestinal inflammation and altered immune response [40-42,44]. Future studies assessing impact of microplastic exposure in humans would provide a deeper understanding into underlying mechanisms that may lead to intestinal inflammation. Further, Bisphenol A, a chemical compound used in plastic manufacturing is linked to intestinal damage, increased oxidative stress, immune activation, and microbiota disruption in mice [47]. Therefore in addition to plastics, chemicals that co-occur with plastics are additional considerations.
While East Asian studies have noted an association between pesticides and organophosphorus compounds and IBD [77], human studies examining the link between IBD and pesticides in East Asia are lacking. Nevertheless, considering data implicating these chemicals in intestinal inflammation and IBD [20], the high level of pesticide contamination of produce in East Asia is a concern and warrants further study and mitigation strategies [78]. In Western populations, studies have reported on both modes of exposure and their associations with IBD. In France, fruit arboriculture and dairy farming has been linked to increased risk of IBD, while crop farming has been associated with elevated risk of CD, and shellfish farming with both CD and IBD [79]. Ever use of dieldrin, toxaphene, parathion and terbufos was associated with increased risk for IBD in a U.S. farming population [80]. With respect to underlying mechanisms, exposure to pesticide and organophosphates are also linked with microbial dysbiosis, intestinal inflammation and intestinal structural damage [51,56,57]. PAH exposure in areas with electronic waste contamination in China may be associated with intestinal inflammation due to transformation of microfold cells [49]. Therefore, the breadth of pollutant sources ranging from agriculture to the electronic industry underscores the evolving landscape driven by urbanization in this region.
A key limitation in interpreting the current literature is the substantial collinearity between environmental pollutants and concurrent urbanization-related exposures in East Asia. Rapid industrialization is accompanied not only by increased exposure to environmental pollutants but also by significant shifts in dietary patterns, including higher consumption of ultra-processed foods, as well as broader lifestyle changes. These factors frequently co-occur and may act synergistically, making it challenging for conventional epidemiological models to disentangle the independent effects of specific toxicants. Future studies incorporating more granular exposure assessment and advanced analytical approaches will be critical to better isolate these effects.
Building strategies directed at prevention warrants understanding of preclinical phase, genetic predisposition and the exposome [81]. Interventions in the preclinical phase are grounded in the hypothesis that significant alterations in the microbiome, intestinal barrier and immune activation transpires during this period [82]. Consortiums such as PROMISE (Prediction and Prevention Through Omics, Microbiota, Immune System and Environment) integrate data from unique cohorts that prospectively follow asymptomatic first-degree relatives of individuals with CD or use pre-existing serum biorepositories that include samples from the preclinical period of individuals who later develop IBD [83]. Leveraging data from these cohorts to characterize the preclinical phase provides a valuable opportunity to identify preclinical serum and stool based biomarkers and integrative models to identify high-risk individuals and design prevention and interception trials for IBD [84-90]. The success of type 1 diabetes prevention, where insights into the preclinical phase led to prevention trials and the approval of teplizumab, delaying disease onset by approximately 2 years, serves as a useful model [91]. These efforts, driven by decades of scientific collaboration and multicenter research, highlight the need for a similar coordinated effort among clinicians and researchers in IBD. These interventions pose several practical challenges such as low positive predictive value of the biomarkers and integrative models, lack of insight into the temporal variation of biomarker levels, lack of practical, clinically applicable, reproducible, and scalable assays that can be used for screening [83].
As prediction and prevention of IBD are becoming increasingly relevant, it is time to evaluate tailoring of these efforts to the individual risk in East Asia, and the unique environmental and socio-cultural framework and resources in the region (Fig. 2) [92]. The individual level risk for IBD in East Asia is likely to be influenced by genetic and exposome heterogeneity and warrants specific study. Therefore, strategies informed by data from Western population may not be directly generalizable. With respect to environmental exposures, monitoring of exposure to chemicals of concern using innovative and contextualized methods would be relevant. Notably, emerging studies in East Asia are evaluating sources and magnitude of exposure, providing an important foundation for future work. For example, in a study from Korea, personal nitrogen dioxide exposure was measured among taxi drivers using passive diffuser samples [93]. A Taiwanese study identified sources of particulate PAHs using a personal air-sampling pump [94,95]. Individual-level interventions that may lower IBD risk specifically, or the harmful impacts of toxicants warrant study, particularly those that may be associated with high uptake in the community. In addition to ongoing work, future directions include building of collaborative consortia, preclinical cohorts and pilot studies implementing strategies proven to be effective in Western settings, such as integrative prevention clinics, environmental scores and targeted prevention trials for high-risk populations [82,85,92].
Inflammatory bowel disease prevention strategies in East Asia.
From a public health perspective, identifying pollutant sources and the extent of contamination is crucial, in addition to studying the impact of toxicants on IBD in East Asia. For example, an innovative inverse model using regression-based multi-step inversion approach has been developed in China to estimate emissions of nitrogen oxide from anthropogenic, lightning and soil sources using ozone monitoring instrument [96]. Beyond identification, strategies to lower exposure and periodic monitoring of pollution levels is key towards regulation efforts [97,98]. A pilot study in China compared rooftop grown hydroponic leafy vegetables to general market produce and found that rooftop grown produce was comparable or exceeded in the nutritional value, had low detectable levels of metals, pesticides [99]. Other interventions in day to day lives such as reducing the intake of ultra-processed foods, minimizing exposure to microplastics from food and beverage packaging would be helpful. Similar works are needed to evaluate contamination of aquatic sources, especially considering the relevance of the marine ecosystem in East Asia. Public health strategies should focus on reducing exposure to environmental pollutants, promote healthy lifestyles and dietary practices. Regional surveillance and longitudinal studies are essential to guide preventive policies and identify at-risk populations.
CONCLUSIONS
Environmental exposures, especially to pollutants, may pose a significant risk by increasing the IBD burden in East Asia due to their potential pathogenic role. Region-specific risk factors need to be defined to mitigate the strain posed on the health care systems. Furthermore, there is an urgent need to develop targeted interventions around preventing environmental exposure through future research and informed health policies.
Notes
Funding Source
This study is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (K23DK129762-03).
Conflict of Interest
Colombel FC reports receiving research grants from AbbVie, Janssen Pharmaceuticals and Takeda; receiving payment for lectures from AbbVie, Amgen, Allergan, Inc. Ferring Pharmaceuticals, Shire, and Takeda; receiving consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Glaxo Smith Kline, Geneva, Iterative Scopes, Janssen Pharmaceuticals, Kaleido Biosciences, Landos, Otsuka, Pfizer, Prometheus, Sanofi, Takeda, Ti- Genix, and holds stock options in Intestinal Biotech Development. Kim ES is a member of the editorial board of this journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. Other authors have no potential conflicts of interest to disclose.
Data Availability Statement
Data sharing is not applicable to this article as no new data were created or analyzed in this study.
Author Contributions
Conceptualization: Shenoy S, Agrawal M, Kim ES, Colombel JF. Data curation: Shenoy S, Chaubey M. Data interpretation: Shenoy S, Chaubey M. Funding acquisition: Agrawal M. Supervision: Agrawal M, Kim ES, Colombel JF. Writing–original draft: Shenoy S, Chaubey M, Agrawal M. Writing–review & editing: Kim ES, Colombel JF, Agrawal M. Approval of final manuscript: all authors.
Additional Contributions
We thank Jill Gregory, Certified Medical Illustrator, Icahn School of Medicine at Mount Sinai, for assistance with illustrations.