NEWS & VIEWS IBD
the ACCES inception cohort showed that infants living in Asia who were breastfed for >12 months were seven and 10 times less likely to develop ulcerative colitis and Crohn’s disease, respectively. Importantly, this finding remained significant after adjusting for multiple comparison errors using a Bonfer roni correction.1 Quitting smoking increases the risk of developing ulcerative colitis in the Western world.5 Similarly, in Asia the odds of being diagnosed with ulcerative colitis were twofold higher among individuals who quit smoking.1 Data from North America suggest that regular physical activity might be protec tive for the development of Crohn’s disease;6 the ACCES study group also showed that in Asian countries individuals with a sedentary lifestyle were nearly two times more likely to develop Crohn’s disease.1 In Asia, the influence of several environ mental risk factors diverged from obser vations in the Western world (Table 1). Meta-analyses have constantly demonstrated that smoking increases the risk of develop ing Crohn’s disease in North America and Europe.5 Similarly, the ACCES study group showed that the odds of developing Crohn’s disease among current smokers were four fold higher than never smokers in Australia.1 Howe ver, surprisingly, smoking did not influence the risk of Crohn’s disease among
Global variations in environmental risk factors for IBD Gilaad G. Kaplan
IBD has emerged as a global disease. Ng and colleagues have identified that some environmental risk factors are shared across the world, whereas others are distinctly unique to individuals living in Asia. This work adds a new clue to the mystery of the environmental determinates of IBD. Kaplan, G. A. Nat. Rev. Gastroenterol. Hepatol. advance online publication 28 October 2014; doi:10.1038/nrgastro.2014.182
In an article published in Gut, Ng et al.1 con ducted a prospective case–control study of environmental risk factors for IBD in Asia. This novel work sheds light on the environ mental determinates of IBD that are both shared across the world and that are distinct in Asia. Moreover, many of the risk factors are modifiable and thus offer the opportu nity for primary prevention to avoid the incidence of IBD in Asia from approximating that in Australia, North America and Europe. The Asia–Pacific Crohn’s and Colitis Epidemiology Study (ACCES) is a collabor ative initiative of eight countries in Asia (China, Hong Kong, Indonesia, Sri Lanka, Macau, Malaysia, Singapore and Thailand) and Australia. In 2011, the ACCES Study Group developed a prospective inception cohort of patients with IBD. The authors con ducted a comparative epidemiological analy sis of IBD in Asian countries and Australia.2 The incidence of IBD in Asia was 1.4 per 100,000, with the highest incidence in China (3.4 per 100,000). Ulcerative colitis was two times more common than Crohn’s disease in Asia. By contrast, Australia reported data that was aligned with most countries in North America and Europe: the incidence of IBD was 23.7 per 100,000 and Crohn’s disease was more common than ulcerative colitis.2 The ACCES inception cohort demon strated that IBD has taken hold in countries throughout Asia; however, the incidence of IBD in Asia is still only a fraction of the occurrence in North America and Europe.3 Subsequently, the ACCES study group has investigated the effect of environmental risk factors on the development of IBD. The authors selected environmental exposures that have been traditionally studied in the
Western world including exposures in child hood (breastfeeding), dietary practices (tea and coffee consumption), smoking habits, hygiene (access to flush toilets) and medi cations (antibiotics). The questionnaire was derived, with appropriate translation, from the International Organization of IBD, which allowed the ACCES study group to determine whether the predominantly studied environ mental risk factors for IBD in the West are also relevant in the East.1 Several environmental risk factors for IBD seem to be shared by all populations regard less of race, ethnicity and geographical loca tion (Table 1). A meta-analysis confirmed that breastfeeding reduces the risk of devel oping IBD in Western populations.4 Likewise,
Table 1 | Environmental risk factors for IBD in Asia and Western nations* Selected environmental risk factors
Western nations
Countries in Asia
Crohn’s disease
Ulcerative colitis
Crohn’s disease (OR [95% CI])
Ulcerative colitis (OR [95% CI])
Breastfeeding >12 months
–
–
0.10 (0.04–0.30)‡
0.16 (0.08–0.31)‡
Appendectomy
+/Null
–
1.02 (0.34–3.06)
0.44 (0.13–1.47)
Antibiotic use ≤15 years of age
+
+
0.19 (0.07–0.52)
0.48 (0.27–0.87)
Pet dog in childhood
ND
ND
0.54 (0.35–0.83)
0.82 (0.60–1.12)
In-house water tap in childhood
+/Null
Null
0.76 (0.48–1.22)
0.67 (0.48–0.93)
Flush toilet in childhood
+/Null
Null
1.21 (0.77–1.92)
0.71 (0.51–0.98)
Smoking: current vs never
+
–
1.22 (0.66–2.25)
1.09 (0.66–1.81)
Smoking: ex-smoker vs never
+/Null
+
1.55 (0.79–3.05)
2.02 (1.22–3.35)
Daily coffee consumption
Null
Null
0.73 (0.49–1.09)
0.51 (0.36–0.72)‡
Daily tea consumption
Null
Null
0.62 (0.43–0.91)
0.63 (0.46–0.86)
Physical activity (daily vs less often)
–
Null
0.58 (0.35–0.96)
0.74 (0.51–1.08)
*Data is derived from a compilation of observational studies of environmental risk factors for IBD in Western nations 7,8,10 and Asian countries (not including Australia).1 The risk factors presented in this table are ones that were either significantly associated with Crohn’s disease and/or ulcerative colitis in the study by Ng et al.1 or have been widely studied in Western nations.7,8,10 ‡Significant after applying a Bonferroni correction. Abbreviations: +, positive association; –, negative association; ND, not determined; null, no association.
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY © 2014 Macmillan Publishers Limited. All rights reserved
ADVANCE ONLINE PUBLICATION | 1
NEWS & VIEWS
‘‘
Several environmental risk factors for IBD seem to be shared by all populations regardless of race…
’’
individuals living in countries in Asia.1 In addition, the ‘hygiene hypothesis’ proposes that improved sanitation and greater utili zation of antibiotics in childhood increases the risk of developing IBD.7 However, the data from Asia seem to contradict this notion as children exposed to antibiotics were protected from developing IBD, and those living in sanitary conditions (such as having access to flush toilets) were protected from ulcerative colitis.1 Also, several novel factors were identified in Asia. For example, consumption of tea protected against the development of IBD and living with a dog during childhood reduced the odds of devel oping Crohn’s disease.1 Discovering unique and divergent environmental risk factors is not surprising because individuals living in countries in Asia will have different genetic susceptibility, microbiome composition and environmental interactions.8 However, an alternative explanation for inconsistent results are methodological chal lenges in studying environmental risk factors for IBD.9 Case–control studies such as this one, and like many others conducted in the Western world, are difficult to conduct and inevitably introduce biases based on recruit ment strategies, selection of representa tive controls, measurement of exposures (for example recall bias of questionnaires), residual confounding, handling missing data and multiple comparison errors (that is, false positives).9 Although the authors took great effort to minimize these biases in their study (for example by applying a Bonferroni
correction), it is nearly impossible to miti gate these biases entirely. For example, the prevalence of smoking in the control group in Asia (11%) was considerably lower than that reported in the general population. This factor could mean that the control popula tion was not entirely representative of the source population that the cases were derived from. Thus, a replication study is necessary to confirm the novel findings reported by the ACCES study group. Although the prevalence of IBD in Asia is low, without interventions the incidence will probably continue to increase and might eventually approximate the rates seen in the Western world. The work from Ng et al.1 highlights the similarities and differences of environmental determinates between the East and the West. However, future studies are necessary to advance our understand ing of IBD in Asia. First, prospective cohort studies should be designed in Asia to address methodological challenges of case–control studies. Second, individuals who develop IBD in Asia should be evaluated for confir mation of novel environmental risk factors (such as tea consumption), exploration of gene–environment interactions and char acterization of the effect of environmental exposures on the gut microbiome. Third, environmental risk factors that were not explored in the current study (for example, NSAID use, pollution and vitamin D levels from sunlight and/or dietary intake) 7,10 should be studied in Asia. Fourth, this work should be extended to other poorly studied regions (such as the Middle East, Africa and South America). Finally, inter ventional studies that modify environmental exposures (such as promoting breastfeeding) are necessary to curb the rising incidence of IBD across the world.
2 | ADVANCE ONLINE PUBLICATION
Departments of Medicine and Community Health Sciences, University of Calgary, 3280 Hospital Drive NW, 6D56, Calgary, AB T2N 4N1, Canada. [email protected] Competing interests The author declares no competing interests. 1.
Ng, S. C. et al. Environmental risk factors in inflammatory bowel disease: a populationbased case-control study in Asia-Pacific. Gut http://dx.doi.org/10.1136/gutjnl-2014307410. 2. Ng, S. C. et al. Incidence and phenotype of inflammatory bowel disease based on results from the Asia-pacific Crohn’s and colitis epidemiology study. Gastroenterology 145, 158–165 (2013). 3. Molodecky, N. A. et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142, 46–54 (2012). 4. Klement, E., Cohen, R. V., Boxman, J., Joseph, A. & Reif, S. Breastfeeding and risk of inflammatory bowel disease: a systematic review with meta-analysis. Am. J. Clin. Nutr. 80, 1342–1352 (2004). 5. Calkins, B. M. A meta-analysis of the role of smoking in inflammatory bowel disease. Dig. Dis. Sci. 34, 1841–1854 (1989). 6. Khalili, H. et al. Physical activity and risk of inflammatory bowel disease: prospective study from the Nurses’ Health Study cohorts. BMJ 347, f6633 (2013). 7. Frolkis, A. et al. Environment and the inflammatory bowel diseases. Can. J. Gastroenterol. 27, e18–e24 (2013). 8. Ananthakrishnan, A. N. Environmental risk factors for inflammatory bowel diseases: a review. Dig. Dis. Sci. http://dx.doi.org/ 10.1007/s10620-014-3350-9. 9. Molodecky, N. A., Panaccione, R., Ghosh, S., Barkema, H. W. & Kaplan, G. G. Challenges associated with identifying the environmental determinants of the inflammatory bowel diseases. Inflamm. Bowel Dis. 17, 1792–1799 (2011). 10. Molodecky, N. A. & Kaplan, G. G. Environmental risk factors for inflammatory bowel disease. Gastroenterol. Hepatol. (NY) 6, 339–346 (2010).
www.nature.com/nrgastro © 2014 Macmillan Publishers Limited. All rights reserved
the ACCES inception cohort showed that infants living in Asia who were breastfed for >12 months were seven and 10 times less likely to develop ulcerative colitis and Crohn’s disease, respectively. Importantly, this finding remained significant after adjusting for multiple comparison errors using a Bonfer roni correction.1 Quitting smoking increases the risk of developing ulcerative colitis in the Western world.5 Similarly, in Asia the odds of being diagnosed with ulcerative colitis were twofold higher among individuals who quit smoking.1 Data from North America suggest that regular physical activity might be protec tive for the development of Crohn’s disease;6 the ACCES study group also showed that in Asian countries individuals with a sedentary lifestyle were nearly two times more likely to develop Crohn’s disease.1 In Asia, the influence of several environ mental risk factors diverged from obser vations in the Western world (Table 1). Meta-analyses have constantly demonstrated that smoking increases the risk of develop ing Crohn’s disease in North America and Europe.5 Similarly, the ACCES study group showed that the odds of developing Crohn’s disease among current smokers were four fold higher than never smokers in Australia.1 Howe ver, surprisingly, smoking did not influence the risk of Crohn’s disease among
Global variations in environmental risk factors for IBD Gilaad G. Kaplan
IBD has emerged as a global disease. Ng and colleagues have identified that some environmental risk factors are shared across the world, whereas others are distinctly unique to individuals living in Asia. This work adds a new clue to the mystery of the environmental determinates of IBD. Kaplan, G. A. Nat. Rev. Gastroenterol. Hepatol. advance online publication 28 October 2014; doi:10.1038/nrgastro.2014.182
In an article published in Gut, Ng et al.1 con ducted a prospective case–control study of environmental risk factors for IBD in Asia. This novel work sheds light on the environ mental determinates of IBD that are both shared across the world and that are distinct in Asia. Moreover, many of the risk factors are modifiable and thus offer the opportu nity for primary prevention to avoid the incidence of IBD in Asia from approximating that in Australia, North America and Europe. The Asia–Pacific Crohn’s and Colitis Epidemiology Study (ACCES) is a collabor ative initiative of eight countries in Asia (China, Hong Kong, Indonesia, Sri Lanka, Macau, Malaysia, Singapore and Thailand) and Australia. In 2011, the ACCES Study Group developed a prospective inception cohort of patients with IBD. The authors con ducted a comparative epidemiological analy sis of IBD in Asian countries and Australia.2 The incidence of IBD in Asia was 1.4 per 100,000, with the highest incidence in China (3.4 per 100,000). Ulcerative colitis was two times more common than Crohn’s disease in Asia. By contrast, Australia reported data that was aligned with most countries in North America and Europe: the incidence of IBD was 23.7 per 100,000 and Crohn’s disease was more common than ulcerative colitis.2 The ACCES inception cohort demon strated that IBD has taken hold in countries throughout Asia; however, the incidence of IBD in Asia is still only a fraction of the occurrence in North America and Europe.3 Subsequently, the ACCES study group has investigated the effect of environmental risk factors on the development of IBD. The authors selected environmental exposures that have been traditionally studied in the
Western world including exposures in child hood (breastfeeding), dietary practices (tea and coffee consumption), smoking habits, hygiene (access to flush toilets) and medi cations (antibiotics). The questionnaire was derived, with appropriate translation, from the International Organization of IBD, which allowed the ACCES study group to determine whether the predominantly studied environ mental risk factors for IBD in the West are also relevant in the East.1 Several environmental risk factors for IBD seem to be shared by all populations regard less of race, ethnicity and geographical loca tion (Table 1). A meta-analysis confirmed that breastfeeding reduces the risk of devel oping IBD in Western populations.4 Likewise,
Table 1 | Environmental risk factors for IBD in Asia and Western nations* Selected environmental risk factors
Western nations
Countries in Asia
Crohn’s disease
Ulcerative colitis
Crohn’s disease (OR [95% CI])
Ulcerative colitis (OR [95% CI])
Breastfeeding >12 months
–
–
0.10 (0.04–0.30)‡
0.16 (0.08–0.31)‡
Appendectomy
+/Null
–
1.02 (0.34–3.06)
0.44 (0.13–1.47)
Antibiotic use ≤15 years of age
+
+
0.19 (0.07–0.52)
0.48 (0.27–0.87)
Pet dog in childhood
ND
ND
0.54 (0.35–0.83)
0.82 (0.60–1.12)
In-house water tap in childhood
+/Null
Null
0.76 (0.48–1.22)
0.67 (0.48–0.93)
Flush toilet in childhood
+/Null
Null
1.21 (0.77–1.92)
0.71 (0.51–0.98)
Smoking: current vs never
+
–
1.22 (0.66–2.25)
1.09 (0.66–1.81)
Smoking: ex-smoker vs never
+/Null
+
1.55 (0.79–3.05)
2.02 (1.22–3.35)
Daily coffee consumption
Null
Null
0.73 (0.49–1.09)
0.51 (0.36–0.72)‡
Daily tea consumption
Null
Null
0.62 (0.43–0.91)
0.63 (0.46–0.86)
Physical activity (daily vs less often)
–
Null
0.58 (0.35–0.96)
0.74 (0.51–1.08)
*Data is derived from a compilation of observational studies of environmental risk factors for IBD in Western nations 7,8,10 and Asian countries (not including Australia).1 The risk factors presented in this table are ones that were either significantly associated with Crohn’s disease and/or ulcerative colitis in the study by Ng et al.1 or have been widely studied in Western nations.7,8,10 ‡Significant after applying a Bonferroni correction. Abbreviations: +, positive association; –, negative association; ND, not determined; null, no association.
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY © 2014 Macmillan Publishers Limited. All rights reserved
ADVANCE ONLINE PUBLICATION | 1
NEWS & VIEWS
‘‘
Several environmental risk factors for IBD seem to be shared by all populations regardless of race…
’’
individuals living in countries in Asia.1 In addition, the ‘hygiene hypothesis’ proposes that improved sanitation and greater utili zation of antibiotics in childhood increases the risk of developing IBD.7 However, the data from Asia seem to contradict this notion as children exposed to antibiotics were protected from developing IBD, and those living in sanitary conditions (such as having access to flush toilets) were protected from ulcerative colitis.1 Also, several novel factors were identified in Asia. For example, consumption of tea protected against the development of IBD and living with a dog during childhood reduced the odds of devel oping Crohn’s disease.1 Discovering unique and divergent environmental risk factors is not surprising because individuals living in countries in Asia will have different genetic susceptibility, microbiome composition and environmental interactions.8 However, an alternative explanation for inconsistent results are methodological chal lenges in studying environmental risk factors for IBD.9 Case–control studies such as this one, and like many others conducted in the Western world, are difficult to conduct and inevitably introduce biases based on recruit ment strategies, selection of representa tive controls, measurement of exposures (for example recall bias of questionnaires), residual confounding, handling missing data and multiple comparison errors (that is, false positives).9 Although the authors took great effort to minimize these biases in their study (for example by applying a Bonferroni
correction), it is nearly impossible to miti gate these biases entirely. For example, the prevalence of smoking in the control group in Asia (11%) was considerably lower than that reported in the general population. This factor could mean that the control popula tion was not entirely representative of the source population that the cases were derived from. Thus, a replication study is necessary to confirm the novel findings reported by the ACCES study group. Although the prevalence of IBD in Asia is low, without interventions the incidence will probably continue to increase and might eventually approximate the rates seen in the Western world. The work from Ng et al.1 highlights the similarities and differences of environmental determinates between the East and the West. However, future studies are necessary to advance our understand ing of IBD in Asia. First, prospective cohort studies should be designed in Asia to address methodological challenges of case–control studies. Second, individuals who develop IBD in Asia should be evaluated for confir mation of novel environmental risk factors (such as tea consumption), exploration of gene–environment interactions and char acterization of the effect of environmental exposures on the gut microbiome. Third, environmental risk factors that were not explored in the current study (for example, NSAID use, pollution and vitamin D levels from sunlight and/or dietary intake) 7,10 should be studied in Asia. Fourth, this work should be extended to other poorly studied regions (such as the Middle East, Africa and South America). Finally, inter ventional studies that modify environmental exposures (such as promoting breastfeeding) are necessary to curb the rising incidence of IBD across the world.
2 | ADVANCE ONLINE PUBLICATION
Departments of Medicine and Community Health Sciences, University of Calgary, 3280 Hospital Drive NW, 6D56, Calgary, AB T2N 4N1, Canada. [email protected] Competing interests The author declares no competing interests. 1.
Ng, S. C. et al. Environmental risk factors in inflammatory bowel disease: a populationbased case-control study in Asia-Pacific. Gut http://dx.doi.org/10.1136/gutjnl-2014307410. 2. Ng, S. C. et al. Incidence and phenotype of inflammatory bowel disease based on results from the Asia-pacific Crohn’s and colitis epidemiology study. Gastroenterology 145, 158–165 (2013). 3. Molodecky, N. A. et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142, 46–54 (2012). 4. Klement, E., Cohen, R. V., Boxman, J., Joseph, A. & Reif, S. Breastfeeding and risk of inflammatory bowel disease: a systematic review with meta-analysis. Am. J. Clin. Nutr. 80, 1342–1352 (2004). 5. Calkins, B. M. A meta-analysis of the role of smoking in inflammatory bowel disease. Dig. Dis. Sci. 34, 1841–1854 (1989). 6. Khalili, H. et al. Physical activity and risk of inflammatory bowel disease: prospective study from the Nurses’ Health Study cohorts. BMJ 347, f6633 (2013). 7. Frolkis, A. et al. Environment and the inflammatory bowel diseases. Can. J. Gastroenterol. 27, e18–e24 (2013). 8. Ananthakrishnan, A. N. Environmental risk factors for inflammatory bowel diseases: a review. Dig. Dis. Sci. http://dx.doi.org/ 10.1007/s10620-014-3350-9. 9. Molodecky, N. A., Panaccione, R., Ghosh, S., Barkema, H. W. & Kaplan, G. G. Challenges associated with identifying the environmental determinants of the inflammatory bowel diseases. Inflamm. Bowel Dis. 17, 1792–1799 (2011). 10. Molodecky, N. A. & Kaplan, G. G. Environmental risk factors for inflammatory bowel disease. Gastroenterol. Hepatol. (NY) 6, 339–346 (2010).
www.nature.com/nrgastro © 2014 Macmillan Publishers Limited. All rights reserved
