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Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 21, 2016; 22(3): 1088-1100
Published online Jan 21, 2016. doi: 10.3748/wjg.v22.i3.1088
Influence of environmental factors on the onset and course of inflammatory bowel disease
Amit Kumar Dutta, Ashok Chacko
Amit Kumar Dutta, Department of Gastrointestinal Sciences, Christian Medical College, Vellore 632004, India
Amit Kumar Dutta, Department of Digestive Disorders, Aberdeen Royal Infirmary, Aberdeen AB24 3FX, United Kingdom
Ashok Chacko, Institute of Gastroenterology and Liver Disease, The Madras Medical Mission, Chennai 600037, India
Author contributions: Dutta AK was involved in the search and review of the literature and preparation of the manuscript; Chacko A was involved in the concept of this study, search and review of the literature, preparation of the manuscript and critical appraisal.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Ashok Chacko, Professor, Director, Institute of Gastroenterology and Liver Disease, The Madras Medical Mission, Chennai 600037, India. chacko.ashok@gmail.com
Telephone: +91-44-26565961 Fax: +91-44-26565906
Received: April 26, 2015
Peer-review started: April 27, 2015
First decision: August 31, 2015
Revised: September 24, 2015
Accepted: November 30, 2015
Article in press: November 30, 2015
Published online: January 21, 2016

Abstract

Numerous environmental factors have been linked with inflammatory bowel disease. These include smoking, diet, hygiene, drugs, geographical and psychosocial factors. These factors may either increase the risk of or protect against developing this condition and can also affect the course of illness in a positive or negative manner. A number of studies have examined the influence of environmental factors on inflammatory bowel diseases as a whole as well as on ulcerative colitis and Crohn’s disease separately. As there are differences in the pathogenesis of ulcerative colitis and Crohn’s disease, the effect of environmental factors on their onset and course is not always similar. Some factors have shown a consistent association, while reports on others have been conflicting. In this article we discuss the current evidence on the roles of these factors on inflammatory bowel disease, both as causative/protective agents and as modifiers of disease course.

Key Words: Environmental factors, Crohn’s disease, Ulcerative colitis, Etiology, Outcome

Core tip: Environmental factors have an important influence on the onset and course of inflammatory bowel disease. Multiple factors have been implicated with some showing a consistent effect, while the roles of others have been variable. The current evidence on their role in inflammatory bowel disease is discussed. A better understanding of these factors may help plan future preventive strategies.


Citation: Dutta AK, Chacko A. Influence of environmental factors on the onset and course of inflammatory bowel disease. World J Gastroenterol 2016; 22(3): 1088-1100
INTRODUCTION

The latter half of the twentieth century witnessed a steep increase in the prevalence of inflammatory bowel disease (IBD) in developed nations of North America and Europe. During the last three decades, populations previously considered to have low risk such as in Asia and eastern Europe are witnessing a substantial increase in this disease[1]. This may be explained by changes in environmental factors in these regions. Environmental factors that have been proposed to play a role in the emergence of IBD are smoking, diet, drugs, major life stressors, hygiene and lifestyle[1,2]. In this paper we review the role of environmental risk factors on the onset and course of ulcerative colitis (UC) and Crohn’s disease (CD), the two main types of IBD.

ENVIRONMENTAL FACTORS IN THE PATHOGENESIS OF IBD

IBD is a complex disorder where interplay between host genetics, gut microbiota and environmental factors are regarded as drivers of chronic inflammation in the gut[3]. Genetic factors play an important role with more than 150 IBD susceptibility gene loci identified to date. However, approximately two-thirds of patients with IBD have no identifiable genetic defect, which suggests that gut microbiota and environmental factors play an important role[4]. Studies on individuals migrating from countries with low prevalence of IBD to regions with high prevalence have shown an increased risk of IBD among migrants further supporting the role for environmental factors[5-8]. These factors include smoking, diet, drugs, psychosocial factors, climate, pollution and hygiene[9]. The composition of gut microbiota, currently considered a key factor in the pathogenesis of IBD, is affected by environmental factors such as breast feeding, antibiotics, smoking, obesity and diet[10,11]. For example, breast fed and formula fed infants showed a difference in the quantity of Bifidobacteria in the gut[12]. Smoking cessation changes the gut flora by increasing the proportion of Firmicutes, reducing Proteobacteria and increasing microbial diversity making the flora different from gut microbiota in IBD where there is an abundance of Proteobacteria and Actinobacteria, reduced Firmicutes along with reduced microbial diversity[10,13]. These data suggest that an alteration in microbial composition of the intestine by environmental factors is one mechanism by which environmental factors increase susceptibility to IBD.

Environmental factors may also directly act on the intestinal mucosa and alter immune function and gene expression. This can be due to a change in intestinal permeability or an alteration in host gene expression by epigenetic modification or other mechanisms[14-16]. The end result is an abnormal host immune function and chronic inflammation in the gut. An interesting example of how environmental factors affect gut immune function is provided by studies on transcription factor aryl hydrocarbon receptor (AhR)[17]. This transcription factor which is altered by dietary and environmental factors affects innate immunity in gut and immune cells (T cells and natural killer cells). Intestinal T cells and natural killer cells isolated from Crohn’s disease patients have shown low levels of AhR expression and these receptors respond to AhR ligands by upregulating interleukin-22 and downregulating inflammatory cytokines[17]. Therefore, it is plausible that environmental factors that downregulate AhR alter immune function and predispose to CD[17]. Smoking has also been shown to affect gene expression and immune function in the gut[18]. The complex interaction between host genes and environmental factors works both ways[19]. While the above examples demonstrate the effect of the environment on host gene expression, host genes can also influence the composition of microbiota which forms the local gut environment. NOD2 gene mutation predisposes to the development of IBD. A possible mechanism may be an alteration in gut microbiota in NOD2 gene mutation as shown in animal studies[20]. Mutation in autophagy-related 16-like 1 gene (ATG16L1) has also been found to increase the risk of IBD and it is possible that defective autophagy may alter the gut microbiome[19]. Further insights into the gene-environment interaction will lead to a better understanding of the pathogenesis of IBD.

The “hygiene hypothesis” has been commonly cited as the reason for the difference in IBD prevalence in different regions[21]. Better hygiene in developed regions leads to reduced microbial exposure in childhood which may affect development of the gut immune system and immune tolerance. Helminth infestation in animal models has been shown to upregulate Th2 cytokines and attenuate the Th1 pathway in the intestinal mucosa leading to suppression of inflammation and enhancement of the mucosal barrier[22,23]. Reduced exposure to helminths in developed societies has been suggested to be a risk factor for CD. Other factors such as stress, linked to exacerbation of IBD, may affect immune function by altering gut permeability and non-steroidal anti-inflammatory drugs (NSAIDs) by non-selective inhibition of cyclo-oxygenase[24,25].

Dietary factors may affect gut immune function directly in addition to their effect on microbiota[26]. There has been a recent increase in interest in the role of vitamin D in CD[27]. Our group and others have shown that vitamin D levels are reduced in patients with CD and levels correlate negatively with disease activity[28]. Data obtained mainly from animal studies have shown that vitamin D has immune regulating properties[29]. This includes maintenance of CD8+ T cells in the quiescent stage, shifting the cytokine profile to anti-inflammatory type and inhibition of epithelial cell apoptosis mediated by the vitamin D receptor[29]. Chen et al[30] have shown that TNF-α downregulates the vitamin D receptor, which in turn may promote inflammation. A high fibre diet protects against IBD by promoting the formation of short chain fatty acids like butyrate, which are a source of energy for colonocytes and by regulating T cell function[31]. The Nurses Health Study showed that soluble dietary fiber (fruits and vegetables) was associated with a reduced risk of CD[31]. The protective effect of fruits and vegetables may be through their antioxidant properties and clearing of reactive oxygen species[32]. Red meat has been associated with increased risk of IBD. Linoleic acid (long-chain omega-6 fatty acid) found in red meat and food oils is metabolized to arachidonic acid metabolites which are involved in the production of inflammatory mediators such as leukotrienes and prostaglandins[33]. Higher consumption of fish oils made up of omega-3 fatty acids (higher omega-3 to omega-6 fatty acid ratio) has been shown to be protective in children with CD[32]. There is some evidence that phytochemicals, such as curcumin found in turmeric, have antioxidant and free radical scavenging properties which may limit inflammation and help maintain remission in IBD[34,35]. These data suggest that environmental factors play a role in the pathogenesis of IBD by altering gut microbiota and affecting gut immunity by numerous mechanisms.

INTERPRETING THE AVAILABLE EVIDENCE

There are a large number of publications exploring the link between environmental factors and IBD. With the exception of smoking and appendectomy, the roles of other risk factors have been inconsistent and it is important to understand the type of study design when interpreting the results of these studies. Many of these are case-control studies which are relatively easy to perform and require few resources. However, an important limitation is the recall bias which affects the accuracy of ascertaining risk factors. Several prospective cohort studies have been carried out and data obtained from them are more robust. An important cohort study of note in this regard is the Nurses Health Study (NHS) I and II from the United States[31]. NHS I was initiated in 1976 and included 121700 subjects and NHS II was initiated in 1989 and included 116000 subjects. Periodic assessment of factors such as smoking, oral contraceptive pills (OCPs), alcohol and diet were carried out prospectively and occurrence of disease was noted. While this was mainly initiated for the outcomes of cardiovascular illness and cancer, a number of studies have been published on the role of these factors and IBD. The main limitation is that the subjects were women and most were white and generalisability across race, gender and various socioeconomic strata was difficult. Some of the studies have made use of a population-based registry to minimise referral bias and reflect population characteristics[36]. Finally, a number of meta-analyses have been published on various risk factors and IBD and these represent a higher quality of evidence. One must be cautious in interpreting the results of a meta-analysis as inclusion of low quality studies and heterogeneity among studies may affect the outcome.

ENVIRONMENTAL FACTORS AND ONSET OF IBD

A large number of environmental factors have been proposed to have a causative or protective effect on the onset of both CD and UC. Available evidence from many of these studies is summarised in Tables 1, 2 and 3. These tables have been grouped according to the study design to keep the quality of evidence in perspective. Table 1 includes meta-analysis, Table 2 cohort studies and Table 3 summarises data from case-control studies.

Table 1 Environmental factors and onset of inflammatory bowel disease - meta-analyses.
AuthorStudy settingEffect on CDEffect on UCEffect on IBD overall
Soon et al[63], 2012Urban living and risk of CD and UCIR (incident rate ratio, 1.42; 95%CI: 1.26-1.6)IR (incident rate ratio, 1.17; 95%CI: 1.03-1.32)
Luther et al[70], 2010H. pylori infection and risk of IBD, (23 studies)DR (RR = 0.64; 95%CI: 0.54-0.75)
Barclay et al[50], 2009Breast feeding and early onset IBD (7 studies)NANADR (OR = 0.69; 95%CI: 0.51-0.94)
Jones et al[42], 2008Prenatal or childhood passive smoking and risk of IBD (13 studies)NANA
Cornish et al[54], 2008OCP and risk of IBD (14 studies)IR (RR = 1.46 ; 95%CI: 1.26-1.70)IR (RR = 1.28 ; 95%CI: 1.06-1.54)
Mahid et al[37], 2007Smoking and risk of IBD (13 studies related to UC and 9 related to CD)IR with current smoking (OR = 1.76; 95%CI: 1.40-2.22)DR with current smoking (OR = 0.58; 95%CI: 0.45-0.75)
IR with former smoking (OR = 1.79; 95%CI: 1.37-2.34)
Table 2 Environmental factors and onset of inflammatory bowel disease - cohort studies.
AuthorStudy subjectsEffect on CDEffect on UC
Timm et al[76], 2014, EuropePopulation-based cohortDR with being born and living on livestock farm for first 5 yr of life
10864 subjects from ECRHS1 cohort
Outcome - place of upbringing and risk of IBD
Khalili et al[53], 2013, United States146681 subjects from NHS I and IINA - Breastfeeding, low or high birth weight, preterm birthNA - Breastfeeding, low or high birth weight, preterm birth
3373726 person-years of follow-up
Outcome - risk of IBD in adulthood
Ananthakrishnan et al[31], 2013, United States170776 subjects from NHS I and IIDR - Long term intake of higher dietary fibre especially from fruitNA with dietary fibre
3317425 person-years of follow-up
Outcome - diet and risk of IBD in adulthood
Ananthakrishnan et al[84], 2013, United States152461 subjects from NHS I and IIIR with recent and baseline depressive symptomsNA with recent and baseline depressive symptoms
1787070 person-years of follow-up
Outcome - Depressive symptoms and risk of IBD
Levi et al[75], 2013, IsraelCohort of 953684 Jewish adolescentsIR with high socioeconomic status, western origin, male sex
Outcome - sociodemographic factors and risk of IBDDR with four or more children in childhood
Higuchi et al[38], 2012, United States229111 subjects from NHS I and IIIR - Current smoker, former smokerNA - Current smoker
Outcome - Smoking and risk of IBDIR - Former smoker
Ananthakrishnan et al[56], 2012, United States76795 subjects from NHS IIR - frequent use of NSAIDIR - frequent use of NSAID
1295317 person-years of follow-up
Outcome - NSAID and aspirin exposure and risk of IBDNA - AspirinNA - Aspirin
Ananthakrishnan et al[48], 2012, United States72719 subjects from NHSDR - Higher predicted level of plasma Vitamin DNA - Vitamin D level in plasma
1492811 person-years of follow-up
Outcome - Vitamin D and risk of IBD
Table 3 Environmental factors and onset of inflammatory bowel disease - case control studies.
AuthorStudy settingEffect on CDEffect on UC
Ng et al[51], 2014, Asia PacificCD - 186DR with breast feeding for > 12 mo, antibiotic use, having dogs, daily tea intake, daily physical activityDR with breast feeding for > 12 mo, antibiotic use, daily tea and coffee intake, presence of hot water tap, flushing toilet in childhood
UC - 256IR with smoking
Controls - 940
Outcome - environmental risk factors and IBD
Sood et al[64], 2014, IndiaUC- 518IR with owning a pet and stressful events
Controls - 188DR with better toilet facilities and having private bed
Outcome - environmental risk factors and UC
Chu et al[62], 2013, South AfricaCD - 88DR - Helminth infection, shared housing, raw beef consumptionDR - Helminth infection, mixed race, smoking, shared housing, raw beef consumption
UC - 63IR - Urban dwelling, parental tertiary educationIR -parental tertiary education
Control - 219
Outcome - childhood risk factors and IBD
Jakobsen et al[114], 2013, DenmarkCD - 59IR with bedroom sharing, prior hospitalisation with gastrointestinal infection, family historyIR with prior hospitalisation with gastrointestinal infection, family history
UC - 56DR with wholemeal bread consumptionDR with daily vegetable consumption
Controls - 477 Outcome - environmental risk factors and pediatric IBD
Hlavaty et al[52], 2013, SlovakiaCD - 190IR with short duration of breast feeding, infrequent childhood sports activity, smoking, infrequent contact with animals in childhoodIR with short duration of breast feeding, infrequent childhood sports activity, smaller family size in childhood
UC - 148
Controls - 355
Outcome - environmental risk factors and IBD
Pugazhendhi et al[45], 2012, IndiaCD - 200IR with safe drinking water
Controls - 200 Outcome - environmental risk factors and CDDR with regular fish consumption and presence of cattle in house
Castiglione et al[115], 2012, ItalyCD - 468NA with any factors except IR with smoking and appendectomyNA with any factors except DR with smoking and appendectomy
UC - 527
Controls - 562
Outcome - environmental risk factors and CD
Hansen et al[44], 2011, DenmarkCD - 123DR with breast feeding, tonsillectomy,DR with breast feeding, tonsillectomy, appendectomy, smoking
UC - 144IR with pertussis and polio vaccine, measles infection, low fibre and high sugar
Controls - 267
Outcome - environmental risk factors and IBDIR with pertussis and polio vaccine, measles infection, smoking, low fibre and high sugar
López-Serrano et al[61], 2010, Spain124 CD and 235 controlsIR - Living in urban area, high educational level, social statusIR - Living in urban area, high educational level, social status
146 UC and 278 controlsDR - Childhood respiratory infection and gastroenteritisDR - Childhood respiratory infection and gastroenteritis, appendectomy, current smoking
Outcome - onset of IBD
Gearry et al[39], 2010, New ZealandPopulation-based case-control studyIR with smoking, high social class at birth, Caucasian ethnicityIR with high social class at birth, Caucasian ethnicity, migrant
CD - 638, UC - 653, Controls - 600 Outcome - risk factors and IBDDR with breastfeeding and childhood vegetable gardenDR with smoking, breast feeding and childhood vegetable garden
Joseph et al[28], 2009, IndiaCD - 34IR - lower levels of Vitamin D
Controls - 34
Outcome - vitamin D and CD
Amre et al[32], 2007, CanadaCD - 130DR - higher consumption of vegetables, fruit, fibre, fish, long chain omega three fatty acid
Controls - 202
Outcome - diet and pediatric CD
Baron et al[116], 2005, FranceCD - 222IR - Family history, Breast feeding, BCG vaccination, history of eczemaIR - Family history, disease during pregnancy, bedroom sharing
UC - 60DR - Regular drinking of tap waterDR- Appendectomy
Matched controls
Outcome - pediatric onset IBD
Smoking

There is adequate evidence linking smoking with IBD. It has opposing effects on CD and UC. The meta-analysis by Mahid et al[37] showed that current smoking increases the risk of CD, but has a protective effect on the onset of UC. Interestingly, former smokers had an increased risk of developing UC. Data from the NHS cohort showed that both current and former smoking was associated with increased risk of CD[38]. Unlike the result from meta-analysis, the study showed current smoking was not protective against UC, but former smoking was a risk factor. Population-based case-control studies from New Zealand, Hungary and Sweden have also shown increased risk of CD and decreased risk of UC with smoking[39-41]. The strong data linking smoking to IBD suggests that prenatal and childhood exposure to passive smoking may predispose to CD. However, a meta-analysis which included 13 studies did not show any significant impact of prenatal and childhood exposure to smoking on the occurrence of CD or protection against UC[42]. Based on these data, there is a strong case to recommend smoking cessation to reduce the risk of CD.

Diet, vitamin D and breast feeding

Western diet which is high in refined sugar and low in fibre has been proposed as a risk factor for IBD[26]. Increasing consumption of western diet is considered a reason for the rising incidence of IBD in Asia. The NHS data on 170776 subjects showed that intake of a median of 24.3 g of fibre per day reduced the risk of CD by about 40%[31]. Further analysis showed that this benefit was highest for soluble fibre in fruits, while insoluble fibre from legumes, whole grains and cereals did not affect the risk. Interestingly the amount and type of fibre had no significant impact on the risk of UC[31]. A case-control study from Canada exploring dietary pattern and risk of CD among subjects up to 20 years of age found a diet containing vegetables, fish, olive oil, fruit, grain and nuts was negatively associated with CD[43]. Another case-control study from Denmark showed an increased risk of both CD and UC in patients on a diet containing low fibre and high sugar[44]. A study from our center showed that regular fish consumption reduces the risk of CD[45]. Tjonneland et al[46] performed a nested case-control study, which included participants in the EPIC (European Prospective Investigation into Cancer and Nutrition) study, to assess the link between dietary linoleic acid (source of arachidonic acid whose metabolites encourage inflammation) and UC. Dietary linoleic acid was found to be associated with an increased risk of developing UC and the effect was greater with higher intake[46].

There has been increasing reports of vitamin D deficiency among patients with IBD, especially CD[27]. While this may be a consequence of the disease, vitamin D may also play a role in modulating gut immune function and have an effect on the onset of IBD[47]. A prospective study of 72719 subjects in the NHS cohort showed a protective role for a higher predicted vitamin D level against the development of CD[48]. A case-control study by our group in India, which included 34 patients with CD and 34 controls found significantly lower levels of serum 25(OH) vitamin D in patients compared with controls (16.3 ± 10.8 ng/mL vs 22.8 ± 11.9 ng/mL, P < 0.05)[28]. Disease severity was negatively correlated with vitamin D levels. Lower duration of sunlight exposure with consequent vitamin D deficiency in northern latitudes might be a factor contributing to the north-south gradient of IBD, but this needs to be confirmed. In contrast to the above positive studies, a case-control study from the United States failed to show a significant difference in the vitamin D levels between IBD subjects and controls[49].

The data on breast feeding and onset of IBD are conflicting. The meta-analysis by Barclay et al[50] showed that breast feeding reduced the overall risk of early onset IBD, but had no impact on the onset of CD or UC separately. The recently published case-control study from the Asia Pacific region which included subjects from different Asian countries and Australia showed that breast feeding for more than a year reduced the risk of both CD and UC[51]. The case-control studies from Slovakia in 2013 and Denmark in 2011 also suggested that breast feeding may be protective[44,52]. In contrast, data from 146681 subjects in the NHS cohort did not show any association between breast feeding and onset of CD or UC[53]. Interestingly, a study from France showed that breast feeding may increase the risk of CD.

The evidence for benefits of high fibre and low fat diet, longer period of breast feeding and correcting vitamin D deficiency in preventing IBD is not conclusive. However, as some studies show that they may be beneficial and as they also have other health benefits, it may be reasonable to encourage these interventions.

Drugs

Among the drugs available, OCPs, NSAIDs and antibiotics have often been linked to the onset and course of IBD. The meta-analysis by Cornish et al[54], which included 14 studies with a total of 75815 subjects showed an increased risk of CD with the use of OCPs and risk increased with longer duration of use. There was also an increased risk of developing UC, but the effect was less than in CD. A large prospective cohort study involving 232452 women (NHS 1 and 2) also showed that oral contraceptive use was associated with CD. The association between OCPs and UC was restricted to women with a history of smoking[55]. Although current evidence suggests that there is a moderate association between exposure to OCPs and the development of CD, no conclusions can be made regarding the use of OCPs and the risk of developing IBD.

A study which explored the risk of IBD with NSAIDs and aspirin intake among 76795 subjects from the NHS I cohort found an increased risk of developing CD and UC among those who used NSAIDs for at least 15 d every month. No association between aspirin use and IBD was found[56]. Antibiotics, by affecting gut microbiota, may modulate gut immune response and might be a risk factor for IBD. A nested case-control study from Canada (2234 patients and 22346 controls) which assessed the risk of IBD with antibiotic use (2-5 years pre-diagnosis) found a positive association between antibiotic use and the risk of both CD and UC[57]. In a case-control study involving 587 patients with CD, antibiotic use 2-5 years pre-diagnosis was found more often in patients than controls[58]. Virta et al[36], from Finland used the National Register to explore the link between antibiotics and risk of UC and CD. They found an increased risk of pediatric CD, but no added risk for pediatric UC with the use of antibiotics. The study also showed a stronger association of CD in boys and with the use of cephalosporins[36]. Interestingly, a study from Asia Pacific showed a decreased risk of CD and UC with antibiotic usage[51]. Data on the association between IBD and specific antibiotics are limited to the pediatric literature. Penicillins, cephalosporins, and tetracyclines have been linked with the development of CD, but the exact mechanism is not well understood[59,60]. Although studies support a link between antibiotic exposure and the onset of CD, causality has not been firmly established. However, prudent use of antibiotics is good clinical practice. Interpreting the association of drugs with IBD is challenging due to the wide variety of antibiotics, NSAIDs and OCPs available as well as the difficulty in determining the magnitude, type of exposure and duration of use of the drugs.

Hygiene

A number of studies have explored surrogate factors associated with the “hygiene hypothesis” and the risk of IBD. These include urban living, family size, toilet facilities, helminth infestation, drinking water facilities, etc[21]. Most were case-control studies, and the results from some of these studies are summarised in Table 3. While the results are quite variable, some studies showed urban living, high social status, high social class and safe drinking water to be associated with an increased the risk of IBD[39,45,61,62]. A meta-analysis which included 40 studies also showed a positive association between urban living and both CD and UC[63]. Pugazhendhi et al[45] from our center showed a positive association between safe drinking water and CD, but not with urban living. Various studies have found that childhood respiratory and gastrointestinal infection, childhood helminth infestation, pet exposure and shared housing reduce the risk[61,62]. In contrast, the Asia Pacific study which showed reduced association of UC with the presence of a hot water tap and flushing toilet in childhood and the recent study from Northern India which showed reduced risk of UC with better toilet facilities and a private bed refute the hygiene hypothesis[51,64]. Evidence for the hygiene hypothesis is conflicting. The reasons may be the inclusion of a wide variety of factors under this category, lack of large prospective cohort studies, presence of confounders or a true lack of association.

Other factors

Several other factors such as appendectomy, infections, air pollution, seasonal variation, physical activity, vaccination, and psychological factors have been implicated in the etiology of IBD. A large Swedish study showed reduced risk of UC in patients whose appendix was removed for inflammatory pathology before the age of 20 years[65]. Other studies have also shown that appendectomy was associated with decreased risk of UC[66,67]. Unlike in UC, some studies including a meta-analysis showed that appendectomy increases the risk of CD up to 5 years after surgery and thereafter the risk falls to that seen in the general population[68,69]. As clinical symptoms of CD may be similar to acute appendicitis, some of the association seen during the initial time period after appendectomy may be related to an erroneous diagnosis. Helicobacter pylori (H. pylori) infection was shown to have a protective association with IBD in a meta-analysis of 23 studies[70]. It is unclear whether this is a reflection of overcrowding and low socioeconomic status associated with H. pylori infection or an effect of this bacterium on gut immunity[71]. On the other hand, a population-based cohort study from Denmark showed that past infection with Salmonella and Campylobacter was associated with an increased risk of both UC and CD[72]. In the past, Mycobacterium avium subspecies paratuberculosis was considered an etiological agent for CD, but recent data does not support this[73,74]. Large cohort studies have also shown a reduced incidence of IBD in subjects with more siblings and those who lived on a farm with livestock in childhood[75,76]. In a study from the United Kingdom, air pollution did not affect the overall onset of IBD; however, subset analysis showed that there was an increased risk of early onset CD with exposure to nitrogen dioxide and early onset UC after exposure to sulphur dioxide[77]. The north-south gradient of IBD observed in some regions may be related to differences in climate. In a Norwegian cohort, Aamodt et al[78] studied the influence of temperature, altitude and precipitation to assess the impact of latitude on the incidence of UC. Temperature had a negative association with UC, while the other factors had no significant effect. Others have shown an association between IBD and both childhood vaccines and physical activity[44,52,79]. Thompson and colleagues were the first to suggest that measles vaccination was associated with a 3-fold increased risk of CD and UC compared to unvaccinated controls[80]. Subsequent studies have not confirmed these findings[81,82]. Available data provide no firm evidence to suggest that routine vaccinations have an effect on the development of CD. Psychological factors have also been linked with the onset and course of IBD[83,84]. Data from 152461 subjects in the NHS cohort showed an increased risk of CD with recent and baseline depression, but no significant impact on UC[84]. Although a number of factors have been suggested to influence the onset of IBD, the data are inconsistent and conflicting.

ENVIRONMENTAL FACTORS AND THE COURSE OF IBD

The usual reasons for disease exacerbation in IBD are natural history of the disease, non-compliance with drugs and gastrointestinal infections; environmental factors may also influence the course of disease. Table 4 summarises data from some of the studies evaluating environmental factors and the course of IBD.

Table 4 Environmental factors and course of inflammatory bowel disease.
AuthorStudy settingEffect on CDEffect on UC
Ott et al[89], 2014, GermanyCohort studyIR of EIMNA
CD - 161
UC - 96
Outcome - Smoking and EIM
Feagins et al[101], 2014, United StatesCase-control studyNA with NSAID, antibiotics, stress, smoking, infection and travel in past 3 mo
Active IBD - 166
IBD in remission - 68
Outcome - triggers for flare of IBD
Ananthakrishnan et al[97], 2013, United StatesMulti-institutional cohort study, CD - 5405, UC - 5429IR of surgery with psychiatric comorbidityNA of surgery with psychiatric comorbidity
Outcome - psychiatric comorbidity and surgery and hospitalisation in CD and UC
Bernstein et al[93], 2010, CanadaPopulation-based cohortIR of flare - High perceived stress
IBD - 704NA with flare - NSAID, antibiotics, non-enteric infection
Outcome - risk factors for flare
Follow-up - 1 yr
Packer et al[110], 2010Systematic review, 7 studiesPhysical activity significantly increased quality of life and decreased disease activity
Outcome - Physical activity and course of IBD
Bitton et al[95], 2008, CanadaCohort study,IR with stress/avoidance coping, higher CRP, fistulising disease behaviour, disease confined to the colon
101 patients with CD in remission
Outcome - biopsychosocial factors and relapse
Follow-up - 1 yr
Takeuchi et al[25], 2006, United KingdomCase seriesIR of flare with non-selective NSAID
IBD - 209
Outcome - risk of flare with NSAID
Sandborn et al[100], 2006, United StatesRCT - Celecoxib vs placebo for 2 wkNo significant difference between celecoxib (3%) and placebo group (4%)
UC - 222
Outcome - exacerbation during 2 wk
Persoons et al[96], 2005, BelgiumCohort studyMajor depressive disorder associated with reduced response to infliximab
CD - 100
Outcome - major depressive disorder and response to infliximab
Cosnes et al[103], 1999, FranceCohort studyNA between OCP use and disease flare
CD - 331
Outcome - OCP and flare of CD
Follow-up -12 to 18 mo
Cosnes et al[87], 1999, FranceCohort studyIR of flare - Current smokers
CD - 622NA with flare - Obesity, dyslipidemia and alcohol consumption
Outcome - risk factors for flare of CD
Follow-up -12 to 18 mo
Boyko et al[117], 1998, United StatesUC - 209, compared smokers with non-smokersDR of hospitalisation
Outcome: Smoking and course of UCNA with colectomy rates

Smoking seems to have a definite, detrimental effect on the course of CD. Several studies have shown an increased risk of flares, more active disease, increased hospitalisation rates, increased risk of surgery and post-operative recurrence in patients with CD who are smokers compared with non-smokers[85-87]. Smoking also affects disease behaviour and is associated with a higher risk of penetrating disease and extra-intestinal manifestations[88,89]. There is a strong case for smoking cessation in CD as shown in an interventional study from France where patients who quit smoking had a reduced rate of disease exacerbations compared to smokers[90]. Based on these findings, smoking cessation should be strongly encouraged in CD. A recent meta-analysis of 20 studies on UC showed lower colectomy rates in active smokers[91]. Another population-based cohort study which included 771 patients with UC from seven European countries and Israel found lower relapse rates in current smokers[92]. The reason for the differential effect of smoking on CD and UC is unclear.

Psychological factors have been proposed to have a greater role in influencing the course of IBD as compared to their etiological role. A large population-based cohort study from Canada showed an increased risk of flare in IBD patients with high perceived stress at one year follow-up[93]. A couple of other cohort studies, one of which included patients with CD and the other with UC, also showed that stress was associated with increased disease exacerbation[94,95]. A prospective observational study from Belgium showed that major depressive disorder was a risk factor for failure to achieve remission with infliximab and for earlier relapse in patients with active CD[96]. In addition to flares, psychiatric comorbidity may also affect the risk of surgery. A multi-institutional cohort study showed that psychiatric comorbidity increased the risk of surgery in patients with CD, but no association was observed with UC[97]. In contrast, a systematic review which included 12 studies showed a lack of convincing evidence that therapy of depression and anxiety alters the disease course of IBD[98]. Although the evidence for psychological factors influencing the course of IBD is not robust, it may be prudent to treat these patients to improve their quality of life.

Drugs may also influence the course of IBD. Data on NSAIDs as a trigger for disease relapse in IBD is conflicting. Case reports and small series suggest that nonselective NSAIDS trigger disease relapse[99]. In an uncontrolled study, Takeuchi et al[25], found an increased risk of flares in IBD patients taking non-selective NSAIDs, but not with selective COX-1 or COX-2 inhibitors. A randomised controlled trial of celecoxib and placebo in UC did not show a significant difference in relapse rates between the two groups[100]. The Canadian population-based cohort study and a recent study from the United States also showed no impact of NSAIDs on disease flare[93,101]. Although the evidence is weak, the American College of Gastroenterology practice guidelines currently recognize NSAID use, including the use of COX-2 inhibitors, as a potential exacerbating factor for relapse of CD[102]. The role of antibiotics and OCPs in modulating disease activity in IBD is unclear[93,101,103]. A systematic review of 10 RCTs involving 1160 patients showed that antibiotics were more effective than placebo in inducing remission in active CD[104]. Shortcomings of the study were moderate heterogeneity between studies and multiple antibiotics used either alone or in combination. As multiple antibiotics were used in different studies, the data are difficult to interpret, and additional studies are required to address the role of antibiotics in influencing the course of IBD. A systematic review that included 10 studies suggested that there is no risk of disease exacerbation in women with IBD who use oral contraceptives[105].

Dietary factors have been suggested as triggers for disease flares. Data on this subject are limited and confusing as patient surveys show heterogeneity regarding trigger foods[106,107]. Fish oil which has omega-3 fatty acid with anti-inflammatory properties may be beneficial in maintaining remission in IBD. They may be of some utility in managing UC, but have not proven to be a substitute for conventional drugs[108]. A prospective study of 191 patients with UC, who were followed-up for one year, to determine the effects of dietary factors on relapse, showed that higher meat and alcohol consumption was associated with an increased risk of relapse[109]. The sulphur content in the food was proposed to be the likely trigger.

Other factors such as air pollution, exposure to ultraviolet light and physical activity have also been linked to the course of IBD. A systematic review of seven studies found physical activity to be associated with increased quality of life and decreased disease activity among patients with IBD[110]. Cucino et al[111], found the manual work and farming were associated with decreased mortality in IBD. Low exposure to ultraviolet light has been associated with an increased risk of hospitalisation and surgery among IBD patients[112]. Exposure to pollutants in air was also shown to increase hospitalisation rates[113]. Although the environmental factors have not been as extensively evaluated with respect to their role on the course of IBD compared to their etiological role, there is modest evidence that some of these factors may influence the course of illness.

CONCLUSION

Data suggest that environmental factors play a significant role in the etiology of IBD and probably on the disease course. While the evidence for some factors is strong, many factors require further supportive data. Interventional studies assessing the effects of modifying these risk factors on natural history and patient outcomes are an important unmet need.

Footnotes

P- Reviewer: Block M, Sollano JDD S- Editor: Yu J L- Editor: Webster JR E- Editor: Liu XM

References
1.  Ng SC. Epidemiology of inflammatory bowel disease: focus on Asia. Best Pract Res Clin Gastroenterol. 2014;28:363-372.  [PubMed]  [DOI]
2.  Ponder A, Long MD. A clinical review of recent findings in the epidemiology of inflammatory bowel disease. Clin Epidemiol. 2013;5:237-247.  [PubMed]  [DOI]
3.  Loh G, Blaut M. Role of commensal gut bacteria in inflammatory bowel diseases. Gut Microbes. 2012;3:544-555.  [PubMed]  [DOI]
4.  Ellinghaus D, Bethune J, Petersen BS, Franke A. The genetics of Crohn’s disease and ulcerative colitis--status quo and beyond. Scand J Gastroenterol. 2015;50:13-23.  [PubMed]  [DOI]
5.  Jayanthi V, Probert CS, Pinder D, Wicks AC, Mayberry JF. Epidemiology of Crohn’s disease in Indian migrants and the indigenous population in Leicestershire. Q J Med. 1992;82:125-138.  [PubMed]  [DOI]
6.  Probert CS, Jayanthi V, Pinder D, Wicks AC, Mayberry JF. Epidemiological study of ulcerative proctocolitis in Indian migrants and the indigenous population of Leicestershire. Gut. 1992;33:687-693.  [PubMed]  [DOI]
7.  Ko Y, Butcher R, Leong RW. Epidemiological studies of migration and environmental risk factors in the inflammatory bowel diseases. World J Gastroenterol. 2014;20:1238-1247.  [PubMed]  [DOI]
8.  Li X, Sundquist J, Hemminki K, Sundquist K. Risk of inflammatory bowel disease in first- and second-generation immigrants in Sweden: a nationwide follow-up study. Inflamm Bowel Dis. 2011;17:1784-1791.  [PubMed]  [DOI]
9.  Cosnes J. Smoking, physical activity, nutrition and lifestyle: environmental factors and their impact on IBD. Dig Dis. 2010;28:411-417.  [PubMed]  [DOI]
10.  Kostic AD, Xavier RJ, Gevers D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology. 2014;146:1489-1499.  [PubMed]  [DOI]
11.  Pérez-Cobas AE, Gosalbes MJ, Friedrichs A, Knecht H, Artacho A, Eismann K, Otto W, Rojo D, Bargiela R, von Bergen M. Gut microbiota disturbance during antibiotic therapy: a multi-omic approach. Gut. 2013;62:1591-1601.  [PubMed]  [DOI]
12.  Voreades N, Kozil A, Weir TL. Diet and the development of the human intestinal microbiome. Front Microbiol. 2014;5:494.  [PubMed]  [DOI]
13.  Biedermann L, Zeitz J, Mwinyi J, Sutter-Minder E, Rehman A, Ott SJ, Steurer-Stey C, Frei A, Frei P, Scharl M. Smoking cessation induces profound changes in the composition of the intestinal microbiota in humans. PLoS One. 2013;8:e59260.  [PubMed]  [DOI]
14.  Johansen FE, Kaetzel CS. Regulation of the polymeric immunoglobulin receptor and IgA transport: new advances in environmental factors that stimulate pIgR expression and its role in mucosal immunity. Mucosal Immunol. 2011;4:598-602.  [PubMed]  [DOI]
15.  Kellermayer R. Epigenetics and the developmental origins of inflammatory bowel diseases. Can J Gastroenterol. 2012;26:909-915.  [PubMed]  [DOI]
16.  Mahmud N, Weir DG. The urban diet and Crohn’s disease: is there a relationship? Eur J Gastroenterol Hepatol. 2001;13:93-95.  [PubMed]  [DOI]
17.  Monteleone I, MacDonald TT, Pallone F, Monteleone G. The aryl hydrocarbon receptor in inflammatory bowel disease: linking the environment to disease pathogenesis. Curr Opin Gastroenterol. 2012;28:310-313.  [PubMed]  [DOI]
18.  Wang MH, Fiocchi C, Zhu X, Ripke S, Kamboh MI, Rebert N, Duerr RH, Achkar JP. Gene-gene and gene-environment interactions in ulcerative colitis. Hum Genet. 2014;133:547-558.  [PubMed]  [DOI]
19.  Rogler G. Interaction between susceptibility and environment: examples from the digestive tract. Dig Dis. 2011;29:136-143.  [PubMed]  [DOI]
20.  Mu C, Yang Y, Zhu W. Crosstalk Between The Immune Receptors and Gut Microbiota. Curr Protein Pept Sci. 2015;16:622-631.  [PubMed]  [DOI]
21.  Koloski NA, Bret L, Radford-Smith G. Hygiene hypothesis in inflammatory bowel disease: a critical review of the literature. World J Gastroenterol. 2008;14:165-173.  [PubMed]  [DOI]
22.  Weinstock JV, Elliott DE. Helminths and the IBD hygiene hypothesis. Inflamm Bowel Dis. 2009;15:128-133.  [PubMed]  [DOI]
23.  Elliott DE, Weinstock JV. Helminth-host immunological interactions: prevention and control of immune-mediated diseases. Ann N Y Acad Sci. 2012;1247:83-96.  [PubMed]  [DOI]
24.  Campos-Rodríguez R, Godínez-Victoria M, Abarca-Rojano E, Pacheco-Yépez J, Reyna-Garfias H, Barbosa-Cabrera RE, Drago-Serrano ME. Stress modulates intestinal secretory immunoglobulin A. Front Integr Neurosci. 2013;7:86.  [PubMed]  [DOI]
25.  Takeuchi K, Smale S, Premchand P, Maiden L, Sherwood R, Thjodleifsson B, Bjornsson E, Bjarnason I. Prevalence and mechanism of nonsteroidal anti-inflammatory drug-induced clinical relapse in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2006;4:196-202.  [PubMed]  [DOI]
26.  Chapman-Kiddell CA, Davies PS, Gillen L, Radford-Smith GL. Role of diet in the development of inflammatory bowel disease. Inflamm Bowel Dis. 2010;16:137-151.  [PubMed]  [DOI]
27.  Mouli VP, Ananthakrishnan AN. Review article: vitamin D and inflammatory bowel diseases. Aliment Pharmacol Ther. 2014;39:125-136.  [PubMed]  [DOI]
28.  Joseph AJ, George B, Pulimood AB, Seshadri MS, Chacko A. 25 (OH) vitamin D level in Crohn’s disease: association with sun exposure & amp; disease activity. Indian J Med Res. 2009;130:133-137.  [PubMed]  [DOI]
29.  Reich KM, Fedorak RN, Madsen K, Kroeker KI. Vitamin D improves inflammatory bowel disease outcomes: basic science and clinical review. World J Gastroenterol. 2014;20:4934-4947.  [PubMed]  [DOI]
30.  Chen Y, Du J, Zhang Z, Liu T, Shi Y, Ge X, Li YC. MicroRNA-346 mediates tumor necrosis factor α-induced downregulation of gut epithelial vitamin D receptor in inflammatory bowel diseases. Inflamm Bowel Dis. 2014;20:1910-1918.  [PubMed]  [DOI]
31.  Ananthakrishnan AN, Khalili H, Konijeti GG, Higuchi LM, de Silva P, Korzenik JR, Fuchs CS, Willett WC, Richter JM, Chan AT. A prospective study of long-term intake of dietary fiber and risk of Crohn’s disease and ulcerative colitis. Gastroenterology. 2013;145:970-977.  [PubMed]  [DOI]
32.  Amre DK, D’Souza S, Morgan K, Seidman G, Lambrette P, Grimard G, Israel D, Mack D, Ghadirian P, Deslandres C. Imbalances in dietary consumption of fatty acids, vegetables, and fruits are associated with risk for Crohn’s disease in children. Am J Gastroenterol. 2007;102:2016-2025.  [PubMed]  [DOI]
33.  Neuman MG, Nanau RM. Inflammatory bowel disease: role of diet, microbiota, life style. Transl Res. 2012;160:29-44.  [PubMed]  [DOI]
34.  Baliga MS, Joseph N, Venkataranganna MV, Saxena A, Ponemone V, Fayad R. Curcumin, an active component of turmeric in the prevention and treatment of ulcerative colitis: preclinical and clinical observations. Food Funct. 2012;3:1109-1117.  [PubMed]  [DOI]
35.  Saxena A, Kaur K, Hegde S, Kalekhan FM, Baliga MS, Fayad R. Dietary agents and phytochemicals in the prevention and treatment of experimental ulcerative colitis. J Tradit Complement Med. 2014;4:203-217.  [PubMed]  [DOI]
36.  Virta L, Auvinen A, Helenius H, Huovinen P, Kolho KL. Association of repeated exposure to antibiotics with the development of pediatric Crohn’s disease--a nationwide, register-based finnish case-control study. Am J Epidemiol. 2012;175:775-784.  [PubMed]  [DOI]
37.  Mahid SS, Minor KS, Soto RE, Hornung CA, Galandiuk S. Smoking and inflammatory bowel disease: a meta-analysis. Mayo Clin Proc. 2006;81:1462-1471.  [PubMed]  [DOI]
38.  Higuchi LM, Khalili H, Chan AT, Richter JM, Bousvaros A, Fuchs CS. A prospective study of cigarette smoking and the risk of inflammatory bowel disease in women. Am J Gastroenterol. 2012;107:1399-1406.  [PubMed]  [DOI]
39.  Gearry RB, Richardson AK, Frampton CM, Dodgshun AJ, Barclay ML. Population-based cases control study of inflammatory bowel disease risk factors. J Gastroenterol Hepatol. 2010;25:325-333.  [PubMed]  [DOI]
40.  Lakatos PL, Vegh Z, Lovasz BD, David G, Pandur T, Erdelyi Z, Szita I, Mester G, Balogh M, Szipocs I. Is current smoking still an important environmental factor in inflammatory bowel diseases? Results from a population-based incident cohort. Inflamm Bowel Dis. 2013;19:1010-1017.  [PubMed]  [DOI]
41.  Lindberg E, Tysk C, Andersson K, Järnerot G. Smoking and inflammatory bowel disease. A case control study. Gut. 1988;29:352-357.  [PubMed]  [DOI]
42.  Jones DT, Osterman MT, Bewtra M, Lewis JD. Passive smoking and inflammatory bowel disease: a meta-analysis. Am J Gastroenterol. 2008;103:2382-2393.  [PubMed]  [DOI]
43.  D’Souza S, Levy E, Mack D, Israel D, Lambrette P, Ghadirian P, Deslandres C, Morgan K, Seidman EG, Amre DK. Dietary patterns and risk for Crohn’s disease in children. Inflamm Bowel Dis. 2008;14:367-373.  [PubMed]  [DOI]
44.  Hansen TS, Jess T, Vind I, Elkjaer M, Nielsen MF, Gamborg M, Munkholm P. Environmental factors in inflammatory bowel disease: a case-control study based on a Danish inception cohort. J Crohns Colitis. 2011;5:577-584.  [PubMed]  [DOI]
45.  Pugazhendhi S, Sahu MK, Subramanian V, Pulimood A, Ramakrishna BS. Environmental factors associated with Crohn’s disease in India. Indian J Gastroenterol. 2011;30:264-269.  [PubMed]  [DOI]
46.  Tjonneland A, Overvad K, Bergmann MM, Nagel G, Linseisen J, Hallmans G, Palmqvist R, Sjodin H, Hagglund G, Berglund G. Linoleic acid, a dietary n-6 polyunsaturated fatty acid, and the aetiology of ulcerative colitis: a nested case-control study within a European prospective cohort study. Gut. 2009;58:1606-1611.  [PubMed]  [DOI]
47.  O’Sullivan M. Vitamin D as a novel therapy in inflammatory bowel disease: new hope or false dawn? Proc Nutr Soc. 2015;74:5-12.  [PubMed]  [DOI]
48.  Ananthakrishnan AN, Khalili H, Higuchi LM, Bao Y, Korzenik JR, Giovannucci EL, Richter JM, Fuchs CS, Chan AT. Higher predicted vitamin D status is associated with reduced risk of Crohn’s disease. Gastroenterology. 2012;142:482-489.  [PubMed]  [DOI]
49.  Veit LE, Maranda L, Fong J, Nwosu BU. The vitamin D status in inflammatory bowel disease. PLoS One. 2014;9:e101583.  [PubMed]  [DOI]
50.  Barclay AR, Russell RK, Wilson ML, Gilmour WH, Satsangi J, Wilson DC. Systematic review: the role of breastfeeding in the development of pediatric inflammatory bowel disease. J Pediatr. 2009;155:421-426.  [PubMed]  [DOI]
51.  Ng SC, Tang W, Leong RW, Chen M, Ko Y, Studd C, Niewiadomski O, Bell S, Kamm MA, de Silva HJ. Environmental risk factors in inflammatory bowel disease: a population-based case-control study in Asia-Pacific. Gut. 2015;64:1063-1071.  [PubMed]  [DOI]
52.  Hlavaty T, Toth J, Koller T, Krajcovicova A, Oravcova S, Zelinkova Z, Huorka M. Smoking, breastfeeding, physical inactivity, contact with animals, and size of the family influence the risk of inflammatory bowel disease: A Slovak case-control study. United European Gastroenterol J. 2013;1:109-119.  [PubMed]  [DOI]
53.  Khalili H, Ananthakrishnan AN, Higuchi LM, Richter JM, Fuchs CS, Chan AT. Early life factors and risk of inflammatory bowel disease in adulthood. Inflamm Bowel Dis. 2013;19:542-547.  [PubMed]  [DOI]
54.  Cornish JA, Tan E, Simillis C, Clark SK, Teare J, Tekkis PP. The risk of oral contraceptives in the etiology of inflammatory bowel disease: a meta-analysis. Am J Gastroenterol. 2008;103:2394-2400.  [PubMed]  [DOI]
55.  Khalili H, Higuchi LM, Ananthakrishnan AN, Richter JM, Feskanich D, Fuchs CS, Chan AT. Oral contraceptives, reproductive factors and risk of inflammatory bowel disease. Gut. 2013;62:1153-1159.  [PubMed]  [DOI]
56.  Ananthakrishnan AN, Higuchi LM, Huang ES, Khalili H, Richter JM, Fuchs CS, Chan AT. Aspirin, nonsteroidal anti-inflammatory drug use, and risk for Crohn disease and ulcerative colitis: a cohort study. Ann Intern Med. 2012;156:350-359.  [PubMed]  [DOI]
57.  Shaw SY, Blanchard JF, Bernstein CN. Association between the use of antibiotics and new diagnoses of Crohn’s disease and ulcerative colitis. Am J Gastroenterol. 2011;106:2133-2142.  [PubMed]  [DOI]
58.  Card T, Logan RF, Rodrigues LC, Wheeler JG. Antibiotic use and the development of Crohn’s disease. Gut. 2004;53:246-250.  [PubMed]  [DOI]
59.  Margolis DJ, Fanelli M, Hoffstad O, Lewis JD. Potential association between the oral tetracycline class of antimicrobials used to treat acne and inflammatory bowel disease. Am J Gastroenterol. 2010;105:2610-2616.  [PubMed]  [DOI]
60.  Hviid A, Svanström H, Frisch M. Antibiotic use and inflammatory bowel diseases in childhood. Gut. 2011;60:49-54.  [PubMed]  [DOI]
61.  López-Serrano P, Pérez-Calle JL, Pérez-Fernández MT, Fernández-Font JM, Boixeda de Miguel D, Fernández-Rodríguez CM. Environmental risk factors in inflammatory bowel diseases. Investigating the hygiene hypothesis: a Spanish case-control study. Scand J Gastroenterol. 2010;45:1464-1471.  [PubMed]  [DOI]
62.  Chu KM, Watermeyer G, Shelly L, Janssen J, May TD, Brink K, Benefeld G, Li X. Childhood helminth exposure is protective against inflammatory bowel disease: a case control study in South Africa. Inflamm Bowel Dis. 2013;19:614-620.  [PubMed]  [DOI]
63.  Soon IS, Molodecky NA, Rabi DM, Ghali WA, Barkema HW, Kaplan GG. The relationship between urban environment and the inflammatory bowel diseases: a systematic review and meta-analysis. BMC Gastroenterol. 2012;12:51.  [PubMed]  [DOI]
64.  Sood A, Amre D, Midha V, Sharma S, Sood N, Thara A, Bansal M, Juyal G, Thelma BK, Seidman E. Low hygiene and exposure to infections may be associated with increased risk for ulcerative colitis in a North Indian population. Ann Gastroenterol. 2014;27:219-223.  [PubMed]  [DOI]
65.  Andersson RE, Olaison G, Tysk C, Ekbom A. Appendectomy and protection against ulcerative colitis. N Engl J Med. 2001;344:808-814.  [PubMed]  [DOI]
66.  Radford-Smith GL, Edwards JE, Purdie DM, Pandeya N, Watson M, Martin NG, Green A, Newman B, Florin TH. Protective role of appendicectomy on onset and severity of ulcerative colitis and Crohn’s disease. Gut. 2002;51:808-813.  [PubMed]  [DOI]
67.  Rutgeerts P, D’Haens G, Hiele M, Geboes K, Vantrappen G. Appendectomy protects against ulcerative colitis. Gastroenterology. 1994;106:1251-1253.  [PubMed]  [DOI]
68.  Kaplan GG, Jackson T, Sands BE, Frisch M, Andersson RE, Korzenik J. The risk of developing Crohn’s disease after an appendectomy: a meta-analysis. Am J Gastroenterol. 2008;103:2925-2931.  [PubMed]  [DOI]
69.  Kaplan GG, Pedersen BV, Andersson RE, Sands BE, Korzenik J, Frisch M. The risk of developing Crohn’s disease after an appendectomy: a population-based cohort study in Sweden and Denmark. Gut. 2007;56:1387-1392.  [PubMed]  [DOI]
70.  Luther J, Dave M, Higgins PD, Kao JY. Association between Helicobacter pylori infection and inflammatory bowel disease: a meta-analysis and systematic review of the literature. Inflamm Bowel Dis. 2010;16:1077-1084.  [PubMed]  [DOI]
71.  Owyang SY, Luther J, Owyang CC, Zhang M, Kao JY. Helicobacter pylori DNA’s anti-inflammatory effect on experimental colitis. Gut Microbes. 2012;3:168-171.  [PubMed]  [DOI]
72.  Gradel KO, Nielsen HL, Schønheyder HC, Ejlertsen T, Kristensen B, Nielsen H. Increased short- and long-term risk of inflammatory bowel disease after salmonella or campylobacter gastroenteritis. Gastroenterology. 2009;137:495-501.  [PubMed]  [DOI]
73.  Jones PH, Farver TB, Beaman B, Cetinkaya B, Morgan KL. Crohn’s disease in people exposed to clinical cases of bovine paratuberculosis. Epidemiol Infect. 2006;134:49-56.  [PubMed]  [DOI]
74.  Qual DA, Kaneene JB, Varty TJ, Miller R, Thoen CO. Lack of association between the occurrence of Crohn’s disease and occupational exposure to dairy and beef cattle herds infected with Mycobacterium avium subspecies paratuberculosis. J Dairy Sci. 2010;93:2371-2376.  [PubMed]  [DOI]
75.  Levi Z, Shamiss A, Fraser GM, Furman M, Derazne E, Tzur D, Gordon B, Welinsky S, Gingold Belfer R, Afek A. The increasing prevalence of inflammatory bowel diseases among Jewish adolescents and the sociodemographic factors associated with diagnosis. Inflamm Bowel Dis. 2013;19:1867-1871.  [PubMed]  [DOI]
76.  Timm S, Svanes C, Janson C, Sigsgaard T, Johannessen A, Gislason T, Jogi R, Omenaas E, Forsberg B, Torén K. Place of upbringing in early childhood as related to inflammatory bowel diseases in adulthood: a population-based cohort study in Northern Europe. Eur J Epidemiol. 2014;29:429-437.  [PubMed]  [DOI]
77.  Kaplan GG, Hubbard J, Korzenik J, Sands BE, Panaccione R, Ghosh S, Wheeler AJ, Villeneuve PJ. The inflammatory bowel diseases and ambient air pollution: a novel association. Am J Gastroenterol. 2010;105:2412-2419.  [PubMed]  [DOI]
78.  Aamodt G, Bengtson MB, Vatn MH. Can temperature explain the latitudinal gradient of ulcerative colitis? Cohort of Norway. BMC Public Health. 2013;13:530.  [PubMed]  [DOI]
79.  Sonnenberg A. Occupational distribution of inflammatory bowel disease among German employees. Gut. 1990;31:1037-1040.  [PubMed]  [DOI]
80.  Thompson NP, Montgomery SM, Pounder RE, Wakefield AJ. Is measles vaccination a risk factor for inflammatory bowel disease? Lancet. 1995;345:1071-1074.  [PubMed]  [DOI]
81.  Morris DL, Montgomery SM, Thompson NP, Ebrahim S, Pounder RE, Wakefield AJ. Measles vaccination and inflammatory bowel disease: a national British Cohort Study. Am J Gastroenterol. 2000;95:3507-3512.  [PubMed]  [DOI]
82.  Davis RL, Kramarz P, Bohlke K, Benson P, Thompson RS, Mullooly J, Black S, Shinefield H, Lewis E, Ward J. Measles-mumps-rubella and other measles-containing vaccines do not increase the risk for inflammatory bowel disease: a case-control study from the Vaccine Safety Datalink project. Arch Pediatr Adolesc Med. 2001;155:354-359.  [PubMed]  [DOI]
83.  Lerebours E, Gower-Rousseau C, Merle V, Brazier F, Debeugny S, Marti R, Salomez JL, Hellot MF, Dupas JL, Colombel JF. Stressful life events as a risk factor for inflammatory bowel disease onset: A population-based case-control study. Am J Gastroenterol. 2007;102:122-131.  [PubMed]  [DOI]
84.  Ananthakrishnan AN, Khalili H, Pan A, Higuchi LM, de Silva P, Richter JM, Fuchs CS, Chan AT. Association between depressive symptoms and incidence of Crohn’s disease and ulcerative colitis: results from the Nurses’ Health Study. Clin Gastroenterol Hepatol. 2013;11:57-62.  [PubMed]  [DOI]
85.  Seksik P, Nion-Larmurier I, Sokol H, Beaugerie L, Cosnes J. Effects of light smoking consumption on the clinical course of Crohn’s disease. Inflamm Bowel Dis. 2009;15:734-741.  [PubMed]  [DOI]
86.  Breuer-Katschinski BD, Holländer N, Goebell H. Effect of cigarette smoking on the course of Crohn’s disease. Eur J Gastroenterol Hepatol. 1996;8:225-228.  [PubMed]  [DOI]
87.  Cosnes J, Carbonnel F, Carrat F, Beaugerie L, Cattan S, Gendre J. Effects of current and former cigarette smoking on the clinical course of Crohn’s disease. Aliment Pharmacol Ther. 1999;13:1403-1411.  [PubMed]  [DOI]
88.  Louis E, Michel V, Hugot JP, Reenaers C, Fontaine F, Delforge M, El Yafi F, Colombel JF, Belaiche J. Early development of stricturing or penetrating pattern in Crohn’s disease is influenced by disease location, number of flares, and smoking but not by NOD2/CARD15 genotype. Gut. 2003;52:552-557.  [PubMed]  [DOI]
89.  Ott C, Takses A, Obermeier F, Schnoy E, Müller M. Smoking increases the risk of extraintestinal manifestations in Crohn’s disease. World J Gastroenterol. 2014;20:12269-12276.  [PubMed]  [DOI]
90.  Cosnes J, Beaugerie L, Carbonnel F, Gendre JP. Smoking cessation and the course of Crohn’s disease: an intervention study. Gastroenterology. 2001;120:1093-1099.  [PubMed]  [DOI]
91.  Dias CC, Rodrigues PP, da Costa-Pereira A, Magro F. Clinical predictors of colectomy in patients with ulcerative colitis: systematic review and meta-analysis of cohort studies. J Crohns Colitis. 2015;9:156-163.  [PubMed]  [DOI]
92.  Höie O, Wolters F, Riis L, Aamodt G, Solberg C, Bernklev T, Odes S, Mouzas IA, Beltrami M, Langholz E. Ulcerative colitis: patient characteristics may predict 10-yr disease recurrence in a European-wide population-based cohort. Am J Gastroenterol. 2007;102:1692-1701.  [PubMed]  [DOI]
93.  Bernstein CN, Singh S, Graff LA, Walker JR, Miller N, Cheang M. A prospective population-based study of triggers of symptomatic flares in IBD. Am J Gastroenterol. 2010;105:1994-2002.  [PubMed]  [DOI]
94.  Levenstein S, Prantera C, Varvo V, Scribano ML, Andreoli A, Luzi C, Arcà M, Berto E, Milite G, Marcheggiano A. Stress and exacerbation in ulcerative colitis: a prospective study of patients enrolled in remission. Am J Gastroenterol. 2000;95:1213-1220.  [PubMed]  [DOI]
95.  Bitton A, Dobkin PL, Edwardes MD, Sewitch MJ, Meddings JB, Rawal S, Cohen A, Vermeire S, Dufresne L, Franchimont D. Predicting relapse in Crohn’s disease: a biopsychosocial model. Gut. 2008;57:1386-1392.  [PubMed]  [DOI]
96.  Persoons P, Vermeire S, Demyttenaere K, Fischler B, Vandenberghe J, Van Oudenhove L, Pierik M, Hlavaty T, Van Assche G, Noman M. The impact of major depressive disorder on the short- and long-term outcome of Crohn’s disease treatment with infliximab. Aliment Pharmacol Ther. 2005;22:101-110.  [PubMed]  [DOI]
97.  Ananthakrishnan AN, Gainer VS, Perez RG, Cai T, Cheng SC, Savova G, Chen P, Szolovits P, Xia Z, De Jager PL. Psychiatric co-morbidity is associated with increased risk of surgery in Crohn’s disease. Aliment Pharmacol Ther. 2013;37:445-454.  [PubMed]  [DOI]
98.  Mikocka-Walus AA, Turnbull DA, Moulding NT, Wilson IG, Andrews JM, Holtmann GJ. Antidepressants and inflammatory bowel disease: a systematic review. Clin Pract Epidemiol Ment Health. 2006;2:24.  [PubMed]  [DOI]
99.  Felder JB, Korelitz BI, Rajapakse R, Schwarz S, Horatagis AP, Gleim G. Effects of nonsteroidal antiinflammatory drugs on inflammatory bowel disease: a case-control study. Am J Gastroenterol. 2000;95:1949-1954.  [PubMed]  [DOI]
100.  Sandborn WJ, Stenson WF, Brynskov J, Lorenz RG, Steidle GM, Robbins JL, Kent JD, Bloom BJ. Safety of celecoxib in patients with ulcerative colitis in remission: a randomized, placebo-controlled, pilot study. Clin Gastroenterol Hepatol. 2006;4:203-211.  [PubMed]  [DOI]
101.  Feagins LA, Iqbal R, Spechler SJ. Case-control study of factors that trigger inflammatory bowel disease flares. World J Gastroenterol. 2014;20:4329-4334.  [PubMed]  [DOI]
102.  Lichtenstein GR, Hanauer SB, Sandborn WJ. Management of Crohn’s disease in adults. Am J Gastroenterol. 2009;104:465-483; quiz 464, 484.  [PubMed]  [DOI]
103.  Cosnes J, Carbonnel F, Carrat F, Beaugerie L, Gendre JP. Oral contraceptive use and the clinical course of Crohn’s disease: a prospective cohort study. Gut. 1999;45:218-222.  [PubMed]  [DOI]
104.  Khan KJ, Ullman TA, Ford AC, Abreu MT, Abadir A, Marshall JK, Talley NJ, Moayyedi P. Antibiotic therapy in inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol. 2011;106:661-673.  [PubMed]  [DOI]
105.  Zapata LB, Paulen ME, Cansino C, Marchbanks PA, Curtis KM. Contraceptive use among women with inflammatory bowel disease: A systematic review. Contraception. 2010;82:72-85.  [PubMed]  [DOI]
106.  Cohen AB, Lee D, Long MD, Kappelman MD, Martin CF, Sandler RS, Lewis JD. Dietary patterns and self-reported associations of diet with symptoms of inflammatory bowel disease. Dig Dis Sci. 2013;58:1322-1328.  [PubMed]  [DOI]
107.  Zallot C, Quilliot D, Chevaux JB, Peyrin-Biroulet C, Guéant-Rodriguez RM, Freling E, Collet-Fenetrier B, Williet N, Ziegler O, Bigard MA. Dietary beliefs and behavior among inflammatory bowel disease patients. Inflamm Bowel Dis. 2013;19:66-72.  [PubMed]  [DOI]
108.  Dziechciarz P, Horvath A, Shamir R, Szajewska H. Meta-analysis: enteral nutrition in active Crohn’s disease in children. Aliment Pharmacol Ther. 2007;26:795-806.  [PubMed]  [DOI]
109.  Jowett SL, Seal CJ, Pearce MS, Phillips E, Gregory W, Barton JR, Welfare MR. Influence of dietary factors on the clinical course of ulcerative colitis: a prospective cohort study. Gut. 2004;53:1479-1484.  [PubMed]  [DOI]
110.  Packer N, Hoffman-Goetz L, Ward G. Does physical activity affect quality of life, disease symptoms and immune measures in patients with inflammatory bowel disease? A systematic review. J Sports Med Phys Fitness. 2010;50:1-18.  [PubMed]  [DOI]
111.  Cucino C, Sonnenberg A. Occupational mortality from inflammatory bowel disease in the United States 1991-1996. Am J Gastroenterol. 2001;96:1101-1105.  [PubMed]  [DOI]
112.  Limketkai BN, Bayless TM, Brant SR, Hutfless SM. Lower regional and temporal ultraviolet exposure is associated with increased rates and severity of inflammatory bowel disease hospitalisation. Aliment Pharmacol Ther. 2014;40:508-517.  [PubMed]  [DOI]
113.  Ananthakrishnan AN, McGinley EL, Binion DG, Saeian K. Ambient air pollution correlates with hospitalizations for inflammatory bowel disease: an ecologic analysis. Inflamm Bowel Dis. 2011;17:1138-1145.  [PubMed]  [DOI]
114.  Jakobsen C, Paerregaard A, Munkholm P, Wewer V. Environmental factors and risk of developing paediatric inflammatory bowel disease -- a population based study 2007-2009. J Crohns Colitis. 2013;7:79-88.  [PubMed]  [DOI]
115.  Castiglione F, Diaferia M, Morace F, Labianca O, Meucci C, Cuomo A, Panarese A, Romano M, Sorrentini I, D’Onofrio C. Risk factors for inflammatory bowel diseases according to the “hygiene hypothesis”: a case-control, multi-centre, prospective study in Southern Italy. J Crohns Colitis. 2012;6:324-329.  [PubMed]  [DOI]
116.  Baron S, Turck D, Leplat C, Merle V, Gower-Rousseau C, Marti R, Yzet T, Lerebours E, Dupas JL, Debeugny S. Environmental risk factors in paediatric inflammatory bowel diseases: a population based case control study. Gut. 2005;54:357-363.  [PubMed]  [DOI]
117.  Boyko EJ, Perera DR, Koepsell TD, Keane EM, Inui TS. Effects of cigarette smoking on the clinical course of ulcerative colitis. Scand J Gastroenterol. 1988;23:1147-1152.  [PubMed]  [DOI]