Epidemiology and

Pathogenesis of Ulcerative
Colitis
Lillian Du, MD, Christina Ha, MD*

KEYWORDS
 Ulcerative colitis  Incidence  Prevalence  Genetics  Diet  Microbiome

KEY POINTS
 The worldwide incidence of ulcerative colitis (UC) is increasing, particularly in newly indus-
trialized countries.
 The worldwide prevalence of UC is increasing substantially due to aging of the population
and earlier UC diagnoses.
 Environmental factors may be associated with UC diagnosis, such as red meat consump-
tion, appendectomy, and smoking; however, their role after the diagnosis is made is less
clear.
 Further investigation is needed to clarify the multitude of factors contributing to UC diag-
nosis and prognosis, these may serve as potential targets for therapy or predictors of dis-
ease activity in the future.

INTRODUCTION

Ulcerative colitis (UC) is a chronic immune-mediated inflammatory disorder of the colon

(IBD) that is hypothesized to be related to exposure to environmental risk factors leading
to inappropriate immune responses to enteric commensal microbes in genetically sus-
ceptible individuals.1,2 The worldwide incidence of UC has been rising and, factoring
morbidity and mortality related to UC, health care and societal costs are substantial.
Studies have estimated that annual direct and indirect costs related to UC range from
V12.5 to V29.1 billion in Europe and $8.1 to $14.9 billion in the United States.3
UC is characterized by relapsing and remitting mucosal inflammation that classically
begins in the rectum and extends proximally through the colon in a continuous
manner. The inflammatory nature of UC, left inadequately treated, can result in contin-
uous bowel damage with increased risks of hospitalizations, surgeries, and colorectal

Inflammatory Bowel Diseases Center, Cedars-Sinai, 8730 Alden Drive Suite E204, Los Angeles,
CA, USA
* Corresponding author.
E-mail address: christina.ha@cshs.org
Twitter: @tinahamd (C.H.)

Gastroenterol Clin N Am - (2020) -–-

https://doi.org/10.1016/j.gtc.2020.07.005 gastro.theclinics.com
0889-8553/20/ª 2020 Elsevier Inc. All rights reserved.
2 Du & Ha

cancer.4,5 This review provides an introduction to the current patterns of UC inci-

dence/prevalence worldwide and a general overview of disease pathophysiology
describing how genetic and environmental influences may affect the development
and natural history of UC.

EPIDEMIOLOGY

Worldwide, the incidence of UC is on the rise with the annual incidence of UC ranging
from 8.8 to 23.1 per 100,000 person-years in North America, 0.6 to 24.3 per 100,000
person-years in Europe, and 7.3 to 17.4 in Oceania (Fig. 1).6,7 Although UC can occur
at any age, the peak incidence of UC occurs in the second to fourth decade of life with
similar incidence between men and women.6,8 Some studies have suggested a
bimodal incidence distribution with a second smaller peak occurring in the sixth to
seventh decades of life with up to 10% to 15% of new diagnoses occurring after
the age of 60 years.6,8–10
Interestingly, in the twenty-first century, studies have found the incidence of UC in
developed nations has stabilized and, in some cases, even declined. However,
despite this stabilization, the prevalence of UC has risen dramatically, potentially
due to including phenotypes with lower mortality, younger ages of onset, and no cur-
rent definable cure for the disease in an aging cohort of patients.7,8 The rising preva-
lence of UC over the past century presents ongoing challenges for health practitioners
faced with a longer duration of disease accompanied by risks of disease or treatment-
related complications including infections, thromboembolic events, and malig-
nancies.10–12 With the growing number of older-onset UC cases and an aging patient
population, the elderly (defined as persons aged 65 and older) are the fastest growing
group of patients with UC. In addition to disease-associated complications, age-

Fig. 1. Worldwide incidence of UC. (From Ng SC, Shi HY, Hamidi N, et al. Worldwide inci-
dence and prevalence of inflammatory bowel disease in the 21st century: a systematic re-
view of population-based studies. Lancet 2018;390:2769-2778.)
 Epidemiology and Pathogenesis of Ulcerative Colitis 3

associated changes in the immune system, sarcopenia, and comorbidities increase

the complexity of UC management.13,14
Although the incidence of UC has stabilized in developed nations, at the turn of the
twenty-first century, it has actually risen in many newly industrialized countries within
South America, Asia, Africa, and the Middle East. Although prevalence remains low in
these countries, it is expected to climb given the rising number of new UC diagno-
ses.15,16 The emergence of IBD in these areas strongly implicates the role of environ-
mental risk factors to the development of the disease. Previous studies have shown
that IBD tends to occur more commonly in urban (vs rural) regions.17–19 This phe-
nomenon partly explains the growing incidence of UC in these developing areas
as they experience greater urbanization, which exposes populations to considerably
different environmental factors including exposures, pollutants and lifestyle changes.
A second hypothesis that may explain the rising incidence of UC in newly industrial-
ized regions centers around the Westernization of these cultures and societies,
including changes in dietary patterns, which subsequently leads to change in the
host microbiome and adaptive immunity. As an example, in the mid to late twentieth
century as the typical Chinese diet began to resemble a Western diet, the incidence
of UC rose precipitously. In 2000, there were approximately 10,000 persons diag-
nosed with UC in China; however, by 2010, an estimated 266,394 individuals carried
a diagnosis of IBD.20

PATHOPHYSIOLOGY

The mucosa of the gastrointestinal tract is exposed to millions of antigens from the
food, environment, and microbiome.21 The outermost layer of the mucosa known as
the epithelium is covered by a thick layer of mucin, which provides the first line of de-
fense for the gut immune system, as it not only provides a physical separation be-
tween antigens and gut immune cells but also possesses antimicrobial properties.
In UC, the synthesis and secretion of mucin is impaired.22 This injury to the epithelium
leads to increased permeability of the mucosa to luminal pathogens, resulting in
increased uptake of these antigens and increased potential stimulation of the gut im-
mune system (Fig. 2).23,24 Because UC tends to be limited to only the colon’s mucosal
and submucosal layers, the colonic epithelial cells (colonocytes) are heavily implicated
in the pathogenesis of the disease. The colonocytes in UC are believed to possess
impaired expression of peroxisome proliferator-activated receptor g (PPAR g), a nu-
clear receptor that downregulates inflammation.25,26
Activation of the innate immune response by antigens occurs through antigen-
presenting cells and T cells, which stimulate an inflammatory cascade that also in-
volves activation of the adaptive immune system.21,24 With UC, there is also an
increased activation and sensitivity of mature dendritic cells, suggesting that these
cells play an important role in generating inflammation.27 These dendritic cells express
an abundance of Toll-like receptors (TLR), which use pattern recognition of pathogens
to signal activation of multiple transcription factors, such as transcription factor nu-
clear factor-kB (NF-kB), that trigger inflammatory cascades.28 These inflammatory
cascades result in production of proinflammatory cytokines notably tumor necrosis
factor alpha (TNF-a), interleukins (IL) 12 and 23.21,24 One of the important functions
of these proinflammatory cytokines is the transduction of messages through intracel-
lular proteins, such as Janus kinases (JAK), which further potentiate lymphocyte acti-
vation and proliferation.29,30 These proinflammatory cytokines and intracellular
proteins are the targets of many of our currently available treatments for moderate
to severe UC including the monoclonal antibodies to TNF-a and IL-12/23 receptors.
4 Du & Ha

Fig. 2. Pathophysiology of UC. (From Ordas I, Eckmann L, Talamini M, et al. Ulcerative colitis.
Lancet 2012;380:1606-19.)

UC is also characterized by a dysregulation of the adaptive immune system with an

imbalance between regulatory T cells and effector T cells, particularly effector T-helper
(Th) 2 cells. The Th2 response activates natural killer T cells in the colon, which secrete
a number of cytokines following stimulation, including IL-13, which induces apoptosis
of epithelial cells and interrupts tight junctions.23,31 Circulating leukocytes are also
recruited to the inflamed mucosa, further potentiating the inflammatory response.
This effect is largely mediated by cytokines, which stimulate expression of adhesion
molecules on the vascular endothelium of blood vessels, thereby promoting leukocyte
adhesion and extravasation into the tissue.32 One important example of this phenom-
enon is the interaction between a4b and mucosal addressin cellular adhesion
molecule-1 (MadCAM-1), which is critical for lymphocyte trafficking to the gut and a
target for vedolizumab, an important treatment for UC.32,33

GENETICS

Although only 8% to 14% of patients with UC have a family history of IBD, first-
degree relatives of persons diagnosed with UC have 4 times the risk of developing
UC themselves and monozygotic twins have concordance rates of 6% to
13%.5,34,35 The risk of developing UC is also 3 to 5 times higher in the Ashkenazi
Jewish population compared with other ethnic groups.5,36 These statistics support
a genetic component to the disease; however, separating environmental from ge-
netic factors remains a challenge, as most patients diagnosed with UC will have
no family history of IBD.
Much of the information relating to genetics in IBD has been obtained from genome-
wide association studies (GWAS) using genome-wide single nucleotide polymorphism
chips based on the idea that the disease is inherited in a polygenic fashion. In other
 Epidemiology and Pathogenesis of Ulcerative Colitis 5

words, it is believed that from a genetic basis, the disease is driven by multiple com-
mon genetic polymorphisms. GWAS have identified more than 200 loci associated
with IBD. Among these loci, 41 are specific to Crohn’s disease (CD), 30 are specific
to UC, and 137 are shared between both diseases.37–39 However, close to 50% of
the IBD-related loci have also been associated with other immune-mediated disease,
such as psoriasis and ankylosing spondylitis.37,40 Many of the putative genes identi-
fied are involved in different aspects of gut immunity, including gut mucosal barrier
function, autophagy, epithelial restitution, microbial defense, and regulation of adap-
tive immunity.41,42 Importantly, although many individuals carry IBD-associated risk
alleles, most never go on to develop the disease, an observation that highlights that
genetics play only a partial role in the development of IBD. Nevertheless, the identifi-
cation of genes and genetic loci that may be involved in disease development, path-
ogenesis, and natural history has allowed for further understanding of immune-
mediated pathways involved in the disease.

DIET

Several studies have examined the role that diet may play in the development of IBD.
Although there is no specific diet that is implicated to aid with UC treatment, there are
some studies that suggest an association between higher consumption and potential
increased risks of being diagnosed with UC. However, the findings must be inter-
preted with caution given the heterogeneity in presentation and severity of persons
diagnosed with UC and inherent limitations in study design, including smaller sample
sizes, recall and selection biases, and retrospective case-control design.43–45
Although fibers pass through the small intestine undigested, most are fermented
within the colon by bacterial enzymes, producing short-chain fatty acids (SCFAs)
that can be used as energy and carbon sources by the colonic mucosa. It has been
hypothesized that specific fibers reduce bacterial adherence and translocation, and
decreased dietary fiber leads to increased bacterial consumption of protective colonic
mucous, thereby increasing the risk of inflammatory changes.46–48 Although there
have been studies suggesting that higher fiber intake reduces the risk for CD, consis-
tent similar results have not been found in UC.49–53
There are some published data suggesting that dietary red meat exacerbates
dextran sodium sulfate–induced colitis in mice; however, supporting data in human
studies are weaker.54 In a systematic review, 5 of 7 studies (however, only 2 demon-
strating statistical significance) found a positive relationship between red meat intake
and incidence of UC. Three of 4 studies found that increased seafood and fish con-
sumption was associated with an increased risk of UC, with 1 study demonstrating
statistical significance.55
Fat consumption, particularly trans-unsaturated fats and n-6 fatty acids, has been
positively associated with the development of UC.56,57 Conversely, a diet high in
n-3 fatty acids has been associated with a decreased risk of development of UC.58
Increased consumption of artificial sweeteners over the past several years has
mirrored rising incidences of IBD.59 Two case-control studies have found a positive
association between added sweeteners and sugars and the development of UC.60,61
Breastmilk is frequently one of the earliest diets provided to infants. Studies have
found that breastfeeding may have an impact on the subsequent development of
immune-mediated diseases by maintaining the integrity of the epithelial barrier, pre-
venting infections, and also providing direct immunologic benefits.62–64 A meta-
analysis of 35 studies found an inverse relationship between breastfeeding and the
risk of subsequent development of UC.65
6 Du & Ha

MICROBIOME

The human gut microbiota makes up the largest collection of microbes within the
body, containing more than 35,000 bacterial species.66,67 In recent years, significant
advances in DNA sequencing and other technologies have provided avenues to better
characterize the gut microbiome leading to the discovery that the composition of the
gut microbiome in a patient with UC is dramatically different from an unaffected pa-
tient.68 Early gut microbial colonization is integral to the development of the immune
system and intestinal homeostasis, providing a synergistic relationship between
defensive and tolerant mechanisms.69 Patients with UC have disturbances in the
composition of their gut microbiota, coined “microbial dysbiosis,” with a reduction
in bacterial diversity with lower proportions of Firmicutes (phylum) and Bacteroides
(genus) and higher proportions of Enterobacteriaceae (family).70–73
Studies have also found decreased loads of Clostridia and Bacteroides in UC. These
bacteria produce SCFAs, such as butyrate, which serve as an energy source for
colonic cells and also possess anti-inflammatory properties. It has therefore been
postulated that decreased SCFAs can result in increased inflammatory responses
and epithelial nutrient deficiency.74 The question remains whether dysbiosis in UC is
a primary or secondary phenomenon. Dissimilar to their role in CD, antibiotics have
no clinical effect in UC, an observation that argues against the importance of bacteria
in the pathogenesis of UC.75 Furthermore, unlike the broad range of autoantibodies
against bacterial antigens that have been found to be associated with CD, to date,
perinuclear antineutrophil cytoplasmic antibody (or pANCA) is the only UC-
associated antibody.76 Finally, although literature suggests that an individual’s micro-
biota is at least partially determined by genetics, studies have also found a relationship
between dysbiosis and drugs, diet, and infections.77,78 Ongoing research into the pre-
cise role of the microbiota and the possible influence of specific organisms on the
development of UC is required.

SMOKING

Harries and colleagues79 first reported a reduced frequency of smoking in patients

with UC compared with healthy controls. Subsequently, a meta-analysis demon-
strated that, compared with nonsmokers, smoking may be protective against the
development of the disease (odds ratio [OR] 0.58, 95% confidence interval [CI]
0.45–0.75).80 However, although current smoking appears protective against UC,
smoking cessation is associated with a significant increase in incidence and disease
severity.81,82 Multiple studies have attempted to explain the association between
smoking and UC, some pointing to the effect of cigarette smoke on oxidative stress
and others suggesting a change in microbiome to be the underlying cause. Ultimately,
however, the mechanism of association remains unclear.83–87

APPENDECTOMY

Similar to the associations noted with smoking, appendectomy appears to potentially

have a protective effect for UC onset. In a cohort of 212,936 patients who underwent
appendectomy before the age of 50, the incidence of UC was substantially lower
among patients who had a history of appendicitis or mesenteric lymphadenitis
compared with those who had undergone surgery for nonspecific abdominal pain.88
A meta-analysis by Koutroubakis and Vlachonikolis89 found that appendectomy
reduced the risk of development of UC by 69% (OR 0.31, 95% CI 0.25–0.38).
 Epidemiology and Pathogenesis of Ulcerative Colitis 7

However, the exact mechanism of action of appendectomy remains uncertain and the
impact of appendectomy following UC is uncertain.

LIVING CONDITIONS AND HYGIENE

The impact of hygiene and living conditions on the risk of developing IBD has long
been debated. One hypothesis is that these exposures early on in childhood stimulate
diversity of the microbiome and maturation of the gut immunity.36,90 An umbrella re-
view of meta-analyses found that living near farm animals, bed sharing, having access
to a personal toilet, having access to hot water, and having pets were protective
against UC.91

MEDICATIONS

It is believed that the use of antibiotics alters the gut microbiome, which may have a
role in the pathogenesis of UC. The microbiome is the most unstable during childhood,
and disturbances to the microbiota in the earliest years of life may alter gut immunity
and therefore susceptibility to IBD.36,92 A Canadian nested case-control study found
that 58% of pediatric patients with IBD had received antibiotics in the first year of life,
compared with 39% of the healthy controls. The study also found a dose-response
relationship between the number of courses of antibiotics and the magnitude of
increased risk of development of UC.93 Although the results of these studies are sig-
nificant, other studies have failed to establish a relationship between the use of anti-
biotics and the risk of UC.94,95
In addition to antibiotic use, it has been widely speculated that the use of nonste-
roidal anti-inflammatory drugs (NSAIDs) increases the risk of UC. Several studies
have demonstrated a positive association between NSAID use and IBD onset
including a study of 76,796 patients reporting an increased risk of UC among those
who used NSAIDs for at least 15 days each month.94,96,97 However, subsequent pro-
spective studies have not found a clear association between NSAID use and incidence
of UC, although a positive association between NSAID use and CD remained.97,98
Last, several studies have suggested a relationship between use of oral contracep-
tive pills (OCPs) and the development of UC. A meta-analysis of 14 studies showed an
increased risk of UC with history of OCP use with a hazard ratio of 1.28 (95% CI 1.06–
1.54).99

SUMMARY

UC is a complex disease that likely results from a complex interplay of genetic suscep-
tibility and stimulation from environmental triggers resulting in immune system dysre-
gulation leading to chronic intestinal inflammation, also known as mucosal damage.
Although our knowledge of the contribution of environmental exposures, genetics,
and the gut microbiome on disease development continues to grow, the exact mech-
anism of disease still remains unclear. With the changing global burden of UC, further
investigations are required to understand disease prevention and to identify potential
new targets for treatment or predictors of future disease burden.

DISCLOSURE

L. Du: None; C. Ha: Advisory Board/Consultant – AbbVie, Genentech, Janssen, Pfizer,

Takeda; Speakers Bureau – AbbVie, Medical Speakers Network.
8 Du & Ha

REFERENCES

1. Abraham BP, Kane S. Fecal markers: calprotectin and lactoferrin. Gastroenterol

Clin North Am 2012;41:483–95.
2. Ng SC, Bernstein CN, Vatn MH, et al. Geographical variability and environmental
risk factors in inflammatory bowel disease. Gut 2013;62:630–49.
3. Cohen RD, Yu AP, Wu EQ, et al. Systematic review: the costs of ulcerative colitis
in Western countries. Aliment Pharmacol Ther 2010;31:693–707.
4. Kirsner JB. The local and systemic complications of inflammatory bowel disease.
JAMA 1979;242:1177–83.
5. Ungaro R, Mehandru S, Allen PB, et al. Ulcerative colitis. Lancet 2017;389:
1756–70.
6. Cosnes J, Gower-Rousseau C, Seksik P, et al. Epidemiology and natural history of
inflammatory bowel diseases. Gastroenterology 2011;140:1785–94.
7. Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflam-
matory bowel disease in the 21st century: a systematic review of population-
based studies. Lancet 2018;390:2769–78.
8. Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of
the inflammatory bowel diseases with time, based on systematic review. Gastro-
enterology 2012;142:46–54.e42 [quiz: e30].
9. Loftus EV Jr. Clinical epidemiology of inflammatory bowel disease: Incidence,
prevalence, and environmental influences. Gastroenterology 2004;126:1504–17.
10. Charpentier C, Salleron J, Savoye G, et al. Natural history of elderly-onset inflam-
matory bowel disease: a population-based cohort study. Gut 2014;63:423–32.
11. Nguyen GC, Targownik LE, Singh H, et al. The impact of inflammatory bowel dis-
ease in Canada 2018: IBD in seniors. J Can Assoc Gastroenterol 2019;2:S68–72.
12. Stepaniuk P, Bernstein CN, Targownik LE, et al. Characterization of inflammatory
bowel disease in elderly patients: a review of epidemiology, current practices and
outcomes of current management strategies. Can J Gastroenterol Hepatol 2015;
29:327–33.
13. Benchimol EI, Bernstein CN, Bitton A, et al. The impact of inflammatory bowel dis-
ease in canada 2018: a scientific report from the Canadian Gastro-intestinal
Epidemiology Consortium to Crohn’s and Colitis Canada. J Can Assoc Gastroen-
terol 2019;2:S1–5.
14. Ha CY, Katz S. Clinical implications of ageing for the management of IBD. Nat
Rev Gastroenterol Hepatol 2014;11:128–38.
15. Kaplan GG. The global burden of IBD: from 2015 to 2025. Nat Rev Gastroenterol
Hepatol 2015;12:720–7.
16. Kaplan GG, Ng SC. Understanding and preventing the global increase of inflam-
matory bowel disease. Gastroenterology 2017;152:313–321 e2.
17. Bernstein CN. Assessing environmental risk factors affecting the inflammatory
bowel diseases: a joint workshop of the Crohn’s & Colitis Foundations of Canada
and the USA. Inflamm Bowel Dis 2008;14:1139–46.
18. Ekbom A, Adami HO, Helmick CG, et al. Perinatal risk factors for inflammatory
bowel disease: a case-control study. Am J Epidemiol 1990;132:1111–9.
19. Klement E, Lysy J, Hoshen M, et al. Childhood hygiene is associated with the risk
for inflammatory bowel disease: a population-based study. Am J Gastroenterol
2008;103:1775–82.
20. Kaplan GG, Ng SC. Globalisation of inflammatory bowel disease: perspectives
from the evolution of inflammatory bowel disease in the UK and China. Lancet
Gastroenterol Hepatol 2016;1:307–16.
 Epidemiology and Pathogenesis of Ulcerative Colitis 9

21. Sands BE, Kaplan GG. The role of TNFalpha in ulcerative colitis. J Clin Pharmacol
2007;47:930–41.
22. Van Klinken BJ, Van der Wal JW, Einerhand AW, et al. Sulphation and secretion of
the predominant secretory human colonic mucin MUC2 in ulcerative colitis. Gut
1999;44:387–93.
23. Heller F, Florian P, Bojarski C, et al. Interleukin-13 is the key effector Th2 cytokine
in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell resti-
tution. Gastroenterology 2005;129:550–64.
24. Ordas I, Eckmann L, Talamini M, et al. Ulcerative colitis. Lancet 2012;380:
1606–19.
25. Dubuquoy L, Jansson EA, Deeb S, et al. Impaired expression of peroxisome
proliferator-activated receptor gamma in ulcerative colitis. Gastroenterology
2003;124:1265–76.
26. Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte
inflammatory cytokines. Nature 1998;391:82–6.
27. Hart AL, Al-Hassi HO, Rigby RJ, et al. Characteristics of intestinal dendritic cells
in inflammatory bowel diseases. Gastroenterology 2005;129:50–65.
28. Zhang FX, Kirschning CJ, Mancinelli R, et al. Bacterial lipopolysaccharide acti-
vates nuclear factor-kappaB through interleukin-1 signaling mediators in cultured
human dermal endothelial cells and mononuclear phagocytes. J Biol Chem 1999;
274:7611–4.
29. Danese S, D’Amico F, Bonovas S, et al. Positioning tofacitinib in the treatment algo-
rithm of moderate to severe ulcerative colitis. Inflamm Bowel Dis 2018;24:2106–12.
30. Danese S, Grisham M, Hodge J, et al. JAK inhibition using tofacitinib for inflam-
matory bowel disease treatment: a hub for multiple inflammatory cytokines. Am J
Physiol Gastrointest Liver Physiol 2016;310:G155–62.
31. Heller F, Fromm A, Gitter AH, et al. Epithelial apoptosis is a prominent feature of
the epithelial barrier disturbance in intestinal inflammation: effect of pro-
inflammatory interleukin-13 on epithelial cell function. Mucosal Immunol 2008;
1(Suppl 1):S58–61.
32. Briskin M, Winsor-Hines D, Shyjan A, et al. Human mucosal addressin cell adhe-
sion molecule-1 is preferentially expressed in intestinal tract and associated
lymphoid tissue. Am J Pathol 1997;151:97–110.
33. Rosario M, Dirks NL, Milch C, et al. A Review of the clinical pharmacokinetics,
pharmacodynamics, and immunogenicity of vedolizumab. Clin Pharmacokinet
2017;56:1287–301.
34. Orholm M, Binder V, Sorensen TI, et al. Concordance of inflammatory bowel dis-
ease among Danish twins. Results of a nationwide study. Scand J Gastroenterol
2000;35:1075–81.
35. Tysk C, Lindberg E, Jarnerot G, et al. Ulcerative colitis and Crohn’s disease in an
unselected population of monozygotic and dizygotic twins. A study of heritability
and the influence of smoking. Gut 1988;29:990–6.
36. Ananthakrishnan AN. Epidemiology and risk factors for IBD. Nat Rev Gastroen-
terol Hepatol 2015;12:205–17.
37. Jostins L, Ripke S, Weersma RK, et al. Host-microbe interactions have shaped
the genetic architecture of inflammatory bowel disease. Nature 2012;491:119–24.
38. Liu JZ, van Sommeren S, Huang H, et al. Association analyses identify 38 sus-
ceptibility loci for inflammatory bowel disease and highlight shared genetic risk
across populations. Nat Genet 2015;47:979–86.
39. McGovern DP, Kugathasan S, Cho JH. Genetics of inflammatory bowel diseases.
Gastroenterology 2015;149:1163–1176 e2.
10 Du & Ha

40. Hindorff LA, Sethupathy P, Junkins HA, et al. Potential etiologic and functional im-
plications of genome-wide association loci for human diseases and traits. Proc
Natl Acad Sci U S A 2009;106:9362–7.
41. Bouma G, Strober W. The immunological and genetic basis of inflammatory
bowel disease. Nat Rev Immunol 2003;3:521–33.
42. Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel
disease. Nature 2011;474:307–17.
43. Chapman-Kiddell CA, Davies PS, Gillen L, et al. Role of diet in the development of
inflammatory bowel disease. Inflamm Bowel Dis 2010;16:137–51.
44. Persson PG, Ahlbom A, Hellers G. Diet and inflammatory bowel disease: a case-
control study. Epidemiology 1992;3:47–52.
45. Tragnone A, Valpiani D, Miglio F, et al. Dietary habits as risk factors for inflamma-
tory bowel disease. Eur J Gastroenterol Hepatol 1995;7:47–51.
46. Desai MS, Seekatz AM, Koropatkin NM, et al. A dietary fiber-deprived gut micro-
biota degrades the colonic mucus barrier and enhances pathogen susceptibility.
Cell 2016;167:1339–1353 e21.
47. Gill PA, van Zelm MC, Muir JG, et al. Review article: short chain fatty acids as po-
tential therapeutic agents in human gastrointestinal and inflammatory disorders.
Aliment Pharmacol Ther 2018;48:15–34.
48. Roberts CL, Keita AV, Duncan SH, et al. Translocation of Crohn’s disease Escher-
ichia coli across M-cells: contrasting effects of soluble plant fibres and emulsi-
fiers. Gut 2010;59:1331–9.
49. Ananthakrishnan AN, Khalili H, Konijeti GG, et al. A prospective study of long-
term intake of dietary fiber and risk of Crohn’s disease and ulcerative colitis.
Gastroenterology 2013;145:970–7.
50. Andersen V, Chan S, Luben R, et al. Fibre intake and the development of inflam-
matory bowel disease: A European prospective multi-centre cohort study (EPIC-
IBD). J Crohns Colitis 2018;12:129–36.
51. Brotherton CS, Martin CA, Long MD, et al. Avoidance of fiber is associated with
greater risk of Crohn’s disease flare in a 6-month period. Clin Gastroenterol Hep-
atol 2016;14:1130–6.
52. D’Souza S, Levy E, Mack D, et al. Dietary patterns and risk for Crohn’s disease in
children. Inflamm Bowel Dis 2008;14:367–73.
53. Thornton JR, Emmett PM, Heaton KW. Diet and Crohn’s disease: characteristics
of the pre-illness diet. Br Med J 1979;2:762–4.
54. Le Leu RK, Young GP, Hu Y, et al. Dietary red meat aggravates dextran sulfate
sodium-induced colitis in mice whereas resistant starch attenuates inflammation.
Dig Dis Sci 2013;58:3475–82.
55. Hou JK, Abraham B, El-Serag H. Dietary intake and risk of developing inflamma-
tory bowel disease: a systematic review of the literature. Am J Gastroenterol
2011;106:563–73.
56. Ananthakrishnan AN, Khalili H, Konijeti GG, et al. Long-term intake of dietary fat
and risk of ulcerative colitis and Crohn’s disease. Gut 2014;63:776–84.
57. Hart AR, Luben R, Olsen A, et al. Diet in the aetiology of ulcerative colitis: a Eu-
ropean prospective cohort study. Digestion 2008;77:57–64.
58. IBD in EPIC Study Investigators, Tjonneland A, Overvad K, Bergmann MM, et al.
Linoleic acid, a dietary n-6 polyunsaturated fatty acid, and the aetiology of ulcer-
ative colitis: a nested case-control study within a European prospective cohort
study. Gut 2009;58:1606–11.
59. Qin X. Etiology of inflammatory bowel disease: a unified hypothesis. World J Gas-
troenterol 2012;18:1708–22.
 Epidemiology and Pathogenesis of Ulcerative Colitis 11

60. Hansen TS, Jess T, Vind I, et al. Environmental factors in inflammatory bowel dis-
ease: a case-control study based on a Danish inception cohort. J Crohns Colitis
2011;5:577–84.
61. Racine A, Carbonnel F, Chan SS, et al. Dietary patterns and risk of inflammatory
bowel disease in Europe: results from the EPIC Study. Inflamm Bowel Dis 2016;
22:345–54.
62. Parigi SM, Eldh M, Larssen P, et al. Breast milk and solid food shaping intestinal
immunity. Front Immunol 2015;6:415.
63. Renz H, Brandtzaeg P, Hornef M. The impact of perinatal immune development on
mucosal homeostasis and chronic inflammation. Nat Rev Immunol 2011;12:9–23.
64. Rogier EW, Frantz AL, Bruno ME, et al. Lessons from mother: long-term impact of
antibodies in breast milk on the gut microbiota and intestinal immune system of
breastfed offspring. Gut Microbes 2014;5:663–8.
65. Xu L, Lochhead P, Ko Y, et al. Systematic review with meta-analysis: breastfeed-
ing and the risk of Crohn’s disease and ulcerative colitis. Aliment Pharmacol Ther
2017;46:780–9.
66. Dave M, Higgins PD, Middha S, et al. The human gut microbiome: current knowl-
edge, challenges, and future directions. Transl Res 2012;160:246–57.
67. Jandhyala SM, Talukdar R, Subramanyam C, et al. Role of the normal gut micro-
biota. World J Gastroenterol 2015;21:8787–803.
68. Frank DN, St Amand AL, Feldman RA, et al. Molecular-phylogenetic characteriza-
tion of microbial community imbalances in human inflammatory bowel diseases.
Proc Natl Acad Sci U S A 2007;104:13780–5.
69. Lathrop SK, Bloom SM, Rao SM, et al. Peripheral education of the immune system
by colonic commensal microbiota. Nature 2011;478:250–4.
70. Brown K, DeCoffe D, Molcan E, et al. Diet-induced dysbiosis of the intestinal mi-
crobiota and the effects on immunity and disease. Nutrients 2012;4:1095–119.
71. Morgan XC, Tickle TL, Sokol H, et al. Dysfunction of the intestinal microbiome in
inflammatory bowel disease and treatment. Genome Biol 2012;13:R79.
72. Nagalingam NA, Lynch SV. Role of the microbiota in inflammatory bowel dis-
eases. Inflamm Bowel Dis 2012;18:968–84.
73. Spor A, Koren O, Ley R. Unravelling the effects of the environment and host ge-
notype on the gut microbiome. Nat Rev Microbiol 2011;9:279–90.
74. Derikx LA, Dieleman LA, Hoentjen F. Probiotics and prebiotics in ulcerative colitis.
Best Pract Res Clin Gastroenterol 2016;30:55–71.
75. Prantera C. What role do antibiotics have in the treatment of IBD? Nat Clin Pract
Gastroenterol Hepatol 2008;5:670–1.
76. Seibold F, Brandwein S, Simpson S, et al. pANCA represents a cross-reactivity to
enteric bacterial antigens. J Clin Immunol 1998;18:153–60.
77. Bernstein CN, Shanahan F. Disorders of a modern lifestyle: reconciling the epide-
miology of inflammatory bowel diseases. Gut 2008;57:1185–91.
78. Rausch P, Rehman A, Kunzel S, et al. Colonic mucosa-associated microbiota is
influenced by an interaction of Crohn disease and FUT2 (Secretor) genotype.
Proc Natl Acad Sci U S A 2011;108:19030–5.
79. Harries AD, Baird A, Rhodes J. Non-smoking: a feature of ulcerative colitis. Br
Med J 1982;284:706.
80. Mahid SS, Minor KS, Soto RE, et al. Smoking and inflammatory bowel disease: a
meta-analysis. Mayo Clin Proc 2006;81:1462–71.
81. Beaugerie L, Massot N, Carbonnel F, et al. Impact of cessation of smoking on the
course of ulcerative colitis. Am J Gastroenterol 2001;96:2113–6.
12 Du & Ha

82. Higuchi LM, Khalili H, Chan AT, et al. A prospective study of cigarette smoking
and the risk of inflammatory bowel disease in women. Am J Gastroenterol
2012;107:1399–406.
83. Ananthakrishnan AN, Nguyen DD, Sauk J, et al. Genetic polymorphisms in
metabolizing enzymes modifying the association between smoking and inflam-
matory bowel diseases. Inflamm Bowel Dis 2014;20:783–9.
84. Bergeron V, Grondin V, Rajca S, et al. Current smoking differentially affects blood
mononuclear cells from patients with Crohn’s disease and ulcerative colitis: rele-
vance to its adverse role in the disease. Inflamm Bowel Dis 2012;18:1101–11.
85. Biedermann L, Brulisauer K, Zeitz J, et al. Smoking cessation alters intestinal mi-
crobiota: insights from quantitative investigations on human fecal samples using
FISH. Inflamm Bowel Dis 2014;20:1496–501.
86. Munyaka PM, Khafipour E, Ghia JE. External influence of early childhood estab-
lishment of gut microbiota and subsequent health implications. Front Pediatr
2014;2:109.
87. Parkes GC, Whelan K, Lindsay JO. Smoking in inflammatory bowel disease:
impact on disease course and insights into the aetiology of its effect. J Crohns
Colitis 2014;8:717–25.
88. Andersson RE, Olaison G, Tysk C, et al. Appendectomy and protection against
ulcerative colitis. N Engl J Med 2001;344:808–14.
89. Koutroubakis IE, Vlachonikolis IG. Appendectomy and the development of ulcer-
ative colitis: results of a metaanalysis of published case-control studies. Am J
Gastroenterol 2000;95:171–6.
90. Kostic AD, Xavier RJ, Gevers D. The microbiome in inflammatory bowel disease:
current status and the future ahead. Gastroenterology 2014;146:1489–99.
91. Piovani D, Danese S, Peyrin-Biroulet L, et al. Environmental risk factors for inflam-
matory bowel diseases: an umbrella review of meta-analyses. Gastroenterology
2019;157:647–659 e4.
92. Penders J, Thijs C, Vink C, et al. Factors influencing the composition of the intes-
tinal microbiota in early infancy. Pediatrics 2006;118:511–21.
93. Shaw SY, Blanchard JF, Bernstein CN. Association between the use of antibiotics
in the first year of life and pediatric inflammatory bowel disease. Am J Gastroen-
terol 2010;105:2687–92.
94. Meyer AM, Ramzan NN, Heigh RI, et al. Relapse of inflammatory bowel disease
associated with use of nonsteroidal anti-inflammatory drugs. Dig Dis Sci 2006;51:
168–72.
95. Ungaro R, Bernstein CN, Gearry R, et al. Antibiotics associated with increased
risk of new-onset Crohn’s disease but not ulcerative colitis: a meta-analysis.
Am J Gastroenterol 2014;109:1728–38.
96. Felder JB, Korelitz BI, Rajapakse R, et al. Effects of nonsteroidal antiinflammatory
drugs on inflammatory bowel disease: a case-control study. Am J Gastroenterol
2000;95:1949–54.
97. Ananthakrishnan AN, Higuchi LM, Huang ES, et al. Aspirin, nonsteroidal anti-
inflammatory drug use, and risk for Crohn disease and ulcerative colitis: a cohort
study. Ann Intern Med 2012;156:350–9.
98. Chan SS, Luben R, Bergmann MM, et al. Aspirin in the aetiology of Crohn’s dis-
ease and ulcerative colitis: a European prospective cohort study. Aliment Phar-
macol Ther 2011;34:649–55.
99. Cornish JA, Tan E, Simillis C, et al. The risk of oral contraceptives in the etiology of
inflammatory bowel disease: a meta-analysis. Am J Gastroenterol 2008;103:
2394–400.