The exposome in development and behaviour of inflammatory bowel disease
van der Sloot, K.W.J.
DOI:
10.33612/diss.158740072
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The exposome in development
and behaviour of InfLammatory
Bowel Disease
Kimberley W.J. van der SlootPrinted by Ridderprint, www.ridderprint.nl Alblasserdam, the Netherlands Design & layout Ellen Beck, www.ellenbeck.nl
Groningen, the Netherlands
© Copyright: 2021 K.W.J. van der Sloot, Groningen, the Netherlands
All rights reserved. No part of this thesis may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, without prior written per-mission of the author, or when appropriate, of the publishers of the publications included in this thesis.
Chapter 1 General introduction and outline of thesis
Part I – The exposome in the complex etiology of IBD
Chapter 2
Inflammatory bowel diseases: review of known environmental protective- and risk factors involved
Inflammatory Bowel Diseases, 2017
Chapter 3
Development and validation of a web-based questionnaire to identify environmental risk factors for inflammatory bowel disease: the Groningen IBD Environmental Questionnaire (GIEQ)
Journal of Gastroenterology, 2019
Chapter 4
Identification of Environmental Risk Factors Associated With the Development of Inflammatory Bowel Disease
Journal of Crohn’s and Colitis, 2020
10
22
44
Part II – The exposome and its implications in
disease course of IBD
Chapter 5
Environmental factors associated with biological use and surgery in inflammatory bowel disease
Journal of Gastroenterology and Hepatology, 2020
Chapter 6
Visceral Adiposity, Genetic Susceptibility, and Risk of Complications Among Individuals with Crohn’s Disease
Inflammatory Bowel Diseases, 2017
Chapter 7
Latent cytomegalovirus infection does not influence long-term disease outcomes in inflammatory bowel disease, but is associated with later onset of disease
Scandinavian Journal of Gastroenterology, 2020
Chapter 8
Isotype specific antibody responses to Mycobacterium Avium subspecies Paratuberculosis antigens are associated with the use of biological therapy in Inflammatory Bowel Disease
Journal of Crohn’s and Colitis, 2021
Chapter 9
Cigarette smoke increases risk for colorectal neoplasia in inflammatory bowel disease
Clinical Gastroenterology and Hepatology, 2021
Discussion
Chapter 10
Summary
Chapter 11
General discussion and future perspectives
Appendices Summary in Dutch Bibliography Curriculum Vitae Dankwoord 84 104 118 130 152 164 172 186
Chapter 1
General introduction and
outline of this thesis
Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, the Netherlands
Epidemiology of infLammatory bowel disease:
importance of the exposome
Inflammatory bowel diseases (IBD) are chronic, immune-mediated inflammatory diseases of the gastro-intestinal tract, mainly consisting of Crohn’s disease (CD) and ulcerative colitis (UC).1
Whereas CD can affect any site of the gastro-intestinal tract with discontinuous, transmural in-flammation and formation of granulomas, UC causes superficial and continuous inin-flammation, starting at the rectum and limited to the colon.2
In the Western world, the incidence of IBD started rising after World War II.3 With the highest
incidence rates seen in industrialized countries, affecting 1.5 million Americans and 2.2 million Europeans, IBD is traditionally attributed as a Western lifestyle disease.1,4 At the turn of the 21st
century however, an epidemiological shift was seen, making IBD a global disease.5 While the
in-cidence rate might be stabilizing in developed countries, it is quickly rising in developing coun-tries, alongside their rapid socioeconomic development.6 Together with economic improvements
in these regions comes urbanization, sanitization and adoption of Western lifestyle; conditions in which IBD is known to thrive.7 A clear example is seen in Brazil with an incidence increase of
14.9% for UC and 11.1% for CD over the past 24 years.5 With an increase of 4.8% for UC and
4.0% in CD in only ten years’ time, a similar trend is seen in Taiwan.8 Although part of this rise
might be due to advanced infrastructure, better access to healthcare and an increased awareness following socioeconomic development, the primary driving force is likely to be the altering envi-ronmental exposures (the so-called exposome, including living environment and lifestyle expo-sures) associated with adopting western lifestyles by these societies.6,7,9 The exposome is a term
used to describe environmental and lifestyle exposures throughout life, starting at conception.10
While complete caption of the exposome will most likely never be feasible, comprehensive and inclusive research into the role of a large number of environmental exposures within a popula-tion, is thought to be the most optimal design to study the role of environmental exposures and lifestyle. The importance of the altered exposome in IBD is further underlined by recent migration studies.11 Migration from developing to developed countries forms a clear risk factor for
devel-opment of IBD. While first generation immigrants from developing countries still have a lower risk of IBD than non-immigrants in Canada, risk is clearly increased when compared to their home country risk, further increasing with younger age at migration.12 Second generation immigrants
were even shown to have a similar risk of IBD as non-immigrants in Sweden, due to the fact that children are likely to take on environmental risk factors from their new environment, while par-ents are more likely to maintain within their original risk pattern.6,13
The exposome in the complex etiology of IBD
Part I of this thesis focuses on the contribution of the exposome in the etiology of IBD. Disease
pathogenesis of IBD is multifactorial, with a complex interplay between host genetics, the gut microbiota, diet and the exposome, leading to an exaggerated host-immune response to the luminal (microbial) content in the gut (Figure 1).14,15
As having a first-degree family member with IBD was identified to be a risk factor for develop-ment of IBD, studies focused on the role of genetic susceptibility.16 The first locus described
to be involved in disease etiology was the Nucleotide-binding oligomerization
domain-con-taining protein 2 (NOD2)-gene on chromosome 16, increasing risk for CD. The NOD2 gene is
thought to play a role through modulation of the innate, as well as the adaptive, immune sys-tem.17,18 Subsequent genome-wide association studies (GWAS) have identified over 200 associated
in IBD, e.g. the maintenance of the integrity of the gut epithelial barrier, host immune respons-es, autophagy and antimicrobial recognition.17,19,20 Though these findings have led to important
insights into the contribution of genetics in disease pathogenesis, the importance of non-ge-netic factors in the etiology have also become increasingly clear. As the concordance rate of IBD in monozygotic twins is 10-15% for UC and 30-35% in CD, and only a small portion of the dis-ease incidence in the general population can be explained with the above-mentioned genetic variances (13.1% in CD and 7.5% in UC), subsequent research has focused on how non-genetic factors influence development of IBD and course of disease.17,21
As many of the previously described genetic associations to development of IBD are hypothe-sized to be involved in the innate immune system and anti-microbial activity, focus shifted to the gut microbiota. The gut microbiota plays a role in the digestion of substrates, training of the immune system and repression of the growth of harmful microorganisms, throughout life.22
Alterations of its composition have been associated with several adverse health outcomes like type 2 diabetes and obesity.22,23 Likewise, studies identified a significant decrease of diversity
of microbial species in patients with IBD, as compared to the healthy population.22 In addition, Faecalibacterium prausnitzii species, a butyrate producing bacteria with thus an
anti-inflamma-tory effect, has been consistently shown to be decreased in patients with IBD.24
Figure 1. Complex etiology of Inflammatory Bowel Disease
However, as shown in Figure 1, the gut microbiota is not independent in its etiology of IBD and is highly influenced by diet, as well as environmental- and lifestyle exposures. For instance, adherence to a Mediterranean diet was shown to decrease inflammatory markers such as C-re-active protein (CRP) and interleukin-17 (IL-17), likely with the gut microbiome as in-between mediator.25 Also, in an experimental setting, plant-based protein intake was shown to increase
microbiota diversity, together with increased levels of Bifidobacterium and Lactobacillus, while pathogenic species such as Bacteriodes fragilis and Clostridium perfringens were decreased.26,27
The gut microbiota is also influenced by environmental exposures, starting as early as during birth. After birth through caesarian section (C-section), overall microbial diversity is decreased, together with a decrease of, amongst others, Bifidobacterium.28 Infants born to mothers with IBD
were also shown to have a decreased biodiversity and altered gut microbiota composition.29
Continuing throughout life, different interactions between lifestyle and the gut microbiota have been described, including associations with pet ownership and medication use.30,31
In addition to genetic factors and alterations of the gut microbiota, strong associations of the exposome, including living environment and lifestyle exposures, with the development of IBD have been seen, in line with many other common diseases. Therefore, their role in health and disease has been of increased interest in the past decades.32 In fact, unhealthy lifestyle
be-haviors have been estimated to account for 63% of deaths due to noncommunicable diseases worldwide.32 Lifestyle and environmental factors are thought to affect the developmental and
maturation of the immune system. The immune system can be seen as a sensory system, sens-ing danger from foreign antibodies. However as with other sensory systems, while present at birth, lifelong training through lifestyle and environmental exposures is needed, and deficits or disruptions within this training are likely to leave the host vulnerable later in life.33 Past studies,
predominantly focusing on single exposome factors, identified large numbers of potentially involved exposome factors in the development of IBD, as described extensively in Chapter 2.34
Cigarette smoking is probably the best known exposome factors involved in pathogenesis of IBD with a divergent effect in disease subtypes.35 Whereas a history of cigarette smoking
in-creases the risk of development of CD, active smoking lowers risk for UC, with an increased risk in those who quit.35 However, non-genetic factors within the exposome are not
indepen-dent factors, and it is highly likely that many of the associated factors face collinearity in their influence on the development of disease, emphasizing the importance of inclusive research examining multiple risk factors.
The exposome and its implications in disease course of IBD
Part II of this thesis focuses on the question whether specific exposome factors contribute to
complicated disease course. After diagnosis of IBD, progression of the disease is highly het-erogeneous.36 While for some patients disease behaviour is relatively mild, others face
dis-ease progression leading to severe disdis-ease complications requiring extensive medical therapy, IBD-related surgery and, in a small subset of CD patients, ultimately even intestinal failure.15,37
Different medical treatment strategies are currently used, based on severity of disease. Corti-costeroids, immunosuppressant therapies (thiopurines, methotrexate, tofacitinib) and biological therapies (anti-tumor necrosis factor-α (anti-TNF-α); infliximab, adalimumab, golimumab, and
certolizumab, anti-adhesion molecules; vedolizumab, and ustekinumab) are mostly used in CD,
while in UC, aminosalicylates can be tried first in mild to moderate disease, followed by the same treatments as for CD.38 Biological therapies were proven most potent, but their use is
restricted to those with complicated disease due to non-response to (combinations of) corti-costeroids and immunosuppressant therapies.15 When medical therapy fails or disease
compli-cations such as penetrating disease with abscess formation and fistula or fibrostenotic disease with strictures and stenosis develop, patients become candidates for surgery. Within five years from diagnosis, 30% of patients will progress to needing biological therapy, while 22% of CD patients requires a surgical intervention, increasing to 50% in ten years.39,40After surgical
inter-vention, an endoscopic recurrence rate up to 80% is reported.41 In UC, a colectomy rate of 15%
was previously seen.42 Although gastrointestinal inflammation is most prominent, patients
with IBD are also at risk of developing extra-intestinal manifestations (EIM), the most import-ant being iritis/uveitis, primary sclerosis cholangitis (PSC), ankylosing spondylitis, pyoderma gangrenosum and erythema nodosum.43 Also, patients have an increased risk of developing
malignant diseases.44 While associations with intestinal, as well as extra-intestinal
malignan-cies have been described, risk of colorectal dysplasia seems most evident, leading to intensive surveillance strategies in patients at risk.45,46 To date, the question of which exposome factors
influence the disease progression, hence contribute to heterogeneity in disease course and response to therapies, hold great challenges in the current management of IBD.
The large improvements of medical treatments for IBD in past years, mostly due to the introduc-tion of biological therapies, have led to a global decrease of IBD-related surgery and mortality.47
However, intensity of treatment has also increased greatly, necessitating further understanding of the heterogeneity of disease course and its interaction with and influence of the exposome.48
This interest is two-sided. First of all, exposome factors might be associated with complicated disease, aiding the stratification of those at high risk of disease complications among the het-erogeneous population of patients.36 Secondly, identification of involved modifiable exposome
factors holds the opportunity of lifestyle-focused, personalized medicine.48 As in disease
devel-opment, the most clear example of an exposome factor influencing course of IBD is formed by cigarette smoking. While a potential beneficial effect of cigarette smoke exposure on inflam-mation was shown in UC, the opposite is true for CD.49,50 Not only is cigarette smoke exposure
associated with more complicated disease in CD, cessation of smoking shows a decreased risk of flare-ups.50,51 Over the past decades, government-initiated campaigns to promote smoking
cessation in the general population have been executed in the Netherlands.52 In line with
gen-eral population-based studies from Statistics Netherlands (CBS), a clear decreasing trend of cigarette smoking is visible in the IBD population.53 When combining patients enrolled in a
previous study from our center published in 2009 to the current, one can clearly see a decrease in active smokers at diagnosis accompanied by an increase of patients that never smoked
(Fig-ure 2).50 This example of cigarette smoking does not only demonstrate the dynamic character
of the exposome, but also its ability to change and thereby be modulated, emphasizing the importance of identifying exposome factors influencing disease course, to possibly predict or even improve disease course. This example of cigarette smoking does not only demonstrate the dynamic character of the exposome, but also its ability to change and thereby be modulat-ed, emphasizing the importance of identifying exposome factors influencing disease course, to possibly predict or even improve disease course.
Research goals and outline of this thesis
The work presented in this thesis aims to identify exposome factors involved in development of IBD (part 1) and behavior of established disease (part 2). In order to achieve these aims, I devel-oped a novel method to study the exposome in IBD in a more structured and universal fashion than before; the Groningen IBD Environmental Questionnaire (GIEQ).
No epidemiological research without extensively
characterized cohorts
The establishment and maintenance of well-defined cohorts is crucial for the type of research as described in this thesis. Two distinct cohorts form the core of this PhD. First of all, the 1000IBD cohort. This prospective cohort consists of over 1,000 patients with IBD treated at the IBD cen-ter of the University Medical Cencen-ter Groningen (UMCG), the Netherlands. Patients enrolled are prospectively followed during their routine care by IBD-specialized gastroenterologists, while detailed information is collected concerning clinical characteristics as well as multiple layers of molecular (“multi-omics”) data.54 Disease characteristics are described in a universal fashion, in
line with international guidelines and research outcomes, allowing easy use of data in various research settings. In addition, for these 1000IBD patients, biomaterials are routinely collected and documented within the Dutch IBD Parelsnoer biobank, in which the UMCG is one of the eight university hospitals participating (www.parelsnoer.org), allowing the studies described in Chapter 7 and 8.2,54
The population-based Lifelines Cohort Study (www.lifelines.nl) was used to supply the needed control population in this thesis. The Lifelines Cohort Study is a multi-disciplinary prospec-tive population-based cohort study, consisting of 167,729 persons, accounting for 10% of the total population in the northern part of the Netherlands.55 The Lifelines Cohort Study has a
unique three-generation design, following its participants for at least 30 years. As participants complete questionnaires every year and a half, and donate biomaterial every five years, the Lifelines Cohort Study has collected enormous amounts of data and biomaterials in the past ten years. This facilitates researchers to study factors associated with health and disease in the general population, but also to work with highly characterized controls as needed in this thesis.
Outline of thesis
Part 1: Role of the exposome in disease etiology
In Chapter 2, I provide a review of literature describing all thus far identified exposome factors across different stages of life, previously hypothesized to be involved in IBD etiology. Factors are stratified based on timing of exposure; childhood, adulthood and lifelong, as timing of expo-sures varies.9,34 Quality of evidence is evaluated for each identified factor using the grading of recommendation, assessment, development and evaluation (GRADE) approach. The conclusions
drawn in this chapter form the basis for the development of the GIEQ. Numerous exposome factors are selected based on previous research and expert opinions and made suitable to study in the comprehensive GIEQ, as shown in Figure 3. Chapter 3 describes the formation as well as the validation of this questionnaire. In total, the GIEQ consists of 844 items, of which 454 are suitable to study associations of a total of 93 exposome factors with development of IBD. In
Chapter 4 of this thesis, we aim to study these 93 factors, comparing participating patients of
the 1000IBD cohort who completed the GIEQ, to matched healthy controls of the Lifelines Co-hort Study, by systematically analyzing these factors for risk of development of either CD or UC.
Figure 3. Structure of the GIEQ and its place in exposome-focused research in IBD
Part 2: Role of the exposome in development of complicated disease
Following the example of cigarette smoke exposure and its role in course of IBD, it is likely that many more exposome factors are involved. Therefore, before focusing on specific, individual exposome factors, a wide scope of exposome factors is examined in Chapter 5. We examine the potential association of 93 exposome factors as measured by the GIEQ in development of com-plicated disease, defined by the need for biological therapy and/or IBD-related surgery. As in
Chapter 4, all factors are examined for CD and UC separately, as with cigarette smoke exposure,
other factors may also hold an opposite effect in disease subtypes.
Since disease course of IBD is highly heterogeneous, different potential indicators of complicat-ed disease course necomplicat-ed to be studicomplicat-ed in more detail. For example, previous research has shown an increased visceral fat volume at diagnosis in patients with CD.56 However, while visceral
ad-ipose tissue (VAT) is known to play a role in systemic inflammation through, amongst others, production of pro-inflammatory markers such as tumor necrosis factor α (TNF-α), the clinical implications of this increased VAT remain unclear.57 Therefore, in Chapter 6, the role of VAT in
course of CD is examined.
Next, I focus on two different pathogens, namely cytomegalovirus (CMV) and Mycobacterium Avi-um subspecies Paratuberculosis (MAP) during disease course. CMV infection is highly common in the general population and known to negatively affect disease course of transplant recipients.58,59
Due to a lack of sufficient detrimental effect, current guidelines do not prescribe routine CMV screening. However, previous studies are performed in small patient cohorts without long-term follow-up, while risk of reactivation remains during the entire course of disease due to the use of immunomodulating medications. Therefore, the aim of Chapter 7 is to explore whether CMV latency, and thus risk of reactivation, affects long-term disease outcomes in the 1000IBD cohort. Another pathogen that has been implicated in IBD is MAP. Being the causative agent of Johne’s disease (JD) in cattle, a disease mimicking ileal CD, MAP has been studied extensively in regard to the etiology of CD.60 However, while a causative association remains highly controversial so
far, and a role in established disease is even more unclear. Extensive studies have been exe-cuted examining the effect of long-term antimycobacterial treatment on the course of CD.61
In Chapter 8, I evaluate the role of MAP in the disease course of IBD by using and comparing different diagnostic laboratory techniques.
Finally, in Chapter 9, I focus on the role of cigarette smoke exposure on the development of a distinct intestinal complication of IBD; colorectal dysplasia, an early stage of colorectal cancer. Cigarette smoke is known to increase risk of colorectal carcinoma in the general population, while its association in the IBD population remains unclear.62 As mentioned, cigarette smoke
exposure holds an opposite effect for disease course of UC and CD.50 Therefore, I aim to explore
its role in dysplasia development and evaluate the potential of cigarette smoke in stratifica-tion of patients at risk of dysplasia when compared to currently used strategies of surveillance guidelines.63
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46. Mattar MC, Lough D, Pishvaian MJ, Charabaty A. Current management of inflammatory bowel disease and colorectal cancer. Gastrointest Cancer Res. 2011;4(2):53-61. 25 47. Alatab S, Sepanlou SG, Ikuta K, et al. The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. 2019.
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49. Beaugerie L, Massot N, Carbonnel F, Cattan S, Gendre JP, Cosnes J. Impact of cessation of smoking on the
course of ulcerative colitis. Am J Gastroenterol. 2001;96(7):2113-2116.
50. van der Heide F, Dijkstra A, Weersma RK, et al. Effects of active and passive smoking on disease course of
Crohnʼs disease and ulcerative colitis. Inflamm Bowel Dis. 2009;15(8):1199-1207.
51. Cosnes J, Beaugerie L, Carbonnel F, Gendre JP. Smoking cessation and the course of Crohn’s disease: An intervention study. Gastroenterology. 2001;120(5):1093-1099. 52. Chavannes NH, Meijer E, Wind L, van de Graaf RC, Rietber-gen C CE. Herziene richtlijn ‘Behandeling van tabaksverslav-ing en stoppen met roken ondersteuntabaksverslav-ing’. - PubMed - NCBI. Ned Tijdschr Geneeskd. 2017;161:1394.
53. Thomas T, Chandan JS, Li VSW, et al. Global smoking trends in inflammatory bowel disease: A systematic review of inception cohorts. PLoS One. 2019;14(9).
54. Imhann F, Van der Velde KJ, Barbieri R, et al. The 1000IBD project: multi-omics data of 1000 inflammatory bowel disease patients; data release 1. BMC Gastroenterol. 2019;19(1):5.
55. Scholtens S, Smidt N, Swertz MA, et al. Cohort Profile: LifeLines, a three-generation cohort study and biobank. Int J Epidemiol. 2015;44(4):1172-1180.
56. Uko V, Vortia E, Achkar JP, et al. Impact of abdominal visceral adipose tissue on disease outcome in pediatric crohn’s disease. Inflamm Bowel Dis. 2014;20(12):2286-2291.
57. Desreumaux P, Ernst O, Geboes K, et al. Inflammatory alterations in mesenteric adipose tissue in Crohn’s disease. Gastroenterology. 1999;117(1):73-81.
58. Slifkin M, Doron S, Snydman DR. Viral prophylaxis in organ transplant patients. Drugs. 2004;64(24):2763-2792. 59. Bate SL, Dollard SC, Cannon MJ. Cytomegalovirus Sero-prevalence in the United States: The National Health and Nutrition Examination Surveys, 1988–2004. Clin Infect Dis. 2010;50(11):1439-1447.
60. Feller M, Huwiler K, Stephan R, et al. Mycobacterium avium subspecies paratuberculosis and Crohn’s disease: a systematic review and meta-analysis. infection.thelan-cet.com. 2007.
61. Feller M, Huwiler K, Schoepfer A, Shang A, Furrer H, Egger M. Long-Term Antibiotic Treatment for Crohn’s Disease: Systematic Review and Meta-Analysis of Place-bo-Controlled Trials.
62. Botteri E, Iodice S, Raimondi S, Maisonneuve P, Lowen-fels AB. Cigarette Smoking and Adenomatous Polyps: A Meta-analysis. Gastroenterology. 2008;134(2). 63. Maaser C, Sturm A, Vavricka SR, et al. ECCO-ESGAR Guideline for Diagnostic Assessment in IBD Part 1: Initial diagnosis, monitoring of known IBD, detection of complications. J Crohn’s Colitis. 2019:144-164.
Chapter 2
InfLammatory Bowel Diseases:
review of known
environmental protective-
and risk factors involved
Inflammatory Bowel Diseases 2017
*Both authors contributed equally to this work.
1 Department of Gastroenterology and Hepatology, University of Groningen, University Medical
Center Groningen, the Netherlands
2 Department of Epidemiology, University of Groningen, University Medical Center Groningen,
the Netherlands
Kimberley W.J. van der Sloot1, Marzyeh Amini2, Vera Peters1,
Abstract
Inflammatory bowel diseases consisting of Crohn’s disease and ulcerative colitis are chronic inflammatory diseases of the gastrointestinal tract. In addition to genetic susceptibility and dis-turbances of the microbiome, environmental exposures forming the exposome play an import-ant role. Starting at birth, the cumulative effect of different environmental exposures combined with a predetermined genetic susceptibility is thought to cause inflammatory bowel disease. All these environmental factors are part of a Western lifestyle, suiting the high incidence rates in Europe and the United States. Whereas receiving breastfeeding, evidence of a Helicobacter pylori infection and vitamin D are important protective factors in Crohn’s disease as well as ulcerative colitis, increased hygiene, experiencing a bacterial gastroenteritis in the past, ur-ban living surroundings, air pollution, the use of antibiotics, non-steroidal anti-inflammatory drugs, and oral contraceptives are likely to be the most important risk factors for both diseases. Current cigarette smoking yields a divergent effect by protecting against ulcerative colitis but increasing risk of Crohn’s disease, whereas former smoking increases chances of both diseases. This review gives a clear overview of the current state of knowledge concerning the exposome. Future studies should focus on measuring this exposome yielding the possibility of combining all involved factors to one exposome risk score and our knowledge on genetic susceptibility.
Introduction
Inflammatory bowel disease (IBD), consisting of ulcerative colitis (UC) and Crohn’s disease (CD), is a gastrointestinal disease characterized by chronic inflammation. UC affects only the colon and inflammation is mostly superficial, whereas CD affects the entire gastrointestinal tract and leads to transmural inflammation, strictures, fistulas, and abscess formation.1 Incidence rates of
IBD are highest in industrialized countries affecting up to 2.4 million persons in Europe and 1.3 million persons in the United States.2 Etiology is complex with a dynamic interaction of
genet-ics, microbiome, and environmental influences (Figure 1).3
Figure 1. Overview of environmental exposures involved in IBD susceptibility
The role of genetics is evident. A positive family history of IBD is the most important risk factor for development of IBD, as a concordance rate of 19% and 50% has been shown in monozy-gotic twins for UC and CD, respectively.4,5 Genome-wide association meta-analyses have
iden-tified 201 independent loci contributing to an increased risk of IBD. Most of these loci were associated with both CD and UC, indicating common pathways for both diseases. However, 37 CD-specific and 27 UC-specific loci have also been identified.6,7 But known loci account for only
a third of risk for either disease. To depict the overall spectrum of disease pathogenesis, the unprecedented accumulating body of evidence on the genetic component of disease should be integrated with all so far known environmental risk factors.8,9 These environmental factors
directly influence the microbiome; the third entity in IBD development. An unbalanced micro-bial community composition is associated with dysregulation of the gut immune response, and therefore associated with IBD.1,10 Species richness decreases while some taxa seem to
over-grow.11 Lastly, environmental factors are also directly involved in IBD pathogenesis though
important environmental risk factors. Whereas the incidence of IBD in developed countries has stabilized incidences in developing countries in Asia, Eastern Europe, and Northern Africa are rising as they change their lifestyle and living environment.12 The hypothesis that these
envi-ronmental factors play an important role in these increases is further supported by the finding that migration from a developing to a developed country leads to an increased risk of IBD in migrants.13,14
Continuous exposure to the collective effect of dynamic environmental factors seems to be affecting the incidence of IBD. Christopher Wild was the first to describe “the exposome” as a way to map a life course of environmental exposures, starting in the neonatal period.15,16 To
cre-ate an IBD exposome, a clear overview of important environmental factors and their estimcre-ated effect size is crucial. Hereby, it is crucial to divide exposures based on their time of influence. Early childhood exposures contribute to formation of the immune system, whereas adulthood exposures might alter established pathways. Many have reviewed IBD and its causes before, but while some focus on a wider perspective than the exposome alone, others lack important environmental factors or specific effect sizes. Also, to the best of our knowledge, stage of life was not taken into account before.9,17–21
In this review, we therefore describe all so-far known risk and protective factors for IBD, based on the time of possible exposure in life and including effect sizes and possible biological back-ground. We aim to give an overview of current knowledge on the role of environment and lifestyle in IBD. Therefore, a literature search was performed to identify primary studies and systematic reviews examining potentially involved factors. Next, a qualitative review of each of these factors was carried out, and studies with the highest quality of evidence, evaluating study limitations, inconsistency, indirectness, imprecision, and the possibility of publication bias based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach were included in this review.22 All environmental exposures are ordered by
the time in life exposure most often starts, providing the opportunity to make a distinction in pathways of effect. For instance, childhood exposures are more likely to affect immunologic development, whereas adulthood exposures are involved through modification of the already existing immunologic system.
Childhood exposures
Starting at birth, exposures to numerous environmental factors occur, of which some may have a considerable impact on disease development, IBD in particular, later in life. Figure 2 shows childhood environmental exposures based on effect type and size for UC and CD separately. The most important childhood exposures include breastfeeding, use of antibiotics, childhood hygiene, and Helicobacter pylori infection, which we discuss below.
Receiving breastfeeding is shown to hold a protective effect for development of IBD, whereas other factors had a more neutral or a subtle risk-increasing effect. Meta-analysis by Klement et al. has shown a 1.8-fold (95% confidence interval: 1.2–2.6) and a 2.2-fold (1.3–3.9) risk de-crease for UC and CD, respectively.23 This falls in line with other reports showing a comparable
protective effect of breastfeeding in other immune-mediated diseases such as bronchial asth-ma, atopic dermatitis, allergic rhinitis, and type 1 diabetes mellitus.24–27 This protective effect
may possibly be explained by induction of immune tolerance to specific food antigens and microbiota, transfer of maternal antibodies in breast milk to the infant, and changing of micro-biota of the gut flora from pathogenic to non-adherent bacteria, as shown in a mice study.28–30
On the same line of evidence, the use of antibiotics during childhood for a variety of reasons may influence the microbiome, and therefore affect the susceptibility to IBD. Nevertheless, the use of antibiotics seems to hold an interesting divergent effect on IBD. Although it showed no effect on development of UC, the risk of developing CD increases in a dose-dependent manner, especially when antibiotics are used in the first year of life by an odds increase of 5.3 (1.6– 17.4).31 This effect tends to decrease (1.6, 1.4–1.8) when antibiotics are used later in childhood
(between 6 and 15 yrs. old), but remains significant.32 The risk increasing effect varies across
different types of antibiotics, with the strongest risk increase reported for broad-spectrum pen-icillin (3.1, 1.3–7.4), followed by penpen-icillin V (2.9, 1.2–7.0), and cephalosporin (1.9, 1.4–2.6).32–34
Though epidemiological studies show support for a role of antibiotics in IBD, biological under-standing is insufficient to explain this relationship. One speculation suggests that neonates are born with germ-free bowels, and formation and colonization of their microbiota start imme-diately through interactions with external factors in the first years of life.32,35 A disruption, or
perhaps better to say derailing, in the formation and composition of the microbiome by using antibiotics within this period may possibly lead to a long-lasting effect and an increased risk of CD.36 By alternating the microbiome composition, antibiotics may pave the way for
patho-genic bacteria to colonize while the normal process of tolerance, crucial for development of the mucosal immune system, could be disrupted.11,32,37 In this reasoning, CD could rise as the
consequence of either an increase of pathogenic bacteria or by an aberrant response of the host immune system to its microflora.38
A comparable reasoning involves the role of the hygiene hypothesis in incidence of IBD.39
Hy-giene is generally measured by using proxies such as living area (urban versus rural area), number of siblings, access to hot water, and animal contact. Overall, a high hygiene level increases the risk of IBD. Meta-analysis has shown an increased risk by living in an urban environment of 1.2-fold (1.0–1.3) for UC and a 1.4-fold (1.3–1.6) for CD.40 Likewise, having a smaller number of siblings
leads to a 2.6-fold (1.5–4.6) risk increase of IBD and in contrast, sharing a bedroom decreases risk of UC 2.1-fold (1.1–3.9) and CD 2.3-fold (1.3–4.4).41 Having a hot water tap at home increased
odds of CD 5-fold (1.4–17.3) and having a separate bathroom 3.3-fold (1.3–8.3), whereas no ef-fect was found for UC.42 Animal contact, an indicator of less hygiene, on the other hand, might
decrease risk of UC and CD in migrants.43 The hygiene hypothesis is not limited to IBD, as similar
effects are seen in eczema and asthma.39 Evidence to explain the association of a higher hygiene
level and IBD (and other inflammatory diseases) proposes that increased hygiene leads to less exposure to harmless microorganisms such as helminthes, predominantly found in areas of poor hygiene, leading to less induction of dendritic cell maturation and ability to drive the T-cell regu-latory system, as is shown in animal models and studies in patients with CD and UC.44–48
Further underscoring the importance of hygiene in disease pathogenesis is the finding that early childhood H. pylori infection is inversely associated with the incidence of IBD. The overall infection rate is lower in patients with IBD when compared with controls (27.1% versus 40.9%), with a 1.7-fold (1.4–2.0) and 1.3-fold (1.1–1.6) protective effect for CD and UC, respectively.49
Of note, a similar effect is described for asthma.50,51 While the underlying mechanism remains to
be explored, H. pylori leads to an increase of mucosal Foxp3 expression, the transcription factor of T-regulatory cells, which might be able to explain this protective effect by down regulation of the inflammatory process.52,53 Vaccination is another way by which our immune system is
exposed to bacterial antigens, and as vaccinations clearly influence the immune system as well, their role in IBD was studied. In contrast to past expectations, recent findings show no support for a causative or protective effect for measles infection, or vaccination against smallpox, diph-theria, tetanus, and poliomyelitis.54–57
As with the hygiene hypothesis, living environment seems to play a more decisive role in IBD. While overall, air pollution seems to have no effect on IBD development, early-onset disease seems to be affected. Living in regions with high sulfur dioxide (SO2) before the age of 25 in-creases chances of UC 2-fold (1.1–3.7), whereas a high nitrogen dioxide (NO2) before the age of 23 increases chances of CD 2.3-fold (1.3–4.3).58 Total pollutant emissions also correlate
sig-nificantly with an increased risk of hospitalization in established IBD.59 Similar effects are seen
for development of other inflammatory diseases, such as rheumatoid arthritis and relapses of multiple sclerosis.60,61 Previous studies have shown an increased sensitivity of children to
pol-lution, partly because of more time outside, partly because of a higher gastrointestinal absorp-tion of pollutants with younger age, explaining these findings.62,63 Once absorbed, pollutants
may incite the inflammatory process characteristic for IBD, but exact pathways remain unclear.64
Examination of all these childhood exposures has shown the long-term effect single factors might have on developing disease later in life by influencing the basis on which the immune system and microbiota are formed. Overall, a high level of hygiene may increase chances of IBD while breastfeeding protects against disease development.
Adulthood exposures
By aging, the pattern of environmental exposures changes. Passed through the maturation of the immune system, lifestyle becomes a more apparent player, when more freedom of choice is gained and diversity among individuals increases. A few particular environmental exposures from this period in life have been linked to IBD development. Figure 2 shows adulthood envi-ronmental exposures based on effect type and size for UC and CD separately. These effect sizes are based on studies selected after a qualitative review of literature using the GRADE approach. The most important adulthood exposures are smoking and the use of non-steroidal anti-inflam-matory drugs (NSAIDs) and oral contraceptives.
One of the most apparent effects of western lifestyle is the diet and subsequent clear rise of obesity. The influence of diet has been reviewed elsewhere. An increased body mass index (BMI) might lead to an increased risk of CD, but not UC, although results are inconsistent. In re-gard to the pro-inflammatory effect of obesity, two large European and American cohort studies have examined this association.65–67 However, only the American cohort shows a 2.5-fold (1.2–
5.0) risk-increasing effect for CD in obese women (BMI ≥ 30 kg/m2) when compared with women
with a normal BMI (20.0–24.9 kg/m2).66 Conflicting results of these different studies have led to
the hypothesis that not total BMI, but visceral adiposity specifically, might be a better measure-ment to predict disease risk. This hypothesis is supported by our findings describing a higher visceral adiposity at disease diagnosis and a more complicated disease course.68–71
Physical activity might also be related to obesity and shows a reverse effect on disease devel-opment with a protective role for risk of CD, but not UC, although reported results are inconsis-tent.67,72 Prospective analyses have shown a risk reduction of 36 percent (6.0%–56.0%) when
comparing high- and low-activity groups, which is supported by findings from other studies.73–75
Animal studies have confirmed this effect by demonstrating a protective effect against inflam-matory diseases, and also insulin resistance, cancer, neurodegenerative disorders, infections, aging, and heart disease by inducing an autophagy pathway; a lysosomal cell destruction path-way which allows cells to adapt to changing nutritional and energy demands, and therefore contributes to beneficial effects of exercise.76–80
Another lifestyle-associated factor is stress. When asked, 70% of patients have the perception that a flare of their disease is associated with stressful life events, and stress is perceived to be the leading causative agent in their disease.81,82 This hypothesis was examined by different
researchers, and findings are inconsistent.83,84 Experiencing depressive feelings, however, was
associated with a 2.4-fold (1.4–4.0) increased risk of CD, but not UC (1.1, 0.7–1.9) in a large prospective cohort study by Ananthakrishnan et al.85 Knowing the adverse effect of stress on
sleep, the latter might also be a good determinant in terms of IBD risk.86 Patients with IBD have
an increased risk of sleep disturbances, leading to a 2-fold increase of disease flare.87,88 Up to 83
percent of underlying mucosal inflammation can be predicted by an abnormal Pittsburg Sleep Quality Index (PSQI).89 A possible explanation for this effect is activation of the immune cascade
by sleep deprivation because a normal sleeping pattern is crucial for maintaining health and a proper regulation of immune function.90,91 Therefore, the assessment of sleep disturbances in
these patients could play an important role in optimal treatment.92
The same line of reasoning may be used for examining the role of smoking in IBD. Cigarette smoke might be the most widely studied lifestyle-associated (environmental) factor in IBD with a protective effect of current smoking on UC, but risk increasing effect on CD. Meta-analysis has shown that current smoking yields a 1.7-fold (1.3–2.2) risk reduction for UC, while being a former smoker increases risk of UC 1.8-fold (1.4–2.3), suggesting that smoking might only post-pone the arise of UC.93 Smoking also leads to a more benign disease course in UC with fewer
flares, less need for steroids, and lower colectomy rates.94–96 The effect of current smoking on
CD is more controversial because not all studies display the same trend. However, combining results of 9 different studies showed a 1.8-fold (1.4–2.2) risk increase of CD.93 Former smoking
also showed a risk increase, although less strong, of 1.3-fold (1.0–1.8).93 These risk-increasing
effects enlarged with increasing pack-years.97 Passive smoke exposure during childhood and
prenatal smoke exposure due to maternal smoking during pregnancy showed no association with the development of IBD.98 Reasons behind the different effects of smoking on both
dis-eases still remain vague because nicotine and smoking both have numerous effects.99 Among
other things, smoking affects the immune system through the cellular and humeral pathways by altering synthesis of pro-inflammatory cytokines.100–102 Other effects include changes of gut
permeability, reduction of smooth muscle tone and contractility due to nitric oxide, and chang-es in microcirculation of the gut.103–105
Gut permeability is also influenced by the use of NSAID use. Using NSAIDs at least 15 days per month increases risk of UC 1.9-fold (1.2–3.0) and risk of CD 1.6-fold (1.0–2.6). These risks in-crease with a higher frequency of use, greater weekly dosages, and a longer duration of use.106
These findings can be explained by the pharmacokinetics of NSAIDs, as they inhibit cyclooxy-genase (COX) leading to a decrease of protective prostaglandins in the gut mucosa, and after undergoing hepatic circulation, this ensures, among other things, an increase in mucosal per-meability, and therefore intestinal barrier function disturbance.107,108
Besides these analgesics, the use of hormone containing medication is likely to play a role in IBD development. The risk increasing effect of using the oral contraceptive pill (OCP) on IBD seems clear, whereas the effect of postmenopausal hormone replacement therapy is more controver-sial. Current use of OCP leads to a 1.3-fold (1.1–1.5) risk increase of UC.109 Risk of developing CD
with current OCP use increases 1.5-fold (1.3–1.7), and this effect might remain visible in former users (1.4, 1.1–1.9), when compared with never-users.109,110 Postmenopausal hormone
replace-ment therapy also leads to a 1.7-fold (1.1–2.7) increase of risk on UC, after correcting for earlier OCP use and increasing with duration of use, whereas no effect is seen in CD.111 A different
study found reverse findings; an association with CD instead of UC, but used a very small num-ber of cases.112 Estrogen promotes the humeral immune system, cellular proliferation and
mediates the effect of Th2-related cytokines, and because UC is a Th2-mediated disease, this could explain the increased risk. The same effect has also been described in other Th2-mediat-ed diseases such as rheumatoid arthritis and systemic lupus erythematous.113,114 However, this
hypothesis does not hold ground for CD because this is a Th1-mediated disease, and further research should focus on the role of oral contraceptives in this specific pathogenesis.115
Modifi-cation of the colonic barrier function, as described for NSAID use, potentially plays a role.116,117
A final medication that has been associated with development of IBD is isotretinoin, commonly used for treatment of severe nodulocystic acne, but its association with risk of IBD develop-ment is most likely due to an association with acne itself.118–120 Reported risk-increasing effects
of isotretinoin are weak (1.1, 0.9–1.4) and described for topic acne medication use as well, supporting the hypothesis of acne as a causative agent.121Acne should be seen as a systemic
inflammatory condition, and was earlier described as part of systemic inflammatory syndromes, although its role remains uncertain.122
Differing from the role childhood exposures play in IBD development, adulthood exposures seem to be involved by changing the already developed immune system, and their cumulative effect is likely to be an important step in progression to disease development.
Lifelong exposures
At last, several (novel) environmental factors have been identified to play a role in IBD devel-opment independent of stage of life. Although its effects might differ in size over the years, it is thought that these factors play a role independently of age. Figure 2 shows lifelong environ-mental exposures based on effect type and size for UC and CD separately. These effect sizes are based on studies selected after a qualitative review of literature using the GRADE approach. The most important exposures are previous development of an acute bacterial gastroenteritis, geographical variation, and vitamin D.
After living through a bacterial gastroenteritis, the risk of developing of UC and CD increas-es significantly (2.4, 1.7–3.3), increas-especially within the first year (4.1, 2.2–7.4). The largincreas-est effect is seen for CD (2.9, 1.5–5.6) compared with UC (2.1, 1.4–3.4).123–125 This same effect has also
been seen for development of Guillain–Barré syndrome and Reiter’s syndrome, suggesting a triggering role for gastroenteritis on inflammation. The type of chronic inflammatory disease that develops afterward may be dependent of genetics and other risk factors.124,126,127 In IBD, the
increased risk may be explained by IL-6 production, nonspecific blockage of regulatory T-cells, and activation of self-reactive T-cells as a result of pathogenic infection, leading to a chronic inflammatory response.128
Another way the immune system can be influenced is through exposure to harmless microor-ganisms as discussed in the childhood exposures section above. Drinking tap water on a regular basis seems to lower risk of CD, while UC is unaffected. Tap water decreases risk of CD by 2-fold (1.3–3.3), although its association is weak and needs further research. A possible explanation for this finding is that because of the presence of harmless environmental species in tap water, regulatory T-cells are triggered, as also suggested in the hygiene hypothesis.129,130 A similar
as-sociation is seen for asthma and allergies, emphasizing the importance of further research into its exact role in IBD pathogenesis.131 But while exposure to harmless microorganisms is likely
risk factor. Meanwhile, infection by Mycobacterium Avium subspecies Paratuberculosis (MAP) and its role in IBD remain controversial. Although MAP infection rates are higher in patients with CD, a causative role remains controversial, and no data are available evaluating the role of MAP in UC. Ever since similarities between MAP-caused Johne’s disease in cattle and CD were noticed, the same association has been suggested for CD.132 Meta-analysis has shown a 7-fold
increased chance of MAP infection in patients with CD, but because of study design timing of infection is unknown.133 Next, a small follow-up study failed to show MAP infection in early
dis-ease development.134 Because its role in disease course also remains unclear, MAP might only
be a bystander in CD.
Whereas developing gastroenteritis seems like a clear risk factor for IBD, undergoing an appen-dectomy, also immune associated, yields a divergent effect. Although a protective effect for UC is seen, risk of CD increases. Meta-analysis has shown a 3.3-fold (2.7–4.0) risk reduction for development of UC accompanied by a decrease of relapse risk in established disease (57.1% versus 78.6%), while risk of colectomy seems unchanged. This effect is largest when appendec-tomy is performed before the age of 20, independently of its cause.135–139 Mouse models have
shown appendectomy to suppress the development of inflammation, whereas tonsillectomy does not show the same protective effect.140 The most probable explanation for this protective
effect states that by the removal of the appendix, which belongs to the gut-associated lym-phoid tissues, imbalance of T-cell helper and inducer cells is altered.136,141,142 The risk-increasing
effect of an appendectomy in CD is controversial and seems most likely caused by diagnostic bias in patients with incipient CD with symptoms mimicking appendicitis.143 Risk increase being
highest within 1 year after surgery and faded after 5 years supports this theory.144
Finally, like the role of living environment as described in childhood exposures, living geogra-phy and altitude also seem to play a role. Novel research has shown an increased risk of disease flare after high-altitude flights or traveling more than 2000m above sea level.145 The mild
hy-poxia this leads to causes increases of inflammatory markers such as IL-1 receptor antagonist, IL-6, and CRP and may therefore worsen disease course, but its role in disease development is unclear and cohort-based evidence is needed for further evaluation.146 Also, the weather is
as-sociated with IBD. A warm summer, for example, yields a protective effect for UC, and although unconfirmed, the same is suggested for CD. An increase of 18°C yields a protective effect for UC of 1.1 (1.0–1.2).147 This same protective pattern is seen in other inflammatory diseases such as
multiple sclerosis, allergies, rheumatoid arthritis, and systemic lupus erythematosus.148–151 It is
thought that an increase of summer temperature accompanies an increase of microbial species richness, and knowing the role of balance disruption between gut flora and immune regulation in UC pathogenesis, microbial richness might counterbalance this part of disease etiology.47,152
Besides summer temperature, living in southern latitudes is also shown to be protective of IBD. When compared with northern latitudes, a protective effect of 1.6 (1.1–2.4) for UC and 2.1 (1.3– 3.3) for CD is seen in U.S. women living in southern latitudes, possibly because of an increase of UV radiation exposure and higher vitamin D level.153 An increase of vitamin D level has also
been shown to be protective in IBD. When comparing high and low predicted vitamin D groups, a protective effect of 1.9 (1.0–3.3) is seen for CD, but not UC. Each 1ng/mL increase of plasma 25(OH)D level seems to decrease risk of UC and CD but does not reach statistical significance.154
This protective association is also seen in other chronic immune-mediated diseases, such as multiple sclerosis and type 1 diabetes.155 Vitamin D is known to play a role in the regulation of
the innate immune system. Through activation of the vitamin D receptor on TH1 lymphocytes and monocytes, the inflammatory response is downregulated.156 These findings have been
confirmed by mice studies; vitamin D receptor deficiency leads to an increase of severity of colitis. A low plasma vitamin D level might lead to a comparable outcome.157,158
Next to vitamin D, diet is a lifelong exposure that cannot be ignored. The relation between diet and etiology and treatment of IBD is apparent for patients as well as their physicians, but is difficult to prove scientifically.159,160 Because of the complexity of diet, it is often classified as
an independent etiologic factor in IBD development and will therefore only be discussed short-ly in this review.161 Whereas sugar and fat, forming important components of a Western diet,
have been identified as risk factors for IBD development, fruits and vegetables seem to hold a protective effect.162–167 However, results are inconclusive, and no firm conclusion can be drawn
given current understandings.
Figure 2. Environmental exposures based on effect type (protective or risk increasing) and
effect size.
*Effect sizes are based on either odds ratios (ORs) or hazard ratios (HRs)
Discussion
In our working hypothesis, environmental exposures either as a part of a Western lifestyle or living surroundings play an important role in IBD pathogenesis. Therefore, in this review, we aimed to give a complete overview of environmental exposures possibly involved, as known to date and summarized in Tables 1 and 2. However, with the interpretation of these results, the quality of evidence should be taken in consideration, and results should be interpreted with caution. For a large number of possibly involved environmental factors, meta-analyses are not available yet. Novel factors thought to be involved are often identified in very well carried-out large cohort or case–control studies, but remain to be reproduced and validated by indepen-dent research groups. Also, results are not always adjusted for known confounding factors. In comparison to meta-analyses, therefore, the level of evidence provided by individual studies remains low, and one should be cautious with firm conclusions and recommendations concern-ing adaptation of lifestyle and livconcern-ing environment to prevent and/or treat IBD. Therefore, fur-ther research is necessary to furfur-ther study the exact complex etiology of IBD.
Whereas breastfeeding, increased hygiene, H. pylori infection, urban living environment, and the use of antibiotics are important childhood exposures affecting either UC, CD, or both, smok-ing, physical activity, depressive feelings and the use of oral contraceptives, hormone replace-ment therapy, and NSAIDs form the most prominent adulthood exposures. Moreover, we have identified several lifelong exposures, some defined by location of residence such as living in southern latitudes, vitamin D level, summer temperature, air pollution, and tap water consump-tion, whereas others reflect medical history such as a previous appendectomy or bacterial gas-troenteritis. As seen for genetic susceptibility, some environmental factors only affect UC or CD, whereas others affect both (Figure 1). Everyone is born with a certain genetic susceptibility for IBD, we believe the following exposure to environmental risk factors in a Western lifestyle and living environment can reach a certain threshold, after which IBD is developed. This can also explain the relatively low concordance rate in twin studies. In this theory, the coherent effect of all environmental exposures from neonatal period to death, named as the exposome by Wild, plays an important role.15 Future studies should focus on measuring this exposome,
either through biomarkers or questionnaires in a longitudinally manner, yielding the possibility of combining all involved environmental risk and protective factors in an exposome risk score. This way, coherence of different factors is used, offering a more complete model of exposures. Also, the exposome risk score could now be combined with the already existing genetic risk score, for a more comprehensive model of disease than ever before.6,7 Also, the role of the
ex-posome in disease course remains mostly unclear and should be explored next.
In contrast to genetic susceptibility, environmental exposures can be influenced actively. Therefore, the exposome is also of clinical value in multiple ways. First of all, as a preventive tool. Families with known genetic IBD susceptibility could be educated about the role of the ex-posome and its factors, because adaptation of lifestyle might delay or even prevent IBD devel-opment, as our suggested exposure threshold might not be reached. Secondly, knowing which environmental exposures are not only involved in development, but also course of disease by increasing chances of disease flare and development of complications, gives you the opportuni-ty to not only treat patients with established disease by medication, but also by environmental exposure changes, leading to a more personalized treatment plan and possibly less need of medications in the future.8 Extensive studies are needed to compare the incidence of
environ-mental exposures between patients with IBD and healthy controls, as well as to determine its role in disease course.
