REVIEWS

Epidemiology and risk factors for IBD

Ashwin N. Ananthakrishnan
Abstract | IBD, comprising Crohn’s disease and ulcerative colitis, is a chronic immunologically mediated
disease at the intersection of complex interactions between genetics, environment and gut microbiota.
Established high-prevalence populations of IBD in North America and Europe experienced the steepest
increase in incidence towards the second half of the twentieth century. Furthermore, populations previously
considered ‘low risk’ (such as in Japan and India) are witnessing an increase in incidence. Potentially
relevant environmental influences span the spectrum of life from mode of childbirth and early-life exposures
(including breastfeeding and antibiotic exposure in infancy) to exposures later on in adulthood (including
smoking, major life stressors, diet and lifestyle). Data support an association between smoking and Crohn’s
disease whereas smoking cessation, but not current smoking, is associated with an increased risk of
ulcerative colitis. Dietary fibre (particularly fruits and vegetables), saturated fats, depression and impaired
sleep, and low vitamin D levels have all been associated with incident IBD. Interventional studies assessing
the effects of modifying these risk factors on natural history and patient outcomes are an important
unmet need. In this Review, the changing epidemiology of IBD, mechanisms behind various environmental
associations and interventional studies to modify risk factors and disease course are discussed.
Ananthakrishnan, A. N. Nat. Rev. Gastroenterol. Hepatol. 12, 205–217 (2015); published online 3 March 2015;
doi:10.1038/nrgastro.2015.34

Introduction
Crohn’s disease and ulcerative colitis are chronic, pro-
gressive immunologically mediated diseases that often
have an onset during young adulthood and a course
characterized by remission and relapse.1–3 IBD affects
an estimated 1.5 million Americans, 2.2 million people
in Europe, and several hundred thousands more world-
wide.1,4 The protracted nature of these diseases exerts a
major toll on patients in burden of therapy, hospitaliza-
tions, surgery, health-related quality of life, economic
productivity and social functioning. The past three
decades have witnessed notable progress towards unrav-
elling the mystery of IBD. The familial nature of these
diseases has been recognized: the first Crohn’s-disease-
associated gene was described in 20015,6 and subsequent
studies identified 163 distinct risk alleles in white popu-
lations.7 This progress has been paralleled by an increase
in our understanding of the functional consequences
of these loci. In addition, there is recognition that the
genetic risk factors do not act in isolation but in synergy
with the external environment as well as the internal
‘environment’, namely the gut microbiota. The devel-
opment of IBD is governed by a series of interactions
between these three spheres, which simultaneously not
only increase the complexity of disease pathogenesis, but
Massachusetts
also offer several avenues for intervention and improve-
General Hospital ment of patient outcomes (Figure 1). This Review sum-
Crohn’s and Colitis marizes the epidemiological trends in the incidence and
Centre, 165 Cambridge
Street, 9th Floor,
Boston, MA 02114,
USA. Competing interests
aananthakrishnan@ A.N.A. has served on the scientific advisory boards for Abbvie
mgh.harvard.edu and Cubist pharmaceuticals.
prevalence of IBD in established and emerging popu-
lations, and how environmental factors might affect
incidence and natural history of IBD, their potential
mechanisms of effect and how they might be intervened
upon to improve patient outcomes.
Epidemiology
Established populations
The annual incidence of ulcerative colitis varies from
0–19.2 per 100,000 in North America and 0.6–24.3 per
100,000 in Europe, corresponding to a prevalence of
37.5–248.6 per 100,000 and 4.9–505 per 100,000, respec-
tively.4 The incidence of Crohn’s disease is similar (0–20.2
per 100,000 in North America; 0.3–12.7 per 100,000 in
Europe). However, this incidence has changed substan-
tially in the past several decades. In a population-based
study from Olmsted County, MN, USA, the incidence
of ulcerative colitis rose substantially from 0.6 per
100,000 person-years in 1940–1943 to 8.3 per 100,000
person years in 1984–1993, with the steepest increase in
the 1970s.8 A similar pattern was observed for Crohn’s
disease;9 however, the rate of increase might now have
slowed for both diseases.10 A systematic review summa-
rizing population trends identified an increase in inci-
dence in three-quarters of studies of Crohn’s disease, and
nearly two-thirds of studies of ulcerative colitis confirmed
this trend to be a general phenomenon.4 No studies have
suggested a consistent decline in incidence rates. Within
a defined geographical area, incidence rates and pat-
terns of change are heterogeneous. Incidence is higher
in urban than in rural populations, and the increase in

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REVIEWS

Key points Within countries considered to have a high incidence of

■■ Crohn’s disease and ulcerative colitis are complex immunologically mediated
diseases that arise due to a dysregulated immune response to commensal
flora in a genetically susceptible host
■■ The incidence of IBD has traditionally been highest in North America and
Western Europe with many cohorts suggesting a substantial secular increase
over the second half of the twentieth century
■■ However, incidence of IBD is increasing in emerging populations such as Asia,
suggesting that changing environmental factors play an important part
■■ Smoking and appendectomy were initially described to increase the risk of
Crohn’s disease and confer protection from ulcerative colitis; however, this
relationship seems more complex and could be mediated by genetics
■■ Diet, lifestyle and behaviour, as well as perturbations of the gut
microbiota through use of antibiotics, might also have important roles
in disease pathogenesis
■■ Modification of IBD risk factors offer avenues of intervention for disease
prevention and improvement of natural history
Hygiene
Vitamin D
UV exposure
Diet
IBD, some populations have a markedly reduced inci-
dence when compared with the general population, such
as the First Nations population in Canada14 or the Arab
Bedouin population in Israel.15
In most studies, the peak incidence of IBD is in the
second to fourth decade of life and has remained so over
several decades. Some cohorts have suggested a bimodal
incidence rate with a modest second peak in the sixth
and seventh decades of life.1,2,4 Incidence in established
populations is similar in men and women, but is influ-
enced by race and ethnicity. The risk of IBD is three-
fold higher in the Jewish population than in non-Jewish
populations.16 Furthermore, risk of IBD is higher par-
ticularly among Ashkenazi populations (compared with
Sephardim populations) and American and European
Jewish populations compared with those residing in Israel.
Although initial estimates suggested a markedly lower
prevalence of IBD in those who were African-American
or of Hispanic ethnicity than white populations, studies
suggest that the gap in incidence between white and non-
white populations is n­arrower than first thought, with
comparable phenotypes.17,18

Stress Sleep Emerging populations and migration

Traditionally, IBD has been considered a disease of the
West and infrequent in the East, a premise compounded
by the scarcity of incidence data from non-Western popu-
lations. However, data suggest that both Crohn’s disease
Smoking Medications
and ulcerative colitis are no longer rare in these emerg-
ing populations and such epidemiological trends can
provide informative clues towards disease epidemiol-
ogy (Figure 2). Japan, Hong Kong and Korea all demon-
strated an increasing incidence of disease between 1980
and 2003.19 Interestingly, in most of these populations,
Appendectomy
Microbiome the incidence of ulcerative colitis is greater than and often
precedes the rising incidence of Crohn’s disease by one
decade. In the population-based Asia–Pacific Crohn’s
and Colitis study, the incidences of ulcerative colitis and
Physical
activity Genetic Crohn’s disease were 0.76 and 0.54 per 100,000, respec-
susceptibility
tively, which is considerably lower than for Western coun-
tries.20 IBD remains rare in Africa and South America,
but case series suggest an increasing frequency of occur-
rence.21,22 An increasing incidence of IBD in Saudi Arabia
has also been observed with a disease course similar to
that observed in the West.23 The peak age of onset in
emerging populations seems similar to that reported from
Figure 1 | The interaction between genetics, immunology, environment and Western countries.20
Nature Reviews
microbiome. IBD develops at the intersection | Gastroenterology
of genetic & Hepatology
predisposition (leading to The distinct genetic background of these emerging pop-
immunological abnormalities), dysbiosis of the gut microbiota and environmental ulations in contrast to IBD in white populations, the lack
influences. None of the risk factors alone are sufficient for development of disease
of replication of some of the risk loci identified in white
and complex interactions between each factor occurs, leading to development of IBD.
individuals,24 and the rapid rise in incidence paralleling
changing lifestyle and behaviour emphasize a key role of
incidence in urban populations preceded that in rural the environment in disease pathogenesis. Added empha-
populations by one decade.8,9 A north–south gradient in sis comes from studies of immigrants. An initial report
terms of latitudes of residence exists, demonstrating a by Probert et al.25 identified the incidence of ulcerative
higher incidence of Crohn’s disease in northern latitudes colitis in first-generation and second-generation Indian
than in southern latitudes.11,12 A similar inverse relation- migrants to the UK to be similar to the native UK popu-
ship might exist in the Southern hemisphere, as a high lation, and higher than the incidence in the countries of
incidence of IBD has been reported in New Zealand.13 origin, whilst the incidence of Crohn’s disease was lower.26

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High incidence of Low incidence Increased risk of IBD Rising incidence in

paediatric IBD in in First Nation in second-generation Asia paralleling
South-Asian population populations14 immigrants from ‘Westernization’
in BC, Canada. Asia in the UK25–27 (1980–2003)19
Male predominance;
more colonic disease28 Rising incidence
from 1940 to 1993 Greater incidence Higher incidence of No association
Similar rates of in Northern IBD in Israeli Jewish with NOD2
ulcerative colitis latitudes12 individuals than CARD15 or
and Crohn’s Arab individuals15 IL-23R variants24
disease8,9 Uncommon
occurrence, although Increasing Incidence in Asia
small studies incidence in lower than in white
Older age of Saudi Arabia individuals
onset and milder suggest a
disease in foreign- rising incidence Similar morbidity Ulcerative colitis
born Hispanics in Africa21,22 as in the West23 more common than
in the USA30 Crohn’s disease
Milder natural
history of disease20

High incidence of
IBD in Canterbury,
New Zealand13

NatureofReviews
Figure 2 | Global map of IBD in established and emerging populations. Patterns | Gastroenterology
changing & Hepatology
incidence of IBD worldwide
provide important clues to potential environmental factors, timing of exposure and genetic predisposition to the
development of IBD.

Subsequent studies from the UK and Sweden suggested
that the increase in risk was most apparent in the second
generation whereas the first-generation immigrants from
low incidence countries continued to have lower risk
than those from the country migrated to.27 This change in
disease risk is more prominent in migrants from West or
South Asia to the West, and less so within areas of similar
socioeconomic status.27 In BC, Canada, the incidence of
paediatric IBD among immigrant South Asians was even
higher than in the native white population.28 In one of the
largest studies examining the effect of immigration on
disease risk, Benchimol et al.29 found a markedly lower
risk of IBD in immigrants, particularly from East Asia,
than in the general population of ON, Canada. Older age
at immigration was associated with a greater reduction in
risk of IBD and the attenuation in risk persisted in children
from East Asia, Central Asia and Latin America but not
the Middle East, South Asia, Africa, or Western Europe.
The phenotype of IBD in emerging populations and
with migration also seems distinct and milder than in
established Western populations, though to what extent
this phenomenon is a reflection of the natural history
of disease compared with differences in health-seekin­g
behaviour, and patient and provider preferences is
unclear. The immigrant Indian population in the UK and
native population in India and rest of Asia have mark-
edly lower rates of surgery than rates from Western coun-
tries.25,26 Foreign-born Hispanic individuals in the USA
had lower rates of surgery or need for biologic therapy
than non-Hispanic white individuals.30
Genetic epidemiology and genetics
Support for a role for genetics in the pathogenesis of IBD
was initially derived from familial aggregation studies
and twin studies, which suggested an important heredi-
tary component.3,31–38 Between 2% and 14% of patients
with Crohn’s disease report a family history of the con-
dition whereas a small proportion of these patients will
have a family history of ulcerative colitis. A similar pro-
portion, 8–14%, of patients with ulcerative colitis will
have a family history of IBD, more commonly ulcerative
colitis. Consequently, the relative risk of developing IBD
for first-degree relatives of a patient with Crohn’s disease
is estimated to be around 5% in non-Jewish and 8% in
Jewish patients, with the corresponding risk of ulcera-
tive colitis being 1.6% and 5.2%, respectively.38 If both
parents were affected, the risk of the offspring developing
IBD before the age of 30 years is estimated to be as high
as one-in-three.31 Twin studies have also suggested a key
heritable component for both Crohn’s disease and ulcera­
tive colitis. For Crohn’s disease, concordance rates in
monozygotic twins is 20–50% whereas that for dizygotic
twins is 10%. The corresponding figures for ulcerative
colitis are lower and are estimated at 16% for mono­
zygotic and 4% for dizygotic twins, suggesting a weaker
heritable component for this disease. Within twin pairs,
there might be discordance both in the type of IBD as
well as natural history of disease, influenced in part by
the environment; for example, a twin who smokes might
develop Crohn’s disease whereas the nonsmoking twin
might develop ulcerative colitis.31,34–36,39

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Genetic loci associated with IBD were initially identi-
fied using linkage studies, which first demonstrated an
association with a locus on chromosome 16.40 This locus
was subsequently characterized as the NOD2 locus in
2001 with three common variants that influence suscep-
tibility to Crohn’s disease.5,6 Homozygosity at the NOD2
locus is associated with a 20–40 fold increase in disease
risk whereas heterozygosity confers a more modest (yet
strongest among the loci identified so far) 2–4 fold eleva-
tion in disease risk.5,6 A subsequent international collab-
orative effort identified 163 distinct risk loci mapping to
a much larger number of potentially associated genes.41
The vast majority of loci are shared between both dis-
eases with similar directions of effect, although some loci
(such as NOD2 and ATG16L1) are specifically associated
with Crohn’s disease alone and others only with ulcera-
tive colitis.7 Despite the divergence in their effects on
the immune system, many of the putative genes can be
broadly divided into those influencing innate immune
responses, autophagy, maintenance of the integrity of the
epithelial barrier, adaptive immune responses, restitu-
tion and injury repair, response to oxidative stress and
microbial defence and antimicrobial activity.32 Several
risk loci might influence immunological function within
a single pathway; for example, ATG16L1, NOD2, IRGM,
LRRK2 all exert an influence on autophagy. Genetic
polymorphisms might also act in synergy and influence
cellular phenotypes such as Paneth cell function.42 A full
discussion of the genetics of these diseases is beyond the
scope of this Review and the reader is directed to several
e­xcellent articles on the topic.3,32,43
Extreme phenotypes, such as very-early-onset disease
characterized by treatment refractoriness and severe peri-
anal fistulization, might have distinct monogenic origins
(for example, IL‑10 receptor mutations). In contrast to the
polygenic pathogenesis of idiopathic IBD, these pheno­
types might respond durably to stem cell transplanta-
tion.44 In spite of the advances in the field, the known risk
loci account for less than one-quarter of the heritability
of these diseases, suggesting a strong role for the envi-
ronment (discussed later).7,32 Furthermore, genetics also
highlight the key part played by the interaction between
the internal microenvironment in the form of gut micro-
bial dysbiosis and associated immunological response,
both processes influenced by the external environment.
In addition, the sharing of risk loci between those influ-
encing risk of IBD and also response to infections (such
as leprosy or tuberculosis) also further highlights the
complex interplay.7,32
Microbiota
The key pathways associated with microbial response
and innate immunity highlighted by the latest advances
in genetic analysis has led to a resurgence in the inter-
est in the gut microbiota in IBD.45–49 Detailed reviews
have been published on this topic highlighting asso-
ciations between microbiota and disease, but a few key
findings merit being highlighted in relation to the envi-
ronment.46,49 Several epidemiological clues point towards
the role of altered host microbiota in IBD. Cohort studies
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and case–control analyses have demonstrated larger
family size, early life exposure to pets and farm animals,
and greater number of siblings to be inversely associated
with risk of IBD, whereas breastfeeding seems to be pro-
tective.50–52 All these early life parameters are known to be
important determinants of the gut microbiota in adult-
hood, lending plausibility to the role of the gut microbiota
in disease pathogenesis. Patients with IBD demonstrate
a dysbiosis in their luminal microbiota, most consist-
ently characterized by a reduction in diversity of this
microbial community compared with healthy individu-
als.45–49 This difference in microbial diversity is greater for
Crohn’s disease than ulcerative colitis, which resembles
the microbiota of healthy individuals to a greater degree.
Additionally, twin studies also suggest that the micro-
biota is different between healthy siblings and discord-
ant twins.53 Mucosal transcripts (showing mucosal gene
expression) from healthy siblings show greater correlation
with bacterial genera than in those with ulcerative colitis
or their healthy twins, suggesting a disordered interaction
between the mucosa and microbiota in IBD.54
Although pathogenic microorganisms have not been
identified in all scenarios, specific phenotypes might be
associated with certain microbial triggers. A more prom-
ising pathogen as a potential causative agent in IBD is
adherent–invasive Escherichia coli (AIEC). Darfeuille-
Michaud et al. 55 identified AIEC strains in 22% of
patients with Crohn’s disease compared with only 6.2%
of healthy controls, with localization in the ileum. AIEC
might have a role in Crohn’s disease because of its ability
to invade the epithelium and persist within macro­
phages. By contrast, certain microbial subpopulations
might confer protection from disease. Bacteria belong-
ing to the Firmicutes phylum are often less commonly
found in those with Crohn’s disease.46,49 In particular,
Faecalibacterium prausnitzii, a butyrate-producing bac-
teria belonging to the Firmicutes phylum, occurs less fre-
quently in patients with IBD than healthy controls and
inversely correlates with severity of endoscopic recur-
rence after resection. In addition, this bacteria amelio-
rates colitis in mice when administered intragastrically
via an anti-inflammatory effect mediated by an increase
in IL‑10 and suppression of IL‑17.56–58
The external environment is a strong determinant
of the gut microbiota, as might be host genetics. Both
long-term and short-term diets affect the intestinal
microbiota and these changes in microbial composition
could mediate the influence of diet on risk of incident
disease. 59,60 Long-term diet clusters the gut micro­
biome into two enterotypes: enterotype 1 is enriched in
Bacteroides spp. and correlates with a Western-style diet
with high intake of animal proteins and saturated fat;
enterotype 2 is enriched in Prevotella spp. and is seen in
individuals with a carbohydrate and fibre-predominan­t
diet. 59 In addition, short-term dietary changes alter
diversity and composition of the gut microbiota and offer
plausible mechanisms of the effect of diet on IBD.60 The
effect of the gut microbiota on IBD is not restricted to
bacterial dysbiosis and there might be important roles
for viruses, Archaea and fungi. Both Crohn’s disease

and ulcerative colitis were associated with expansion
of bacterio­phages belonging to the Caudovirales family
independent of bacterial dysbiosis.61 Moreover, in studies
in mice, altered immune responses to indigenous fungi
in the gut mediated through the innate immune response
receptor Dectin‑1 influenced susceptibility to chemically
induced colitis.62
Environmental risk factors
Smoking
The association between smoking and ulcerative
colitis was first described by Harries et al.63 who noted
a reduced frequency of smokers among patients with
ulcerative colitis compared with healthy controls.
A meta-analysis quantified the increase in risk associ-
ated with smoking to be twofold for Crohn’s disease (OR
1.76, 95% CI 1.40–2.22).64 The same magnitude of asso-
ciation was seen between former smoking and ulcera­tive
colitis, but not for current smoking, which demon-
strated a strong inverse association (OR 0.58, 95% CI
0.45–0.75). In a prospective cohort of female nurses, the
risk of ulcerative colitis increased within 2–5 years after
smoking cessation and remained elevated for 20 years.65
Early life exposure to smoke and passive smoking have
similar effects.66 However, although smoking is one of
the most consistently replicated risk factors, gender
and ethnic variations in susceptibility suggest complex
gene–environment interactions. Not all cohorts have
uniformly identified an effect of smoking on IBD. In an
Israeli study, smoking cessation was associated with
an increased risk of ulcerative colitis, but not of Crohn’s
disease.67 In an elegant study by Cosnes et al.,68 current
smoking was associated with later age of onset of ulcera-
tive colitis and lower risk of need for immunosuppres-
sion in men but not women. By contrast, smoking was
associated with early age of onset and more frequent
need for immunosuppression in Crohn’s disease among
women, but not men.68 Consistent with the direction of
effect on incident disease, smoking is associated with a
more-aggressive disease course in Crohn’s disease.69–72
Smokers are more likely to require immunosuppression
and surgery, and have greater likelihood of recurrence
after ileocecal resection. By contrast, in ulcerative colitis,
smoking cessation is frequently a precipitant for disease
flares within a year of cessation,69,73 and current smokers
have a milder disease course, fewer surgeries and less
need for immunosuppression.
Several hypotheses have been proposed to explain
the association between smoking and IBD though none
have demonstrated convincingly the reason behind
the divergent effect on Crohn’s disease and ulcerative
colitis.72,73 Nicotine was long-believed to be the trigger;
however, trials of nicotine replacement therapy in ulcera-
tive colitis yielded equivocal results74 and no association
was observed between oral tobacco use and Crohn’s
disease,75 suggesting that other components of tobacco
smoke might be important. Smoking could alter smooth
muscle tone and influence endothelial function through
nitric oxide production,76 or affect the integrity of the gut
mucous barrier.77 The effect of smoking could also be
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mediated by oxidative stress. Bergeron et al.78 found that
mononuclear cells from smokers with Crohn’s disease
but not ulcerative colitis were less sensitive to anti-
inflammatory protection against oxidative free radical
stress because of reduced levels of synthesis of heat shock
protein 70. Polymorphisms in genes contributing to nico­
tine metabolism and cellular oxidative response might
modify susceptibility to smoke.79 Smoking also exerts an
influence on the microbiota. Smoking cessation is asso-
ciated with an early change in the microbiome, and this
interaction with the immune response could underlie the
effect of smoking cessation on ulcerative colitis.80–82
Appendectomy
Similar to smoking, appendectomy demonstrates a
divergent effect on Crohn’s disease and ulcerative colitis.
In a large cohort of 212,963 patients who underwent
appendectomy before the age of 50 years, the incidence
of ulcerative colitis was markedly lower among those
who underwent appendectomy for perforated or non­
perforated appendicitis and mesenteric lymphadenitis
than for those with nonspecific abdominal pain, suggest-
ing that inflammation of the appendix rather than the
mere removal of the organ might be responsible for this
protective association.83 This effect is limited to appen-
dectomy before the age of 20 years. By contrast, the same
cohort found an increased risk of Crohn’s disease for up
to 20 years after the appendectomy;84 however, when
patients were operated on below the age of 10 years, the
risk of Crohn’s disease was reduced.84 The association
between appendectomy and Crohn’s disease is more dif-
ficult to interpret as some of the inconsistency in find-
ings between the different studies could reflect surgery for
abdominal pain in Crohn’s disease before formal diagno-
sis, thereby leading to a spurious association of increased
risk.85 Several studies have also evaluated whether appen-
dectomy alters the natural history of these diseases.84,86–89
For Crohn’s disease, one study suggested a later diagnosis
of Crohn’s disease in those who had undergone an appen-
dectomy previously.88,89 As noted for incident disease,
the reason for appendectomy seems to be important in
determining outcomes. Appendectomy for perforating
appendicitis was associated with increased risk of sub-
sequent intestinal resection, whereas appendectomy for
other causes was associated with a reduced risk of Crohn’s
disease.84 For ulcerative colitis, prior appendectomy was
associated with a greater risk of coexisting primary sclero­
sing cholangitis and pancolitis distribution of disease, and
reduced need for immunosuppression, but had no clear
effect on risk of colectomy.87–89
Hygiene
The hygiene hypothesis was first proposed by Strachan
et al.90 to explain the rising incidence of autoimmune
diseases in the developed world. Indeed, several studies
provided support for this hypothesis in the context of
IBD. Number of siblings, larger family size, drinking
un­p asteurized milk, living on a farm and exposures
to pets (particularly early on in childhood) have been
inversely associated with risk of Crohn’s disease or
REVIEWS
ulcerative colitis.16,52,91,92 However, most such studies have
been case–control in design and could not rule out effect
of recall bias or confounders. Other early life factors have
been examined in the context of disease risk under the
hypothesis of an early influence of such factors on the gut
microbiota and development and maturation of immune
responses. Although several studies have demonstrated
a strong inverse association between a history of being
breastfed and IBD, this finding is not consistent across
all cohorts and is stronger for ulcerative colitis than for
Crohn’s disease.93 Although mode of childbirth also has
an important influence on the gut microbiota in infancy,
the association with risk of IBD is less robust.94 In devel-
oping countries, measures of hygiene have not demon-
strated the inverse association reported in the West, and
have in fact been associated with an increased risk of
ulcerative colitis.95
Infectious pathogens and antibiotics
Infections
A putative association between infectious pathogens
and IBD has been of long-standing interest; generally
speaking, the lack of transmissibility, excellent response
to immunosuppression and poor response to antibiotics
argues against a direct causal association. However, the
importance of innate and adaptive immune responses,
maintenance of barrier integrity, and host recognition
and response to pathogens in disease pathogenesis sug-
gests a more complex interaction of disease susceptibil-
ity with potential infectious triggers. Among the various
pathogens, interest has been strongest for Mycobacterium
avium subspecies paratuberculosis (MAP) responsible
for Johne disease in cattle. A high frequency of MAP
in patients with Crohn’s disease was found in some but
not other studies,96–99 and a randomized controlled trial
demonstrated no clinical benefit with antimycobacterial
treatment.99 Cohort studies from Denmark suggested an
association of IBD with Salmonella or Campylobacter
infection,100 whereas others using data from the US mili-
tary population101 as well as the UK primary care data-
base102 have demonstrated an increase in risk of IBD
after episodes of gastroenteritis without a firm bacterial
or viral aetiology. This increased risk is strongest in the
year immediately after the diagnosis of infection, suggest-
ing that the reported association might at least in part be
due to a detection bias.103 Interest in the potential role
of viruses initially centred on a direct pathogenic link
with the measles virus or vaccination, although rigorous
studies refuted this link.104–106 Viruses could act as triggers
in the setting of genetic susceptibility. In animal models,
norovirus infection in mice with autophagy defects led
to Paneth cell abnormalities and a Crohn’s-disease-like
inflammatory reaction.107 This effect was dependent on
TNF and IFN‑γ and was ameliorated by treatment with
broad-spectrum antibiotics. The same result was not
seen in mice without an autophagy defect, suggesting a
complex interaction between viruses, bacteria and host
genetics in disease pathogenesis.
Infections are frequently triggers of relapse in those
with established IBD. Of these, one of the most common
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triggers is Clostridium difficile.108 This infection is fre-
quently associated with relapses of disease, particularly
in the hospitalized population, and is associated with a
substantial burden of both mortality and morbidity with
an effect that might last for over a year after the initial
infection.108 Systemic infections could also act as triggers
for relapse in those with established disease though the
supporting data are less robust.109
Antibiotics
The gut microbiota is diverse and unstable during
early childhood.110 Perturbation of this microbiota in early
childhood could influence the gut immune response and
alter susceptibility to IBD. In a nested case–control analy­
sis from the University of Manitoba IBD cohort, 58% of
paediatric patients with IBD received an antibiotic in
their first year of life compared with only 39% of the
controls.111 The association is greater for Crohn’s disease
than ulcerative colitis,112 is observed with different classes
of antibiotics113 and is stronger for exposure in the first
year of life compared with later use.114 A dose-response
relationship also exists with multiple courses of anti­
biotics contributing to a greater increase in disease risk
than a single course.114 However, most of the association
studies of antibiotics have been in Western populations
who have low exposure to early life infectious pathogens
or have good sanitation. In contrast to this prevailing data,
antibiotic exposure demonstrated a protective association
with both Crohn’s disease and ulcerative colitis in a large
population-based study in Asia.45
Medications
Other medications have been associated with IBD includ-
ing aspirin,115 NSAIDs,116 oral contraceptives117,118 and
postmenopausal hormone therapy.119 The association
with NSAIDs was stronger with higher doses and longer
duration of NSAID use and was similar for Crohn’s disease
and ulcerative colitis.116 NSAIDs might trigger relapses
in up to one-third of users. Their effect might be due to
the nonselective inhibition of cyclo-oxygenase (COX)
enzymes, as selective COX‑2 inhibitors are associated with
a reduced rate of relapse.109 Oral contraceptive use confers
an increased risk of Crohn’s disease but the magnitude of
this effect decreases with cessation of use.117,118
Diet
Fibre
Most epidemiological studies of diet and IBD have
focused on macronutrients and have relied on a case–
control design susceptible to numerous limitations.120,121
Despite heterogeneity in design, the most consistent
macronutrient association has been an inverse associa-
tion with dietary fibre.122,123 Newly diagnosed paediatric
patients with Crohn’s disease had markedly lower intake
of fruits and vegetables than controls without IBD.122 In
a prospective cohort study, women in the highest quin-
tile of long-term fibre intake had a 40% reduction in
risk of Crohn’s disease (OR 0.59, 95% CI 0.39–0.90);123
this inverse association was stronger for fibre from
fruits and vegetables and not seen with whole grains

or cereals. Several potential mechanisms could explain
an inverse association with fibre. Soluble fibre (from
fruits and vegetables) is metabolized by the intestinal
bacteria to short-chain fatty acids that inhibit transcrip-
tion of pro­inflammatory mediators.124 In addition, fibre
helps maintain the integrity of the epithelial barrier and
reduces translocation of E. coli across Peyer’s patches
in vitro.125 Finally, the indole‑3-carbinol present in fruits
and crucifer­ous vegetables activates the aryl hydrocarbon
receptor and attenuates colitis in animal models.123
Dietary fat
Dietary fat, particularly saturated fats, might also have a
role in pathogenesis.120–122,126–131 In mice, a high-saturated-
fat diet promotes expansion of a sulphite-reducing patho-
biont, Bilophila wadsworthia, and was associated with
an inflammatory response mediated by type 1 T helper
cells and colitis in IL‑10-knockout mice.132 In humans,
although saturated fats have been associated with risk of
IBD in small case–control studies, prospective cohorts
have not identified such an association, suggesting a
more complex effect.120,122,126,130,133 High consumption of
n‑6 polyunsaturated fatty acids (omega-6 PUFA) and low
consumption of n‑3 PUFA (or a high n‑6:n‑3 ratio) has
been associated with an increased risk of both ulcera-
tive colitis and Crohn’s disease. This association might
be modified by polymorphisms in fatty acid metabo-
lism, particularly in the CYP4F3 and FADS2 enzymes.134
Inconsistent associations with IBD have been demon-
strated with carbohydrate intake, refined sugars and
animal protein.120,121,135,136 In contrast to the literature
on diet and incident disease, few studies have examined
the role of diet in established disease. Studies relying
on self-reported diet suggest heterogeneity in ‘protec-
tive’ and ‘harmful’ foods.137 The marked interindividual
variation in the gut microbiota confirms this expected
h­eterogeneity in response to dietary i­nterventions in IBD.
Vitamin D
Few studies have examined an association of IBD with
micronutrients but such a relationship is based on consid-
erable biological plausibility from supporting laboratory
studies. Emerging data suggest that vitamin D might have
a role in the pathogenesis and course of IBD.138–140 In mice,
deficiency of 1,25-dihydroxy vitamin D3 (1,25(OH)2D3)
or knockout of vitamin D receptor is asso­ciated with an
increased risk of colitis; administration of 1,25(OH)2D3
ameliorates this inflammation and suppresses expression
of proinflammatory genes including TNF.141–144 Vitamin D
might also suppress responsiveness of mononuclear
cells to circulating antigens.138 Deficiency of vitamin D
is common in patients with newly diagnosed IBD and
more common than in healthy individuals.145 In a pro-
spective cohort assessing predicted vitamin D status using
a validated regression model, women in the highest quar-
tile of predicted vitamin D status (median 32.2 ng/ml) had
a significantly lower risk of Crohn’s disease than those in
the lowest quartile (OR 0.54, 95% CI 0.30–0.99).146 Low
levels of vitamin D (<20 ng/ml) were associated with
increased risk of Crohn’s-disease-related surgery and
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REVIEWS
h­ospitalization and normalization of levels attenuated
this risk.147
Zinc and iron
Zinc has a panoply of effects on immune function and
modulates the function of innate immune cells including
macrophages, neutrophils and natural killer T cells.148–150
Zinc also inhibits transcription of inflammatory media-
tors in the NF‑κB pathway and reduces myeloperodixase
activity. Specifically in the context of Crohn’s disease,
intracellular zinc is important for autophagy and bacte-
rial clearance, reduces intestinal permeability and, in a
small study, reduced likelihood of relapses.149–151 Dietary
iron might induce colonic inflammation through IL‑6–
IL‑11–STAT3 signalling 152 and enhancement of oxida-
tive stress,153 although studies of oral iron replacement
in established disease do not lend clinical support to an
adverse effect of dietary iron. A single epidemiological
study suggested an association between high iron content
in drinking water and increased risk of IBD.154
Lifestyle—stress, sleep and exercise
IBD has long been associated with certain personal-
ity types including neuroticism, obsessive–compulsive
behaviour, dependency and perfectionism, as well as
psychosocial stressors that are common patient-reported
triggers.155 Stress can influence gut inflammation through
various mechanisms via the hypothalamus–pituitary–
adrenal axis and the autonomic nervous system, result-
ing in the production of proinflammatory cytokines,
activation of macrophages, and alteration of intestinal
permeability and the gut microbiota.156 In mice, expo-
sure to a stressful stimulus reduced bacterial diversity and
increased levels of IL‑6.157 Interestingly, this effect on IL‑6
levels was ameliorated by antibiotics.157 Mice subjected to
intracerebroventricular injection of reserpine (mimick-
ing depression) demonstrate severe colitis, which can be
attenuated by administration of desmethyl imipraime, an
antidepressant.158 Observational studies in large cohorts
support an association between major life stressors,
anxiety and depression and increased risk of IBD.155,159–167
In those with established disease, depression or anxiety is
associated with relapse, hospitalization, surgery, reduced
responsiveness to immunosuppressive therapy and
impairment of quality of life, although it is challenging to
tease out the relative contribution of disease severity in
this bidirectional association.109,155,159–161,163,165,167–169
The association between physical activity and IBD
was supported by an interesting study by Sonnenberg
et al.170 who identified sedentary occupations (including
administration and office work, mechanics, blacksmiths
and locksmiths) as being ‘high risk’ for the development
of IBD, whereas heavy manual labour (including build-
ing and construction, cleaning and maintenance) were
associated with a low risk of IBD. In mice, forced tread-
mill exercise exacerbated inflammation and increased
proinflammatory gene expression whereas volun-
tary wheel training alleviated symptoms of colitis and
reduced inflammatory gene expression.171 Supporting
this hypothesis, a prospective cohort study demonstrated
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Table 1 | Intervention studies examining effect of environmental modifications on disease activity in IBD
Factor Population
Smoking
Smoking178 Crohn’s disease
(n = 474)
Diet—macronutrients and dietary patterns
Low microparticle Active Crohn’s
diet199 disease (n = 20)
Low microparticle Active Crohn’s
diet200 disease (n = 83)
Fish oil (Cochrane Quiescent Crohn’s
review)188 disease (n = 1,039)
Fish oil (Cochrane Quiescent ulcerative
review)201 colitis (n = 148)
Milk-free diet202 Active ulcerative
colitis (n = 77)
Fibre-rich diet203 Inactive or mildly
active Crohn’s
disease (n = 352)
Highly restricted Active Crohn’s
diet (bread and disease (n = 18)
red meat)204
Semi-vegetarian Quiescent Crohn’s
diet205 disease (n = 22)
Enteral nutrition Active Crohn’s
(Cochrane review)206 disease (n = 192)
Diet—micronutrient supplementation
Vitamin D187 Quiescent Crohn’s
disease (n = 94)
Lifestyle—stress, depression, and anxiety
Stress (Cochrane IBD (n = 1,745)
Review)191
Stress190 IBD (n = 24)
Stress207 IBD with continuous
disease activity or
relapse over previous
18 months (n = 114)
Only studies with a control group in addition to the intervention arm were included. When Cochrane reviews included most relevant studies with that
intervention, the reviews were listed in lieu of each individual study. Abbreviations: CDAI, Crohn’s disease activity index; n‑3 PUFA, omega 3 polyunsaturated
fatty acid; n‑6 PUFA, omega‑6 polyunsaturated fatty acid.
Intervention Outcome
Counselling to stop smoking Over 29 months, risk of flares, need for
steroids and immunosuppressive therapy
was lower in quitters than those who
continued smoking
Low microparticle diet or Progressive decrease in CDAI was noted with
control diet intervention diet compared to control diet
Low microparticle diet or No difference in Crohn’s disease activity
control diet between the two groups
n‑3 PUFA or placebo Slightly lower risk of relapse at 1 year with
fish oil than with placebo
n‑3 PUFA or placebo No difference in risk of relapse between n‑3
PUFA and placebo
Milk-free, low-fibre diet compared Fewer relapses on milk-free diet than on
to dummy diet dummy diet
Unrestricted sugar and low-fibre No difference in disease activity, outpatient
diet compared to no sugar and treatment, surgery or hospitalizations
high unrefined carbohydrate
Restricted diet (based on bread Radiological and endoscopic improvement in 3
and red meat) compared with of 4 patients in active group and 1 of 9 patients
control diet (low fibre, low fat, in the control group (P = 0.027); no difference in
high carbohydrate) CDAI improvement between the two groups
Semi-vegetarian diet or Remission was maintained in 94% with
omnivorous diet semi-vegetarian diet compared with 33%
with omnivorous diet
Enteral nutrition or corticosteroids Enteral nutrition was less effective than
corticosteroids in induction of remission;
no difference between elemental and
nonelemental diets (n = 334 patients)
Vitamin D3 1,200 IU daily Relapse rate was lower among patients
or placebo treated with vitamin D3 (13%) than placebo
(29%) (P = 0.06)
Psychotherapy (multimodality) No difference in quality of life, proportion
in remission or emotional status
Supportive outpatient Treated patients had fewer relapses and
psychotherapy from an outpatient attendances, steroid use
IBD counsellor and relapse-related use of IBD medications
Stress management No difference in disease activity or relapses
psychotherapy with psychotherapy; IBD-related quality of
life improved in those with ulcerative colitis

rigorous physical activity to be associated with a 44%
reduction in risk of Crohn’s disease.172 Data regarding the
beneficial effects of exercise on intestinal inflammation
or prevention of relapse are limited.
Disturbed sleep quality is common in society, but is more
frequent in patients with IBD and is associated with active
disease.173–175 This association might be bidirectional such
that whilst increased disease activity might disrupt sleep,
poor sleep quality in turn might exacerbate inflammation.
Both prolonged and reduced duration of sleep were asso-
ciated with increased risk of ulcerative colitis,176 whereas
impaired sleep quality was associated with increased
h­istological activity 177 and risk of clinical relapse.173
Modification of environmental factors
A growing trove of literature describes the effect of the
environment on incident disease and natural history. Yet,
few studies have examined whether these influences can
be modified to improve patient outcomes (Table 1). In
an elegant interventional study, counselling regarding
smoking cessation was administered to 474 patients
with Crohn’s disease who were smokers.178 Patients who

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stopped smoking for >1 year were less likely to relapse
and require steroids or immunosuppressive therapy than
those who continued smoking. By contrast, nicotine sup-
plementation in ulcerative colitis has yielded equivocal
results in clinical trials,74,179 although case reports suggest
efficacy in small series with refractory colitis.180 Given
the inverse association between appendectomy and inci-
dence of ulcerative colitis, therapeutic appendectomy for
the management of refractory ulcerative colitis has been
attempted. However, evidence is limited to a few case
reports suggesting benefit.88,181,182
Few studies have intervened with dietary modifications
and most such studies have been in the form of uncon-
trolled case series (Table 1). An elemental diet can restore
diversity of gut microbiota and has been shown to be effi-
cacious in inducing remission in paediatric IBD.183,184 The
specific carbohydrate diet has also demonstrated limited
clinical benefit in paediatric Crohn’s disease, but rigor-
ous studies are lacking.185 Self-reported adherence to a
gluten-free diet has been associated with clinical improve-
ment, although it might not influence endoscopic activ-
ity.186 Jorgensen et al.187 randomly assigned 94 patients
with quiescent Crohn’s disease to 1,200 IU of vitamin D or
placebo daily and found reduced relapse in the vitamin D
group (29% versus 13%, P = 0.06). In a small series, zinc
supplementation reduced intestinal permeability and rate
of relapse.151 In contrast to the epidemiological data sup-
porting an association between n‑3 and n‑6 PUFA intake
and IBD, randomized controlled trials of fish oil or n‑3
PUFA in patients with established Crohn’s disease have
been unsuccessful in inducing or maintaining remis-
sion,188 whereas a small study of dietary modification
to reduce n‑6:n‑3 PUFA intake in ulcerative colitis was
e­ffective in maintaining remission.189
Few intervention studies have been published that
have examined the effect of modifying stress.163,168,169
Psychological counselling was associated with reduced
relapses in some, but not all, studies.190,191 In one small
study, antidepressant use was associated with reduced
rates of relapse in the year after initiation of therapy.192 As
interventional studies are developed to evaluate the effect
of environmental modifications, be it behavioural or
dietary changes, one also needs to recognize that under-
lying host genetics could influence susceptibility to the
effect of environmental modifications. Sex and ethnic-
ity could also alter the likelihood of beneficial effect of
smoking cessation (or nicotine replacement) in IBD,68 as
might polymorphisms involved in nicotine and oxidative
free radical clearance.79 Similarly, FADS2 and CYP4F3
mutations could influence any beneficial effect of an
alteration in the n3:n6 PUFA ratio by altering plasma
levels of PUFA metabolites.134
Exposome and continuous monitoring
The term ‘exposome’ was first coined in 2005 to include
the entire life course of environmental exposures from the
perinatal period onwards,193 which could be further sub-
divided into an ‘adductome’, encompassing chemical
exposures leading to formation of DNA adducts contrib-
uting to carcinogenesis,194 and an ‘infectome’, measuring
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REVIEWS
Box 1 | Unanswered epidemiological questions in IBD
When is the environmental exposure relevant to the
pathogenesis of IBD?
■■ Early life and infancy?
■■ Recent exposure?
■■ Remote exposure?
In whom are environmental exposures important?
■■ In those who are otherwise genetically susceptible
to IBD?
■■ In those who have low genetic risk of IBD?
■■ In those with variants in metabolizing enzymes or
other pathways that makes them susceptible to an
environmental influence?
Are the environmental influences that affect
development of disease the same as those that
influence natural history?
What is the role of modifying environmental exposures
in improving patient outcomes?
■■ Prevent disease in high-risk individuals?
■■ Avoid need for existing therapies or supplement
existing agents?
■■ Induce remission in active disease?
■■ Maintain remission and prevent relapse in
quiescent disease?
lifetime exposure to infections.195 Quantification of expo-
sures encompassing various environmental factors could
be useful in patients with IBD to predict natural history
and might also be useful in those at risk (for example,
first-degree relatives). Such exposures (including peri­
natal, early life and recent exposures) could be assessed
in blood, stool or urine, each reflecting different routes of
exposure. Electronic applications and wearable devices
offer another attractive modality to monitor expo-
sure, including physical activity, sleep, diet and stress.
Biological measures such as sequencing the gut micro­
biome or quantifying epigenetic changes can supplement
these passively collected or self-reported exposures and
the genome can be used to determine susceptibility to the
effect of various exposures. One could then intervene at
the onset of environmental perturbations (for example,
increased stress, reduced sleep or change in diet) before
the development of gut inflammation and relapse.
Conclusions
IBD is a complex disease occurring at the intersection
of genetics, the environment and the gut microbiota.
Neither factor in itself is sufficient for development of
disease. Increasing incidence and emergence in previ-
ously low-risk populations provide strong evidence sup-
porting the effect of the environment for both Crohn’s
disease and ulcerative colitis. Progress in genetic and
microbiome analysis has demonstrated the key role of
the interface between the immune response and the
gut microbiota. Although a number of environmental
associations have been identified, high-quality interven-
tion studies are needed and several questions remain
un­answered (Box 1). Existing and ongoing prospective
cohorts such as the Genetics, Environmental, Microbial
(GEM) Project in Canada studying those with Crohn’s
REVIEWS

disease and their healthy siblings,196 as well as paediat- Review criteria

ric initiatives for patients with newly diagnosed Crohn’s
disease and ulcerative colitis (RISK197 and PROTECT198)
will provide important insights into the interplay between
genetics, the environment and microbiota in disease
pathogenesis, natural history and response to treatment.
Comprehensive management of patients with IBD will
need to not just resolve existing inflammation and achieve
mucosal healing, but also incorporate modification of
the external environment to aid, achieve and maintain
durable remission and improve patient outcomes.
The MEDLINE database was searched for English-
language reports using the search terms: “Crohn’s
disease”; “ulcerative colitis”; “epidemiology”;
“incidence”; “risk factors”; “smoking”; “environment”;
“diet”; “stress”; “vitamin D”; and “lifestyle”. Nearly all
the articles identified were within the past three decades,
most within the past 10 years. The reference list of
review articles identified as part of this search strategy
was further searched for relevant articles not identified
in the original search.

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Acknowledgements
A.N.A. is supported by funding from the US National
Institutes of Health (K23 DK097142).