Original Article

The association between Helicobacter pylori

infection and inflammatory bowel disease based
on meta-analysis

United European Gastroenterology Journal

2015, Vol. 3(6) 539550
! Author(s) 2015
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DOI: 10.1177/2050640615580889
ueg.sagepub.com

T Rokkas1, JP Gisbert2, Y Niv3 and C OMorain4

Abstract
Background: In humans there are epidemiological data suggesting a protective effect of Helicobacter pylori (H. pylori)
infection against the development of autoimmune diseases and in addition, there are laboratory data illustrating H. pyloris
ability to induce immune tolerance and limit inflammatory responses. Thus, numerous observational studies have examined
the association between H. pylori infection and inflammatory bowel disease (IBD) with various results.
Objective: We performed a meta-analysis of available studies to better define the association of H. pylori infection and IBD.
Methods: Medical literature searches for human studies were performed through September 2014, using suitable keywords.
In each study the risk ratio (RR) of H. pylori infection in IBD patients vs controls was calculated and pooled estimates were
obtained using fixed- or random-effects models as appropriate. Heterogeneity between studies was evaluated using
Cochran Q test and I2 statistics, whereas the likelihood of publication bias was assessed by constructing funnel plots.
Results: Thirty-three studies were eligible for meta-analysis, including 4400 IBD patients and 4763 controls. Overall 26.5% of
IBD patients were positive for H. pylori infection, compared to 44.7% of individuals in the control group. There was
significant heterogeneity in the included studies (Q 137.2, df (Q) 32, I2 77%, p < 0.001) and therefore the randomeffects model of meta-analysis was used. The obtained pool RR estimation was 0.62 (95% confidence interval (CI) 0.550.71,
test for overall effect Z 7.04, p < 0.001). There was no evidence of publication bias.
Conclusion: The results of this meta-analysis showed a significant negative association between H. pylori infection and IBD
that supports a possible protective benefit of H. pylori infection against the development of IBD.

Keywords
Helicobacter pylori, inflammatory bowel disease, Crohns disease, ulcerative colitis, meta-analysis
Received: 3 January 2015; accepted: 14 March 2015

Introduction
Inammatory bowel disease (IBD), including ulcerative
colitis (UC) and Crohns disease (CD), is a signicant,
growing global health burden.13 In recent decades,
many developing countries have seen a dramatic rise in
the incidence of IBD.24 It is speculated that improved
access to a cleaner environment and the resulting
decreased incidence of common childhood infections
may be contributing to this rise by altering susceptibility
to certain diseases with an autoimmune component, such
as IBD.5,6 Thus, according to this speculation, microbial
infections during childhood may protect from IBD.
Helicobacter pylori is a bacterium that causes
chronic gastritis and consequently mainly peptic ulcer
disease and to a less extent, mucosa-associated lymphoid tissue (MALT) lymphoma and gastric cancer in

infected individuals.7,8 The inammatory response of

the gastric mucosa is mainly attributed to the stimulation of the hosts immune system caused by the bacterium. This results in a T helper type 1 (Th1) response
1

Gastroenterology Clinic, Henry Dunant Hospital Center, Athens, Greece

Gastroenterology Unit, La Princesa University Hospital, Instituto de
Investigacion Sanitaria Princesa (IIS-IP), Centro de Investigacion
Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD),
Madrid, Spain
3
Department of Gastroenterology, Rabin Medical Center, Tel Aviv University,
Tel Aviv, Israel
4
Department of Gastroenterology, Meath/Adelaide Hospital, Dublin, Ireland
2

Corresponding author:
Theodore Rokkas, Gastroenterology Clinic, Henry Dunant Hospital Center,
107 Messogion Ave., Athens 11526, Greece.
Email: sakkor@otenet.gr

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540

United European Gastroenterology Journal 3(6)

and elevated levels of Th1 cytokines.911 As a consequence, products of the local immune reactions may
migrate to extra-gastric sites and this may explain the
link between H. pylori infection and a variety of extragastric diseases, including autoimmune disorders.12,13
However, epidemiological data exist that suggest a
protective eect of H. pylori infection against the development of some diseases with an autoimmune component, such as asthma, most probably by H. pyloris
ability to induce immune tolerance and limit inammatory responses.14,15 The mechanism underlying this
protective role of H. pylori infection is thought to be
dierential expression of local mucosal inammatory
response, which may elicit a systemic release of cytokines, which in turn may downregulate systemic
immune responses and suppress autoimmunity.
Triggered by the above, numerous studies have
examined the association between H. pylori infection
and IBD. However, the published literature is diverse.
Thus, many studies have reported that the prevalence
of H. pylori infection is lower in patients with IBD
compared to controls, whereas this has not been conrmed by other studies. This prompted us to further
investigate this association by performing a metaanalysis in which we pooled the results of all existing
relevant studies.

Selection criteria

Methods
Identification of studies and data extraction

Statistical analysis

We searched the PubMed, MEDLINE and Embase

databases through September 2014 to identify all relevant English-language medical literature for human
studies using the following key words or Medical
Subject Headings (MeSH) terms: Helicobacter pylori
AND (inammatory bowel disease OR ulcerative colitis
OR Crohns disease). In detail, the following search
items were used: (helicobacter pylori (MeSH
Terms) OR (helicobacter (All Fields) AND
pylori (All Fields)) OR (helicobacter pylori (All
Fields) OR (h pylori (All Fields)) AND ((inammatory bowel diseases (MeSH Terms) OR (inammatory (All Fields) AND bowel (All Fields) AND
diseases (All Fields)) OR inammatory bowel diseases (All Fields) OR (inammatory (All Fields)
AND bowel (All Fields) AND disease (All
Fields))
OR
inammatory
bowel
disease
(All Fields)) OR (colitis, ulcerative (MeSH Terms)
OR (colitis (All Fields) AND ulcerative (All
Fields)) OR ulcerative colitis (All Fields) OR
(ulcerative (All Fields) AND colitis (All Fields))
OR (crohn disease (MeSH Terms) OR (crohn (All
Fields) AND disease (All Fields)) OR crohn disease (All Fields) OR (crohns (All Fields) AND

disease (All Fields)) OR crohns disease

(All Fields)). In addition we performed a full manual
search of all review articles and published editorials and
retrieved original studies. Data were extracted independently from each study by two of the authors
(T.R. and J.P.G) by using a predened form, and disagreements were resolved by discussion with a third
investigator and consensus. The work was conducted
in accordance with the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA)
statement.16

Inclusion and exclusion criteria were dened before

the commencement of the literature search; thus, eligible studies were included in this meta-analysis if they
met all the following criteria: (1) published as full article, (2) include data for retrieval on the association
between H. pylori infection and IBD and (3) H. pylori
infection was conrmed by serology and/or histology
and/or urea breath test (UBT) and/or rapid urea test
(RUT) and/or culture. Studies that did not meet the
aforementioned criteria and duplicate publications
were excluded. When two papers reported the same
study, the publication that was more informative was
selected.

The risk ratio (RR, 95 % condence intervals (CIs))

was used to describe the ratio of the probability of
the H. pylori infection occurring in IBD patients vs
the controls. Thus in each study the RR of H. pylori
infection in IBD patients vs controls was calculated and
then pooled estimates were obtained using the
xed-model (Mantel and Haenszel) method,17 unless
signicant heterogeneity was present or if the design
of the studies was considered to be dierent enough,
in which case the random-eects model was applied
(DerSimonian and Laird method18). Heterogeneity
between studies was evaluated with the Cochran
Q-test19 and it was considered to be present if the Qtest provided a p value of less than 0.10.20 In addition I2
statistic was used to measure the proportion of inconsistency in individual studies that could not be
explained by chance, with I2 > 50% representing
substantial heterogeneity.21 We also performed a cumulative meta-analysis to examine whether the association
between H. pylori and IBD changed over time.22 Forest
plots were constructed for visual display of individual
study RR. Data, in various formats, i.e. as dichotomous (number of events) or computed eect sizes,
were meta-analyzed by choosing the most suitable
data entry option for the meta-analysis software used

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Rokkas et al.

541

(Comprehensive Meta-Analysis, version 2; Biostat Inc,

Englewood, NJ, USA).

Sensitivity analyses/publication bias

In the presence of signicant statistical heterogeneity,
apart from the random-eects model, we performed
sensitivity analyses to evaluate the consistency of our
results. Firstly, to evaluate any possible excessive inuence of a single study, we examined whether the exclusion of this study substantially altered the magnitude or
heterogeneity of the summary estimate. This was
achieved by repeating the meta-analyses with exclusion
of each individual study one at a time, to assess the
overall eect of the exclusion on the pooled RRs.22
Secondly, as dierent study designs and populations
may incorporate dierent biases, we performed subgroup analyses, stratifying by factors that could potentially inuence the results. These factors were
established a priori to the analysis. Where needed, we
further explored heterogeneity by performing metaregression analyses (method of moments).23 The likelihood of publication bias was assessed by constructing
funnel plots, which were obtained by plotting the log
RRs vs SE of individual studies.24 Their symmetry was
estimated by Eggers regression test and the Begg and
Mazumdar adjusted rank correlation test,25,26 whereas
the adjustment for publication bias, i.e. calculation of
the number of studies missing from the meta-analysis,

was estimated using Duval and Tweedies nonparametric trim and ll rank-based method.27

Results
Descriptive assessment and study characteristics
A owchart describing the process of study selection is
shown in Figure 1. Out of 468 titles initially generated
by the literature searches, 33 studies, from various
countries, remained eligible for meta-analysis.2860
Some studies contained separate data on UC and CD
and therefore in the 33 meta-analyzed studies there
were in total 50 sets of data (22 on UC and 28 on
CD) comparing H. pylori infection in patients and controls. The main characteristics of the papers eligible for
meta-analysis are shown in Table 1. They were conducted in dierent parts of the world and contained a
total of 4400 IBD patients and 4763 controls.

H. pylori prevalence in IBD patients vs controls

In the 33 eligible for meta-analysis studies, in the IBD
group, overall 1168/4400 patients were positive for
H. pylori infection (26.5%, 95% CI (25.227.8)), compared to 44.7% (43.346.1) of individuals in the control
group (2129/4763). There was signicant heterogeneity
in the included studies (Q 137.2, degree of freedom
(df) (Q) 32, I2 77%, p < 0.001) and therefore the

468 potentially eligible studies

initially generated by the
literature searches
376 rejected (title suggested
article not appropriate)
92 abstracts retrieved
55 excluded
(duplications,
editorials,
review articles)
37 papers with extractable data
4 excluded as not fulfilling
the inclusion criteria
33 papers meta-analyzed
50 sets of data
(28 Crohns disease,
22 ulcerative colitis)

Figure 1. Flow diagram of the studies identified in this meta-analysis.

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1997

1998

1998

2000

2000

2001

2001

2001

2002

2002

2002

DInca35

Duggan36

Pearce37

Parente38

Matsumura39

Parlak40

Vare41

Feeney42

Furusu43

Guslandi44

1997

Oberhuber32

Wagtmans34

1997

Meining31

1997

1996

Halme30

Parente33

1995

1994

Publication/
Year

Mantzaris29

el-Omar

28

First author
(reference)

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Italy

Japan

UK

Finland

Turkey

Japan

Italy

UK

UK

Italy

Netherlands

Italy

Germany

Germany

Finland

Greece

UK

Country

Prospective
(cross-sectional)
Retrospective
(cohort)
Prospective
(cohort)
Prospective
(case control)
Prospective
(cohort)
Prospective
(cohort)
Prospective
(cohort)
Prospective
(cohort)
Prospective
(cohort)
Prospective
(case-control)
Prospective
(cohort)
Not reported
(cohort)

Prospective
(cohort)
Prospective
(cohort)
Prospective
(cohort)
Prospective
(case control)
Prospective (cohort)

Study design

Table 1. The main characteristics of the included studies

60 (60/0)

50 (25/25)

276 (139/137)

279 (94/185)

111 (45/66)

90 (90/0)

220 (141/79)

93 (42/51)

323 (110/213)

108 (67/41)

386 (386/0)

216 (123/93)

75(75/0)

36 (36/0)

200 (100/100)

90 (0/90)

110 (63/47)

IBD pts (n)

(CD/UC)

30 (Irritable bowel syndrome)

25 (patients without IBD)

276 (Outpatient controls)

77 (Patients with non-organic

dyspepsia)
70 (Healthy individuals)

525 (Dyspeptic patients)

141(CD- and UC-free controls)

337 (Hospital patients for elective

surgery)
40 (Patients with IBS)

43 (Non-IBD patients)

277 (Blood donors)

200 (Crohns disease-free

controls)
216 (Blood donors)

100 (Patients with acute bacterial

diarrhea)
36 (Healthy individuals)

100 (Hospital patients for elective

surgery)
120 (Healthy individuals)

Controls (n)
(group composition)

Not reported

Histology

Chart review/face to face

interview
Conventional clinical criteria

Not reported

Not reported

Chart review

Radiology and/or histology

Chart review

Chart review

Chart review

Chart review

Histology

Histology

Not reported

Not reported

Chart review

IBD diagnosis

(continued)

Serology,
histology
Serology

Serology

Serology

Histology

Histology

UBT, histology

Serology, UBT

Serology

Histology

Serology

Serology

Histology

Histology

Serology

Serology/RUT

Serology

H.pylori
diagnostic
method

542
United European Gastroenterology Journal 3(6)

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2003

2003

2003

2004

2004

2006

2007

2008
2009

2009

2010

2010

2010

2011

2013

2013

Pascasio45

Piodi46

Triantafillidis47

Oliveira48

Pronai49

Oliveira50

Sladek51

Ando52
Lidar53

Song54

Garza-Gonzalez55

Pellicano56

Varas-Lorenzo57

Zhang58

Jin59

Xiang60
China

China

China

Spain

Italy

Mexico

Korea

Japan
Israel

Poland

Brazil

Italy

Brazil

Greece

Italy

US

Country

Prospective
(cohort)
Prospective
(cohort)

Retrospective
(cohort)
Prospective
(cohort)
Prospective
(cohort)
Prospective
(cohort)
Prospective
(cohort)
Prospective
(cohort)
Not reported
(cohort)
Prospective (cohort)
Prospective
(cohort)
Prospective
(case control)
Prospective
(cohort)
Prospective
(case-control)
Prospective
(cohort)
Prospective
(case-control)

Study design

229 (229/0)

153 (0/153)

208 (104/104)

60 (30/30)

20 (12/8)

44 (21/23)

316 (147/169)

38 (38/0)
119 (80/39)

94 (50/44)

43 (43/0)

133 (51/82)

42 (0/42)

116 (39/77)

72 (30/42)

56 (56/0)

IBD pts (n)

(CD/UC)

248 (Non-CD patients)

121 (Non-UC patients)

416 (Healthy individuals)

29 (Patients with idiopathic

constipation)
20 (Non-IBD patients)

75 (Non-IBD patients)

316 (Non-IBD patients)

12 (Healthy individuals)
98 (Non-IBD patients)

194 (Non-IBD patients)

74 (Non-IBD patients)

200 (Non-IBD patients)

74 (Non-IBD patients)

127 (Healthy controls)

72 (Non-CD patients)

382 (Non-CD patients)

Controls (n)
(group composition)

Clinical presentation, endoscopic, histological, radiological findings

Endoscopic, histological,
findings
Endoscopy manifestation and
biopsy, as adopted by AsiaPacific consensus

Chart review

Not reported

Chart review/personal
interview
Not reported

Not reported
Not reported

Clinical criteria/histology

Histology

Histology

Histology

Chart review

Chart review

Histology

IBD diagnosis

UBT, culture,
histology

UBT

UBT

UBT

UBT, histology

Serology

UBT

UBT
Serology

RUT, histology

UBT

UBT

Serology, UBT

Serology

UBT

Histology

H.pylori
diagnostic
method

IBD: inflammatory bowel disease; IBS: irritable bowel syndrome; CD: Crohns disease; UC: ulcerative colitis; UBT: urea breath test; RUT: rapid urea test; UK: United Kingdom; US: United States.

Publication/
Year

First author
(reference)

Table 1. Continued

Rokkas et al.
543

544

United European Gastroenterology Journal 3(6)

(a)

(b)

Parlak 2001
Vare 2001
Feeney 2002
Furusu 2002
Guslandi 2002
Pascasio 2003

Piodi 2003
Triantafillidis 2003
Oliveira 2004
Pronai 2004
Oliveira 2006
Sladek 2007
Ando 2008
Lidar 2009
Song 2009
GarzaGonzalez 2010
Pellicano 2010
VarasLorenzo 2010
Zhang 2011
Jin 2013
Xianq 2013

Risk
ratio

Lower
limit

Upper
limit

ZValue

p Value

0.42
0.57
0.35
0.23
0.87
0.80
0.34
0.73
0.95
0.76
0.69
0.41
1.02
0.66
0.60
0.58
0.41
0.70
0.77
0.58
1.02
0.33
0.73
0.25
0.19
0.66
0.48
1.07
1.00
1.08
0.40
0.98
0.56
0.62

0.28
0.40
0.24
0.07
0.59
0.67
0.25
0.45
0.73
0.60
0.34
0.26
0.82
0.45
0.35
0.33
0.19
0.47
0.57
0.42
0.71
0.20
0.52
0.13
0.05
0.46
0.39
0.75
0.60
0.59
0.30
0.69
0.44
0.55

0.63
0.82
0.52
0.74
1.26
0.96
0.47
1.17
1.23
0.96
1.38
0.67
1.27
0.95
1.01
1.02
0.88
1.04
1.05
0.79
1.47
0.53
1.01
0.47
0.68
0.96
0.60
1.55
1.66
1.99
0.54
1.41
0.72
0.71

4.25
3.06
5.22
2.46
0.75
2.39
6.71
1.32
0.42
2.31
1.05
3.64
0.17
2.24
1.92
1.90
2.29
1.78
1.65
3.47
0.11
4.59
1.90
4.23
2.56
2.16
6.61
0.38
0.00
0.26
6.10
0.09
4.51
7.04

0.00
0.00
0.00
0.01
0.45
0.02
0.00
0.19
0.67
0.02
0.29
0.00
0.86
0.02
0.05
0.06
0.02
0.07
0.10
0.00
0.91
0.00
0.06
0.00
0.01
0.03
0.00
0.70
1.00
0.80
0.00
0.93
0.00
0.00

Relative
weight

0.1 0.2 0.5 1

Random effects model

(%)

3.14
3.33
3.18
0.99
3.24
4.09
3.55
2.82
3.77
3.88
1.98
2.82
3.95
3.29
2.58
2.44
1.78
3.16
3.57
3.56
3.31
2.81
3.48
2.15
0.86
3.27
3.95
3.31
2.68
2.28
3.64
3.32
3.82

Favors patients

Funnel Plot of Stansard Error by Log risk ratio

0.0

0.2
Standard Error

EI Omar 1994
Mantzaris 1995
Halme 1996
Meining 1997
Oberhuber 1997
Parente 1997
Wagtmans 1997
Dlnca 1998
Duggan 1998
Parente 2000
Pearse 2000
Matsumura 2001

Pooled data

Risk ratio and 95% CI

Statistics for each study

Study name

0.4

0.6

0.8
2.0

1.5

1.0

0.5

0.0

0.5

1.0

1.5

2.0

Log risk ratio

5 10

Favors controls

Figure 2. (a) Forest plot showing individual and pooled RRs (95% CIs) in studies comparing Helicobacter pylori prevalence in IBD patients
and controls. (b) Funnel plot of all studies included in the meta-analysis. RR: risk ratio; CI: confidence interval; IBD: inflammatory bowel
disease.

random-eects model of meta-analysis was used. The

obtained pool RR estimation was 0.62 (95% CI (0.55
0.71), test for overall eect Z 7.04, p < 0.001))
(Figure 2(a)). There was no evidence of publication
bias as judged by the construction of funnel plot and
estimation of its symmetry (p 0.15, by the Eggers
regression test) (Figure 2(b)).

Subgroup analyses/sensitivity analyses

Due to signicant heterogeneity, apart from using the
random-eects model, subgroup analyses were performed. Thus, we grouped by stratifying for disease,
i.e. meta-analyzing separately 28 sets of data for CD
and 22 for UC (Figure 3). These subgroup analyses
showed signicant results for both diseases, with a
trend toward a greater eect for CD (0.38 (0.310.47),
Z 8.98, p < 0.001) when compared to UC (0.53
(0.420.67), Z 5.39, p < 0. 001). However, there
was signicant heterogeneity in the included studies
for both diseases; CD: Q 66.67, df (Q) 27,
I2 59.5%, p < 0.001 and UC: Q 55.33, df (Q) 21,
I2 62%, p < 0.001. In an attempt to further explore
the observed heterogeneity, we stratied data based
on the study design (cohort vs case control) and
H. pylori diagnosis (serology vs UBT vs histology)
(Table 2). However, none of these subgroup analyses
were able to account for the observed heterogeneity. As
dierent study designs and populations may incorporate dierent biases, except for grouping for the aforementioned diseases, study design and method of

H. pylori diagnosis, further sensitivity analyses were

performed. Thus, exclusion of any study did not considerably alter the magnitude of the summary estimate
(Figure 4(a)). In addition, the results of the cumulative
meta-analysis of studies, ordered by the year of publication (Figure 4(b)), were consistent over the years.
Finally, the meta-regression analysis evaluating the
regression of publication year on log risk ratio,
showed no signicant results (z 0.48, p 0.63)
(Figure 4(c)).

Discussion
H. pylori infection is acquired early in childhood and if
not treated is carried throughout life. Epidemiological
data show that IBD is more prevalent in areas with
lower rates of H. pylori infection and suggest a possible
protective eect of H. pylori infection against IBD and
some diseases with an autoimmune component such as
asthma.14,15,61 In parallel, there is a steady rise in the
incidence of IBD in H. pylori endemic regions that may
correspond to the beginning of anti-H. pylori therapy
for peptic ulcer disease.2
All the above piqued research interest and triggered
numerous observational studies examining the relationship between H. pylori infection and IBD. This metaanalysis pooled all data from eligible relevant studies
and showed a statistically signicant inverse relationship between H. pylori infection and IBD (both CD and
UC), which may suggest a possible protective eect of
H. pylori against the development of IBD. These results

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Rokkas et al.

Study name

EI Omar 1994
Halme 1996
Meining 1997
Oberhuber 1997
Parente 1997
Wagtmans 1997
Dlnca 1998
Duggan 1998
Parente 2000
Pearse 2000
Matsumura 2001
Parlak 2001
Vare 2001
Feeney 2002
Furusu 2002
Guslandi 2002
Pascasio 2003
Piodi 2003
Triantafillidis 2003
Pronai 2004
Oliveira 2006
Sladek 2007
Ando 2008
Song 2009
Garza-Gonzales 2010
Varas-Lorenzo 2010
Zhang 2011
Xiang 2013

545

Subgroup within study

CD
CD
CD
CD
CD
CD
CD
CD
CD
CD
CD
CD
CD
CD
CD
CD
CD
CD
CD
CD
CD
CD
CD
CD
CD
CD
CD
CD

Pooled data
EI Omar 1994
Mantzaris 1995
Halme 1996
Parente 1997
Dlnca 1998
Duggan 1998
Parente 2000
Pearse 2000
Parlak 2001
Vare 2001
Feeney 2002
Furusu 2002
Piodi 2003
Triantafillidis 2003
Oliveira 2004
Pronai 2004
Sladek 2007
Song 2009
Garza-Gonzales 2010
Varas-Lorenzo 2010
Zhang 2011
Jin 2013

Pooled data

UC
UC
UC
UC
UC
UC
UC
UC
UC
UC
UC
UC
UC
UC
UC
UC
UC
UC
UC
UC
UC
UC

Statistics for each study

Odds
ratio

Lower
limit

Upper
limit

0.16
0.19
0.16
0.92
0.48
0.25
0.61
0.38
0.49
0.41
0.30
1.27
0.25
0.28
0.52
0.30
0.55
0.72
0.32
0.25
0.44
0.26
0.12
0.19
1.16
1.50
0.23
0.40
0.38
0.34
0.39
0.28
0.89
0.63
0.40
0.87
0.83
0.94
0.73
0.86
0.29
0.47
0.42
1.04
0.22
0.08
0.42
1.15
0.87
0.28
0.98
0.53

0.07
0.09
0.04
0.52
0.31
0.17
0.27
0.21
0.30
0.13
0.17
0.58
0.11
0.12
0.17
0.11
0.31
0.31
0.15
0.11
0.20
0.11
0.02
0.12
0.44
0.48
0.14
0.27
0.31
0.17
0.22
0.15
0.54
0.25
0.25
0.50
0.31
0.47
0.41
0.44
0.09
0.21
0.23
0.49
0.11
0.02
0.29
0.45
0.27
0.17
0.58
0.42

0.39
0.38
0.63
1.61
0.75
0.37
1.36
0.68
0.80
1.31
0.53
2.77
0.54
0.68
1.61
0.85
1.01
1.67
0.70
0.58
0.97
0.60
0.62
0.31
3.05
4.72
0.40
0.59
0.47
0.67
0.69
0.53
1.45
1.57
0.66
1.51
2.19
1.85
1.31
1.67
0.98
1.03
0.75
2.22
0.45
0.32
0.63
2.92
2.78
0.47
1.64
0.67

Random effects model

Odds ratio and 95% CI

Relative
(%)
weight

Z-Value p -Value
4.00
4.62
2.63
0.29
3.19
6.87
1.21
3.25
2.88
1.50
4.09
0.59
3.53
2.80
1.13
2.27
1.94
0.76
2.86
3.22
2.05
3.12
2.53
6.72
0.30
0.69
5.33
4.65
8.98
3.10
3.22
3.87
0.47
0.99
3.61
0.50
0.39
0.19
1.05
0.46
2.00
1.88
2.93
0.11
4.16
3.50
4.29
0.29
0.24
4.89
0.09
5.39

0.00
0.00
0.01
0.77
0.00
0.00
0.22
0.00
0.00
0.13
0.00
0.56
0.00
0.01
0.26
0.02
0.05
0.45
0.00
0.00
0.04
0.00
0.01
0.00
0.76
0.49
0.00
0.00
0.00
0.00
0.00
0.00
0.64
0.32
0.00
0.62
0.70
0.85
0.30
0.65
0.05
0.06
0.00
0.92
0.00
0.00
0.00
0.77
0.81
0.00
0.93
0.00

3.02
3.81
1.75
4.50
5.10
5.41
3.35
4.41
1.94
2.16
4.41
3.46
3.49
3.05
2.27
2.57
4.34
3.22
3.47
3.20
3.48
3.19
1.31
4.96
2.76
2.24
4.66
5.45
4.69
5.31
4.89
5.84
3.54
5.84
5.46
3.26
4.69
5.30
4.78
2.49
4.12
5.24
4.27
4.47
1.91
6.47
3.44
2.62
5.73
5.66

0.1 0.2 0.5

Favors patients

2
5 10
Favors controls

Figure 3. Forest plot showing individual and pooled RRs (95% CIs) in studies (grouped by disease, i.e. CD and UC) comparing the
Helicobacter pylori prevalence in patients and controls. RR: risk ratio; CI: confidence interval; CD: Crohns disease; UC: ulcerative colitis.

conrmed an earlier study that pooled the data of studies published up to March 2009.62 In addition our
results are also in agreement with those of a recent
large study63 that examined whether the prevalence of
H. pylori is lower among IBD patients compared with
non-IBD individuals based on material from surgical
pathology and concluded that these ndings may
open new avenues to study the pathogenesis of IBD.
In attempting to explain the negative association
between H. pylori infection and IBD, the possibility
that the treatment previously given against IBD is
responsible for the lower prevalence of H. pylori infection in IBD patients remains a controversial subject.

Thus, the aspect that treatment with drugs, such as

sulfasalazine, could be responsible for H. pylori eradication and lower H. pylori prevalence in IBD patients has
been raised by some authors.28 However, others did not
support this notion as treatment with sulfasalazine or
any other medical therapy (i.e. 5-aminosalicylic acid
(5-ASA), steroids, thiopurines, antibiotics) had no inuence on H. pylori prevalence.30,36,44,54 Furthermore, it
seems that even newer therapeutic modalities, such as
anti-tumor necrosis factor (TNF) treatment, have no
inuence on H. pylori status in IBD patients.64
Nonetheless, the notion that the immunomodulatory
properties of H. pylori may confer protection against

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United European Gastroenterology Journal 3(6)

Table 2. Sub-group analyses by stratifying the data according to study design and method of Helicobacter pylori diagnosis
Heterogeneity

Study design
Case control
Cohort
H. pylori diagnosis
Histology
Serology
Urea breath test

RR (95% CI)

Z value

p value

Q value

df(Q)

I2 %

p value

0.59 (0.430.82)
0.62 (0.530.72)

3.12
6.04

0.002
<0.001

29.15
100.41

5
25

82.85
75.10

<0.001
<0.001

0.61 (0.450.83)
0.62 (0.510.76)
0.63 (0.500.79)

3.15
4.72
3.93

0.002
<0.001
<0.001

29.48
58.99
42.85

6
14
10

79.65
76.27
76.66

<0.001
<0.001
<0.001

RR: risk ratio; CI: confidence interval.

(a)

(b)

Study name

Risk ratio (95% CI)

with study removed

Statistics with study removed

Point

EI Omar 1994
Mantzaris 1995
Halme 1996
Meining 1997
Oberhuber 1997
Parente 1997
Wagtmans 1997
Dlnca 1998
Duggan 1998
Parente 2000

Pearse 2000
Matsumura 2001

Parlak 2001
Vare 2001
Feeney 2002
Furusu 2002
Guslandi 2002
Pascasio 2003
Piodi 2003
Triantafillidis 2003
Oliveira 2004
Pronai 2004
Oliveira 2006
Sladek 2007
Ando 2008
Lidar 2009
Song 2009
GarzaGonzalez 2010
Pellicano 2010
VarasLorenzo 2010
Zhang 2011
Jin 2013
Xianq 2013

0.63
0.62
0.63
0.63
0.61
0.61
0.64
0.62
0.61
0.62
0.62
0.63
0.61
0.62
0.62
0.62
0.63
0.62
0.62
0.62
0.61
0.63
0.62
0.64
0.63
0.62
0.63
0.61
0.61
0.61
0.63
0.61
0.62
0.62

Lower
limit

Upper
limit

0.55
0.54
0.56
0.55
0.54
0.53
0.56
0.54
0.54
0.54
0.54
0.55
0.54
0.54
0.54
0.54
0.55
0.54
0.54
0.54
0.54
0.56
0.54
0.56
0.55
0.54
0.55
0.53
0.54
0.54
0.55
0.54
0.54
0.55

6.78
6.81
6.80
6.90
7.05
6.89
6.87
6.95
7.17
6.88
6.96
6.79
7.39
6.87
6.89
6.89
6.86
6.91
6.94
6.78
7.21
6.79
6.91
6.82
6.91
6.88
6.74
7.27
7.14
7.16
6.80
7.17
6.73
7.04

0.72
0.71
0.72
0.72
0.74
0.71
0.73
0.71
0.70
0.71
0.71
0.72
0.70
0.71
0.71
0.71
0.72
0.71
0.71
0.71
0.70
0.72
0.71
0.72
0.72
0.71
0.72
0.73
0.70
0.70
0.72
0.70
0.72
0.71

Cumulative statistics
Point

EI Omar 1994
Mantzaris 1995
Halme 1996
Meining 1997
Oberhuber 1997
Parente 1997
Wagtmans 1997
Dlnca 1998
Duggan 1998
Parente 2000

0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00

Pearse 2000
Matsumura 2001

Parlak 2001
Vare 2001
Feeney 2002
Furusu 2002
Guslandi 2002
Pascasio 2003
Piodi 2003
Triantafillidis 2003
Oliveira 2004
Pronai 2004
Oliveira 2006
Sladek 2007
Ando 2008
Lidar 2009
Song 2009
GarzaGonzalez 2010
Pellicano 2010
VarasLorenzo 2010
Zhang 2011
Jin 2013
Xianq 2013

0.5

Favors patients

Random effects model

(c)

Study name

ZValue p Value

0.42
0.50
0.44
0.43
0.49
0.54
0.50
0.53
0.57
0.59
0.60
0.58
0.61
0.62
0.62
0.61
0.60
0.61
0.62
0.62
0.64
0.62
0.62
0.60
0.60
0.60
0.59
0.61
0.62
0.63
0.61
0.62
0.62
0.62

Lower
limit
0.28
0.37
0.33
0.32
0.34
0.39
0.36
0.39
0.43
0.46
0.47
0.46
0.49
0.50
0.50
0.51
0.50
0.51
0.53
0.53
0.54
0.53
0.54
0.52
0.51
0.52
0.51
0.53
0.54
0.54
0.53
0.54
0.55
0.55

Upper
limit
0.63
0.67
0.59
0.57
0.71
0.77
0.71
0.72
0.76
0.76
0.76
0.73
0.76
0.76
0.75
0.74
0.73
0.73
0.73
0.73
0.74
0.72
0.72
0.71
0.70
0.70
0.69
0.70
0.71
0.72
0.71
0.72
0.71
0.71

ZValue p Value
4.25
4.55
5.60
5.93
3.72
3.48
3.94
4.08
3.85
4.15
4.28
4.68
4.34
4.59
4.81
5.02
5.26
5.45
5.60
5.93
5.74
6.01
6.18
6.41
6.55
6.74
7.07
6.82
6.72
6.60
6.85
6.73
7.04
7.04

Cumulative risk ratio

(95% CI)

3.14
6.48
9.66
10.65
13.89
17.98
21.53
24.34
28.12
31.99
33.97
36.79
40.74
44.03
46.63
49.05
50.83
54.00
57.57
61.13
64.44
67.25
70.72
72.87
73.73
77.01
80.96
84.26
86.94
89.22
92.86
96.18
100.00

0.1 0.2 0.5 1

Favors patients

Random effects model

Favors controls

Relative
(%)
weight

0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00

5 10

Favors controls

0.10
0.11

Log risk ratio

0.32
0.53
0.74
0.95
1.16
1.37
1.58
1.79
2.00
1992

1994

1996

1998

2001

2003

2005

2008

2010

2012

2014

Publication Year

Figure 4. (a) Exclusion sensitivity plot showing the effect of exclusion of any study on the magnitude of the summary estimate. (b)
Cumulative meta-analysis of studies ordered by year of publication. (c) Meta-regression analysis showing regression of publication year
on log risk ratio. Circles represent each study in the meta-analysis, and the size of the circle is proportional to study weighting.

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Rokkas et al.

547

allergic and chronic inammatory disorders has been

addressed and recently reviewed.65,66 Toward this
notion there is laboratory evidence illustrating
H. pyloris role in the regulation of the immune
system. Thus, a proposed model of H. pyloris eect
on host immune regulation is that H. pylori, through
its interaction with dendritic cells (DCs), is able to upregulate regulatory T-cells leading to decreased production of proinammatory cytokines. In more detail, H.
pylori has been associated with increased gastric mucosal expression of Foxp3 (a T-regulatory cell marker)
altering the host immunologic response away from
the
inammatory
Th1/Th17
pathway.6771
Furthermore, in mice evidence has emerged proving
protective eects of H. pylori infection against
Salmonella typhimurium-induced colitis.72 Thus in coinfection with both bacteria, H. pylori suppressed
Salmonella-specic Th17 responses in the cecum, reducing cecal inammation. These protective eects were
attributed to increased levels of interleukin (IL)-10 in
the mesenteric lymph nodes of co-infected mice as
opposed to Salmonella-only-infected mice, suggesting
that this regulatory cytokine modulates the dierentiation and/or activity of Th17 cells. In addition it is
speculated that the protective eect of H. pylori on colitis may be associated with H. pyloris chromosomal
DNA, which in mice, through a high ratio of immunoregulatory to immunostimulatory sequences, is capable
of preventing sodium dextran sulfate-induced experimental colitis.73 Nonetheless it must be stressed that
whether H. pylori DNA is indeed a relevant factor in
the protection against IBD remains to be elucidated in
more detail, since data showing protection by live bacterial infection in IBD models, other than acute
Salmonella-induced colitis, are currently not available.
The consistency of the results over the years, as
shown in the cumulative meta-analysis of studies
ordered by the year of publication and the lack of publication bias, strengthens the results of this meta-analysis. However, despite the random-eects model used and
the sensitivity analyses performed, the persisting signicant heterogeneity found among the studies may call the
results into question. An additional drawback is that
the possible role of confounders, which could inuence
the results, was not adequately addressed in the studies
involved. For example, low socioeconomic status could
be a strong common confounder and perhaps the real
cause for both the higher H. pylori prevalence and the
lower IBD prevalence observed. In fact the prevalence of
both may not be truly associated, and it should be
stressed that epidemiological studies and meta-analyses
based on epidemiological studies can only suggest associations, but not establish cause-eect relationships.
In the future, in order to overcome problems that
may contribute to signicant heterogeneity, relevant

prospective studies should address all the related confounders, stratifying by factors that could potentially
inuence the results, such as the method of H. pylori
diagnosis, method of IBD diagnosis, study origin and
study population age. Ideally, controls who are ageand sex-matched to the IBD group should be selected
from the same area as the IBD group, tested for
H. pylori by the same method and in addition in both
IBD and control groups previous H. pylori treatment
should be taken into account. Most important,
H. pylori testing should be conducted at the time of
IBD diagnosis, i.e. in patients na ve for IBD treatment,
which potentially could inuence H. pylori status.
Furthermore, in H. pylori-positive patients the presence
of cagA should be considered, as it is claimed that the
possible protective eects of H. pylori against other
autoimmune diseases come from cagA-positive
strains.74,75 The mechanism underlying the inverse
association between cagA-positive H. pylori strains
and the lower incidence of autoimmune disease has
yet to be dened. However, it has been suggested that
the intense host immune responses to cagA-positive
H. pylori strains may further alter Th1- and Th2-type
immune responses with subsequent induction of immunoregulatory lymphocytes.74
In conclusion, the results of this meta-analysis support a protective eect of H. pylori infection against
the development of IBD. However, the heterogeneity
among studies may limit the value of these results.
Therefore, further prospective studies examining the
precise role of H. pylori and its eradication in the
development of IBD may be necessary, taking into
account the role of confounders such as environmental factors.
Funding
This research received no specic grant from any funding
agency in the public, commercial, or not-for-prot sectors.

Conflict of interest
None declared.

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