Changing Global Epidemiology of Inflammatory Bowel Diseases: Sustaining Health Care Delivery Into the 21st Century

Crohn’s disease and ulcerative colitis have emerged as global diseases. They affect over 2 million individuals in the North America, 3.2 million in Europe, and millions more worldwide. The recent decades have been characterized by several important changes in the epidemiology of these diseases, in particularly an increasing incidence rates in newly industrialized countries experiencing a westernization of lifestyle. While rates of surgery have experienced a temporal decline attributable in part to increasing availability of medical treatments, earlier initiation of effective therapy, and changes in clinical practice, the healthcare costs associated with these diseases have continued to increase, in part due to costly therapies. Robust epidemiologic and experimental studies have defined the role of the external environment and microbiome on disease pathogenesis and have offered opportunities for disease prevention by modifying such factors. We propose several important steps that are necessary to provide globally sustainable inflammatory bowel disease care in the 21st century. Crohn’s disease and ulcerative colitis have emerged as global diseases. They affect over 2 million individuals in the North America, 3.2 million in Europe, and millions more worldwide. The recent decades have been characterized by several important changes in the epidemiology of these diseases, in particularly an increasing incidence rates in newly industrialized countries experiencing a westernization of lifestyle. While rates of surgery have experienced a temporal decline attributable in part to increasing availability of medical treatments, earlier initiation of effective therapy, and changes in clinical practice, the healthcare costs associated with these diseases have continued to increase, in part due to costly therapies. Robust epidemiologic and experimental studies have defined the role of the external environment and microbiome on disease pathogenesis and have offered opportunities for disease prevention by modifying such factors. We propose several important steps that are necessary to provide globally sustainable inflammatory bowel disease care in the 21st century. In the 21st century, inflammatory bowel disease (IBD) has emerged as a global disease. Hundreds of population-based studies on the incidence and prevalence of IBD have been reported throughout the world.1Molodecky N.A. Soon I.S. Rabi D.M. et al.Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review.Gastroenterology. 2012; 142 (quiz e30): 46-54Abstract Full Text Full Text PDF PubMed Scopus (3335) Google Scholar,2Ng S.C. Shi H.Y. Hamidi N. et al.Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies.Lancet. 2018; 390: 2769-2778Abstract Full Text Full Text PDF PubMed Scopus (2448) Google Scholar The compilation of these studies paints a striking pattern for the epidemiology of IBD with broad implications from improving the understanding of the pathogenesis of IBD to highlighting the evolving burden of disease. These epidemiologic patterns are best conceptualized through separate lenses focused on the Western world, newly industrialized countries, and the developing world.3Kaplan G.G. Ng S.C. Understanding and preventing the global increase of inflammatory bowel disease.Gastroenterology. 2017; 152: 313-321Abstract Full Text Full Text PDF PubMed Scopus (549) Google Scholar As the economic status of a country improves, fundamental changes occur within a society: urbanization, industrialization, changing agricultural practices, evolving health care infrastructure, sanitization, and adoption of a Western lifestyle. In this milieu, IBD emerges and flourishes within society.3Kaplan G.G. Ng S.C. Understanding and preventing the global increase of inflammatory bowel disease.Gastroenterology. 2017; 152: 313-321Abstract Full Text Full Text PDF PubMed Scopus (549) Google Scholar The changing patterns in the epidemiology of IBD will impact the future burden of IBD. In Western countries prevalence is rising and the IBD population is aging.4Coward S. Clement F. Benchimol E.I. et al.Past and future burden of inflammatory bowel diseases based on modeling of population-based data.Gastroenterology. 2019; 156: 1345-1353 e4Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar Hospitalizations and surgeries are declining, whereas the cost of therapeutics are climbing. Incidence is climbing in newly industrialized countries in Asia and Latin America, and with time may approximate the burden of IBD in the Western world.2Ng S.C. Shi H.Y. Hamidi N. et al.Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies.Lancet. 2018; 390: 2769-2778Abstract Full Text Full Text PDF PubMed Scopus (2448) Google Scholar Addressing the global rise of IBD requires a tandem effort of modulating in environmental risk factors to prevent IBD and innovating delivery of health care to patients with IBD.5Kaplan G.G. The global burden of IBD: from 2015 to 2025.Nat Rev Gastroenterol Hepatol. 2015; 12: 720-727Crossref PubMed Scopus (1191) Google Scholar The purpose of this review is to highlight trends in epidemiologic patterns of IBD, explore modifiable environmental exposures that may reduce incidence of IBD, and discuss the evolving global health care burden of IBD. During the 20th century, IBD was considered a disease of the Western world. The prevailing theory was that IBD occurred because of shared genetic susceptibility interacting with environmental exposures of the Western lifestyle.3Kaplan G.G. Ng S.C. Understanding and preventing the global increase of inflammatory bowel disease.Gastroenterology. 2017; 152: 313-321Abstract Full Text Full Text PDF PubMed Scopus (549) Google Scholar In the Western world, the incidence of IBD took off post–World War II. A systematic review identified hundreds of population-based studies that indicated that most countries reported steadily rising incidence of IBD throughout the Western world.1Molodecky N.A. Soon I.S. Rabi D.M. et al.Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review.Gastroenterology. 2012; 142 (quiz e30): 46-54Abstract Full Text Full Text PDF PubMed Scopus (3335) Google Scholar Rochester, Minnesota,6Shivashankar R. Tremaine W.J. Harmsen W.S. et al.Incidence and prevalence of Crohn's disease and ulcerative colitis in Olmsted County, Minnesota from 1970 through 2010.Clin Gastroenterol Hepatol. 2017; 15: 857-863Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar and Cardiff, United Kingdom7Gunesh S. Thomas G.A. Williams G.T. et al.The incidence of Crohn's disease in Cardiff over the last 75 years: an update for 1996-2005.Aliment Pharmacol Ther. 2008; 27: 211-219Crossref PubMed Scopus (70) Google Scholar conducted longitudinal epidemiologic studies dating back to the mid-20th century: decades of data highlighted a steadily rising incidence of IBD in these well-defined regions. The rising incidence of IBD in the 20th century alluded to environmental determinates ingrained in Western society as being the predominant drivers of IBD development.5Kaplan G.G. The global burden of IBD: from 2015 to 2025.Nat Rev Gastroenterol Hepatol. 2015; 12: 720-727Crossref PubMed Scopus (1191) Google Scholar At the turn of the 21st century, epidemiologic studies from the Western world indicated a paradigm shift in the incidence of IBD. Countries from the Western world started reporting stabilization of incidence and even decreasing incidence in some regions.2Ng S.C. Shi H.Y. Hamidi N. et al.Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies.Lancet. 2018; 390: 2769-2778Abstract Full Text Full Text PDF PubMed Scopus (2448) Google Scholar Although sporadic elevations in IBD incidence are still being reported, the overall incidence is coalescing around a range between 5 and 15 per 100,000 person years for both Crohn’s disease (CD) and ulcerative colitis (UC).2Ng S.C. Shi H.Y. Hamidi N. et al.Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies.Lancet. 2018; 390: 2769-2778Abstract Full Text Full Text PDF PubMed Scopus (2448) Google Scholar Moreover, the ceiling in the incidence of IBD seems to be between 40 and 50 per 100,000 person-years.2Ng S.C. Shi H.Y. Hamidi N. et al.Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies.Lancet. 2018; 390: 2769-2778Abstract Full Text Full Text PDF PubMed Scopus (2448) Google Scholar Future studies are needed to confirm if the peak in the incidence of IBD has been reached in the Western world. During the 20th century, the incidence of IBD was sparsely reported in Asia, Africa, and Latin America, and the data available showed dramatically lower values compared with the Western world.1Molodecky N.A. Soon I.S. Rabi D.M. et al.Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review.Gastroenterology. 2012; 142 (quiz e30): 46-54Abstract Full Text Full Text PDF PubMed Scopus (3335) Google Scholar Studies on the migration of individuals from the developing world to the Western world indicated that migration increased the risk of developing IBD particularly in the first-generation offspring of immigrants.8Probert C.S. Jayanthi V. Hughes A.O. et al.Prevalence and family risk of ulcerative colitis and Crohn's disease: an epidemiological study among Europeans and south Asians in Leicestershire.Gut. 1993; 34: 1547-1551Crossref PubMed Scopus (178) Google Scholar,9Benchimol E. Mack D. Guttmann A. et al.Inflammatory bowel disease in immigrants to Canada and their children: a population-based cohort study.Am J Gastroenterol. 2015; 110: 553-563Crossref PubMed Scopus (149) Google Scholar At the turn of the 21st century, numerous higher quality epidemiologic studies from newly industrialized countries in Asia and Latin America reported sharply rising incidence of IBD.10Ng S.C. Kaplan G.G. Tang W. et al.Population density and risk of inflammatory bowel disease: a prospective population-based study in 13 countries or regions in Asia-Pacific.Am J Gastroenterol. 2019; 114: 107-115Crossref PubMed Scopus (110) Google Scholar,11Kotze P.G. Underwood F.E. Damiao A. et al.Progression of inflammatory bowel diseases throughout Latin America and the Caribbean: a systematic review.Clin Gastroenterol Hepatol. 2019; 18: 304-312Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar For example, incidence of CD and UC increased by 11.1% and 14.9%, respectively, per year in Brazil from 1988 to 2012,12Parente J.M. Coy C.S. Campelo V. et al.Inflammatory bowel disease in an underdeveloped region of Northeastern Brazil.World J Gastroenterol. 2015; 21: 1197-1206Crossref PubMed Scopus (54) Google Scholar and 4.0% and 4.8% per year in Taiwan from 1998 to 2008.13Wei S.C. Lin M.H. Tung C.C. et al.A nationwide population-based study of the inflammatory bowel diseases between 1998 and 2008 in Taiwan.BMC Gastroenterol. 2013; 13: 166Crossref PubMed Scopus (46) Google Scholar In contrast to the Western world, a peak in the incidence of IBD in Asia and Latin America has yet to be reached. Future studies are needed to determine whether the rising incidence of IBD in newly industrialized countries will eventually reach the same peak of incidence observed in the Western world. Although awareness, access to health care, and advancing infrastructure contributes to the rising incidence of IBD in newly industrialized countries, the primary driving force is environmental exposure associated with the Westernization of society.3Kaplan G.G. Ng S.C. Understanding and preventing the global increase of inflammatory bowel disease.Gastroenterology. 2017; 152: 313-321Abstract Full Text Full Text PDF PubMed Scopus (549) Google Scholar Prevailing theories suggest that environmental exposures, particularly those early in life, alter the diversity, composition, and function of the intestinal microbiome leading to IBD development later in life. Modulating environmental exposures in the general population, and particularly in patients at greatest susceptibility for IBD, has the potential to prevent the development of IBD and reduce its incidence in the future.3Kaplan G.G. Ng S.C. Understanding and preventing the global increase of inflammatory bowel disease.Gastroenterology. 2017; 152: 313-321Abstract Full Text Full Text PDF PubMed Scopus (549) Google Scholar Environmental factors play a major role in IBD, including, but not limited to: antibiotic use, childbirth mode, breastfeeding, nonsteroidal anti-inflammatory drugs use, air pollution, diet, and urban environments.14Ananthakrishnan A.N. Khalili H. Konijeti G.G. et al.Long-term intake of dietary fat and risk of ulcerative colitis and Crohn's disease.Gut. 2014; 63: 776-784Crossref PubMed Scopus (296) Google Scholar, 15Ng S.C. Tang W. Leong R.W. et al.Environmental risk factors in inflammatory bowel disease: a population-based case-control study in Asia-Pacific.Gut. 2015; 64: 1063-1071Crossref PubMed Scopus (242) Google Scholar, 16Kaplan G.G. IBD: Global variations in environmental risk factors for IBD.Nat Rev Gastroenterol Hepatol. 2014; 11: 708-709Crossref PubMed Scopus (23) Google Scholar The timing of environmental exposures varies across the age spectrum of IBD with some factors specific to early life (eg, breastfeeding) and others more relevant for adults diagnosed with IBD.17van der Sloot K.W.J. Amini M. Peters V. et al.Inflammatory bowel diseases: review of known environmental protective and risk factors involved.Inflamm Bowel Dis. 2017; 23: 1499-1509Crossref PubMed Scopus (65) Google Scholar Cigarette smoking is one of the most consistent risk factors for IBD. In UC, quitting smoking increases the risk of developing UC in the Western world. Similarly, in Asia, the odds of being diagnosed with UC was 2-fold higher among individuals who quit smoking.15Ng S.C. Tang W. Leong R.W. et al.Environmental risk factors in inflammatory bowel disease: a population-based case-control study in Asia-Pacific.Gut. 2015; 64: 1063-1071Crossref PubMed Scopus (242) Google Scholar However, unlike consistent reporting of Western cohorts, whereby smoking is a risk factor for CD development and worsens disease outcomes,18Burisch J. Pedersen N. Cukovic-Cavka S. et al.East-West gradient in the incidence of inflammatory bowel disease in Europe: the ECCO-EpiCom inception cohort.Gut. 2014; 63: 588-597Crossref PubMed Scopus (257) Google Scholar data from the Asia-Pacific Crohn’s and Colitis Epidemiologic Study Group (ACCESS) study showed that smoking was not a risk factor for CD in Asia.15Ng S.C. Tang W. Leong R.W. et al.Environmental risk factors in inflammatory bowel disease: a population-based case-control study in Asia-Pacific.Gut. 2015; 64: 1063-1071Crossref PubMed Scopus (242) Google Scholar Furthermore, there are specific examples from Western studies whereby the association between CD and smoking has not been shown in particular populations (eg, Israeli Jews, seniors) and regions of high smoking prevalence do not correlate with regions of high IBD prevalence.19Ng S.C. Bernstein C.N. Vatn M.H. et al.Geographical variability and environmental risk factors in inflammatory bowel disease.Gut. 2013; 62: 630-649Crossref PubMed Scopus (395) Google Scholar Hence, smoking is a predictor of aggressive disease course but is unlikely to account for worldwide trends in disease incidence. Several studies have suggested a significant association between childhood antibiotic exposure and the onset of IBD later in life. However, discrepancies of this association across different populations and ethnicities are observed. For example, greater use of antibiotics in childhood increases the risk of developing UC in the Western world, but data from Asia seem to contradict this notion because children exposed to antibiotics were protected from developing UC.15Ng S.C. Tang W. Leong R.W. et al.Environmental risk factors in inflammatory bowel disease: a population-based case-control study in Asia-Pacific.Gut. 2015; 64: 1063-1071Crossref PubMed Scopus (242) Google Scholar Furthermore, antibiotic use reduced the risk of CD in Middle Eastern migrants to Australia but increased the risk in white persons.20Ko Y. Kariyawasam V. Karnib M. et al.Inflammatory bowel disease environmental risk factors: a population-based case-control study of Middle Eastern migration to Australia.Clin Gastroenterol Hepatol. 2015; 13: 1453-1463Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar Risk factors likely differ at different stages of industrialization; hygiene factors might be important in developing countries, whereas immunologic factors may play a more important role in developed countries. A meta-analysis of 17 papers examined the association between breastfeeding and IBD and demonstrated a strong inverse association with both CD and UC.21Barclay A.R. Russell R.K. Wilson M.L. et al.Systematic review: the role of breastfeeding in the development of pediatric inflammatory bowel disease.J Pediatr. 2009; 155: 421-426Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar Likewise, the ACCESS inception cohort study found that infants living in Asia who were breastfed for more than 12 months were 7 times less likely to develop UC. A New Zealand study found that breastfeeding for a longer duration lowered the odds of developing IBD.22Gearry R.B. Richardson A.K. Frampton C.M. et al.Population-based cases control study of inflammatory bowel disease risk factors.J Gastroenterol Hepatol. 2010; 25: 325-333Crossref PubMed Scopus (177) Google Scholar Overall, breastfeeding has a marked protective effect on development of CD and UC and a beneficial dose effect of breastfeeding has been observed. Prevention studies have focused on general populations, using serum repositories to identify changes in individuals who are known to develop disease later, and on at-risk populations, such as family members. In the PREDICT (PRoteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects) study, prediagnostic sera from soldiers with IBD was collected and analyzed for antimicrobial antibodies and protein markers; immune dysregulation was detectable in serum up to 6 years before the diagnosis of CD.23Porter C.K. Riddle M.S. Gutierrez R.L. et al.Cohort profile of the PRoteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects (PREDICTS) study: rationale, organization, design, and baseline characteristics.Contemp Clin Trials Commun. 2019; 14: 100345Crossref PubMed Scopus (13) Google Scholar The proportion of positive antimicrobial markers including ASCA IgG, ASCA IgA, anti-OmpC, anti-Fla2, anti-FlaX, and anti-CBir1 were found to progressively increase toward disease diagnosis.23Porter C.K. Riddle M.S. Gutierrez R.L. et al.Cohort profile of the PRoteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects (PREDICTS) study: rationale, organization, design, and baseline characteristics.Contemp Clin Trials Commun. 2019; 14: 100345Crossref PubMed Scopus (13) Google Scholar,24Choung R.S. Stockfisch T.P. Princen F. et al.Longitudinal status of serological markers predict Crohn's disease phenotype before diagnosis: a 'PREDICTS' study.Gastroenterology. 2015; 148: S22Abstract Full Text PDF PubMed Google Scholar Importantly, individuals with higher serum levels of antimicrobial antibodies and a different profile of proteins years before diagnosis were at highest risk of presenting with a complicated disease phenotype including fistula/abscess or strictures. There was also an inverse relationship between the time to first complication and the magnitude of serology markers.25Choung R.S. Petralia F. Torres J. et al.Innate immune dysregulation, detectable up to 6 years before the diagnosis of Crohn's disease, is significantly amplified in patients with a complicated phenotype.Gastroenterology. 2019; 156: S413-S414Abstract Full Text PDF Google Scholar,26Dubinsky M.C. Kugathasan S. Mei L. et al.Increased immune reactivity predicts aggressive complicating Crohn's disease in children.Clin Gastroenterol Hepatol. 2008; 6: 1105-1111Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar These findings suggest that innate immune activation with involvement of complement pathways may occur early in the natural history of complicated disease; this highlights the potential role of serologic markers as a noninvasive tool to screen and detect preclinical IBD and to identify individuals at higher risk of progression to complications. Studying preclinical IBD in the general population is challenging because of the enormous sample size and long duration of follow-up necessary for disease to develop. Given that the strongest established risk factor for the development of IBD is having a first-degree relative (FDR) with the disease, earlier cross-sectional studies focusing on healthy relatives of patients with IBD reported altered intestinal permeability, positive antimicrobial marker, raised fecal calprotectin, and altered stool bacterial composition in a subset of IBD relatives. However, the significance of these biomarkers and their predictive value for disease development remains unclear.27Torres J. Burisch J. Riddle M. et al.Preclinical disease and preventive strategies in IBD: perspectives, challenges and opportunities.Gut. 2016; 65: 1061-1069Crossref PubMed Scopus (51) Google Scholar The Genetics, Environmental, Microbial (GEM) Project is a multicenter study that recruits FDRs age 6–35 years of affected CD probands, and prospectively collects biologic samples (blood, urine, stool), and environmental exposure data assessing etiologic factors in CD. It was found that elevated fecal calprotectin was significantly associated with a future diagnosis of CD in asymptomatic FDRs of patients with CD.28Lee S.H. Power N. Turpin W. et al.Elevated fecal calprotectin in healthy first degree relatives of patients with Crohn's disease is associated with future diagnosis of Crohn's disease.Gastroenterology. 2019; 156: S413Abstract Full Text PDF Google Scholar Emerging evidence has shown that early life, including neonatal life, is a critical window for development of gut microbiome and certain environmental exposures to neonates could impact the risk of different diseases later in life.29Barker D.J. The origins of the developmental origins theory.J Intern Med. 2007; 261: 412-417Crossref PubMed Scopus (1711) Google Scholar In IBD, this concept has been supported by epidemiologic data demonstrating an increasing incidence in individuals who spent years living in an urban environment during childhood who received antibiotics during early life or who had not been breastfed.30Ananthakrishnan A.N. Bernstein C.N. Iliopoulos D. et al.Environmental triggers in IBD: a review of progress and evidence.Nat Rev Gastroenterol Hepatol. 2018; 15: 39-49Crossref PubMed Scopus (378) Google Scholar A recent population-based Swedish study showed that children exposed to antibiotics had a 93% increased risk of developing very early onset IBD and CD and that risk was driven by exposures occurring during the third trimester of pregnancy compared with earlier trimesters.31Ortqvist A.K. Lundholm C. Halfvarson J. et al.Fetal and early life antibiotics exposure and very early onset inflammatory bowel disease: a population-based study.Gut. 2019; 68: 218-225Crossref PubMed Scopus (77) Google Scholar In addition, a Canadian population-based cohort showed that maternal diagnosis of IBD was the strongest risk factor for the offspring developing IBD and risk factors included infection in the first year of life, suggesting that the most important predictor for subsequent diagnosis of IBD is a genetic effect and a close mother-child relationship. What remains less clear is whether infections themselves are the risk factor for subsequent IBD or whether it is instead the exposure to antibiotics to treat the infections that incur the most risk.32Bernstein C.N. Burchill C. Targownik L.E. et al.Events within the first year of life, but not the neonatal period, affect risk for later development of inflammatory bowel diseases.Gastroenterology. 2019; 156: 2190-2197Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar The importance of early life exposures in the risk of developing IBD suggests that the composition, diversity, and function of the intestinal microbiome is related to the development of IBD.33Ni J. Wu G.D. Albenberg L. et al.Gut microbiota and IBD: causation or correlation?.Nat Rev Gastroenterol Hepatol. 2017; 14: 573-584Crossref PubMed Scopus (734) Google Scholar Prospective studies, such as the MECONIUM study (Exploring MEChanisms Of disease traNsmission In Utero through the Microbiome), which follows pregnant women with IBD and their infants by collecting biosamples, clinical, and dietary data to study their microbiome, biomarkers of disease susceptibility, and environmental exposures, will help to better understand the very early risk factors (as far back as during pregnancy) for disease development and help develop preventive strategies during this early life period. Mothers with IBD had altered bacterial composition and diversity in their gut during pregnancy with enrichment of Gammaproteobacteria and depletion of Bacteroidetes.34Torres J. Hu J. Seki A. et al.Infants born to mothers with IBD present with altered gut microbiome that transfers abnormalities of the adaptive immune system to germ-free mice.Gut. 2019; 69: 42-51Crossref PubMed Scopus (79) Google Scholar Furthermore, infants born to mothers with IBD showed lower diversity and altered bacterial gut composition in up to at least 3 months of life. The altered microbiota induced changes to the adaptive immune system in germ-free mice, suggesting that microbial factors in maternal IBD may impact the immune system of offspring. Overall, targeting perturbations of the microbiome in pregnant women with IBD or neonates could foster the development of a healthy microbiome in the offspring, and it is also possible that primary interventions at this stage could be established to reduce the risk of diseases later in life.35de Aguero M.G. Ganal-Vonarburg S.C. Fuhrer T. et al.The maternal microbiota drives early postnatal innate immune development.Science. 2016; 351: 1296-1301Crossref PubMed Scopus (667) Google Scholar,36Dominguez-Bello M.G. De Jesus-Laboy K.M. Shen N. et al.Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer.Nat Med. 2016; 22: 250-253Crossref PubMed Scopus (570) Google Scholar Epidemiologic evidence suggests a link between dietary Westernization and CD. Specific mixtures of macronutrients and emulsifiers within the diet have been shown to affect intestinal permeability, gut microbiota density, and predisposition to intestinal inflammation in IBD in animal studies.37Chassaing B. Koren O. Goodrich J.K. et al.Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome.Nature. 2015; 519: 92-96Crossref PubMed Scopus (1112) Google Scholar, 38Dunn K.A. Boneh R.S. Bielawski J.P. et al.Crohn's disease exclusion diet and partial enteral nutrition (CDED plus PEN) vs exclusive enteral nutrition (EEN) microbiome changes of a randomized clinical trial (RCT) in pediatric CD: remission is associated with similar structural and functional profiles.Gastroenterology. 2017; 152: S213Abstract Full Text PDF Google Scholar, 39Llewellyn S.R. Britton G.J. Contijoch E.J. et al.Interactions between diet and the intestinal microbiota alter intestinal permeability and colitis severity in mice.Gastroenterology. 2018; 154: 1037-1046Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar, 40Suez J. Korem T. Zeevi D. et al.Artificial sweeteners induce glucose intolerance by altering the gut microbiota.Nature. 2014; 514: 181-186Crossref PubMed Scopus (1207) Google Scholar Human studies, such as the ENIGMA41Chinese University of Hong Kong, University of Melbourne, The University of Queensland, et al. The ENIGMA study: eastern inflammatory bowel disease gut microbiota. 2020. Available at: https://www.agirf.com/the-gut-microbiota#!Google Scholar study, aim to investigate the role of food additives and diet in subjects with CD across different populations and geography (China, Hong Kong, Australia). There is increasing interest in diet as a treatment of CD, especially exclusion diets, specific carbohydrate diet, and IBD anti-inflammatory diet.42Sigall-Boneh R. Pfeffer-Gik T. Segal I. et al.Partial enteral nutrition with a Crohn's disease exclusion diet is effective for induction of remission in children and young adults with Crohn's disease.Inflamm Bowel Dis. 2014; 20: 1353-1360Crossref PubMed Scopus (168) Google Scholar,43Sigall Boneh R. Sarbagili Shabat C. Yanai H. et al.Dietary therapy with the Crohn's disease exclusion diet is a successful strategy for induction of remission in children and adults failing biological therapy.J Crohns Colitis. 2017; 11: 1205-1212Crossref PubMed Scopus (103) Google Scholar There are several ongoing diet prevention studies. The ADDapt trial (ADDitives using and app trial)44King's College LondonThe ADDapt diet in reducing Crohn's disease inflammation.2021Google Scholar is a randomized controlled trial in patients with stable CD that investigate the efficacy and acceptability of a low-emulsifier diet by using a mobile telephone application and dietary counseling. Crohn’s Disease Treatment with Eating (CD-TREAT)45University of GlasgowThe impact of “Crohn's Disease-TReatment-with-EATing” diet and exclusive ente