Skip to main content
NCBI home page
United European Gastroenterology Journal logoLink to United European Gastroenterology Journal
. 2015 Dec;3(6):539–550. doi: 10.1177/2050640615580889

The association between Helicobacter pylori infection and inflammatory bowel disease based on meta-analysis

T Rokkas 1,✉, JP Gisbert 2, Y Niv 3, C O’Morain 4
PMCID: PMC4669512  PMID: 26668747

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. pylori’s 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 random-effects model of meta-analysis was used. The obtained pool RR estimation was 0.62 (95% confidence interval (CI) 0.55–0.71, 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, Crohn’s disease, ulcerative colitis, meta-analysis

Introduction

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a significant, growing global health burden.1–3 In recent decades, many developing countries have seen a dramatic rise in the incidence of IBD.2–4 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 inflammatory response of the gastric mucosa is mainly attributed to the stimulation of the host’s immune system caused by the bacterium. This results in a T helper type 1 (Th1) response and elevated levels of Th1 cytokines.9–11 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 extra-gastric diseases, including autoimmune disorders.12,13 However, epidemiological data exist that suggest a protective effect of H. pylori infection against the development of some diseases with an autoimmune component, such as asthma, most probably by H. pylori’s ability to induce immune tolerance and limit inflammatory responses.14,15 The mechanism underlying this protective role of H. pylori infection is thought to be differential expression of local mucosal inflammatory 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 confirmed by other studies. This prompted us to further investigate this association by performing a meta-analysis in which we pooled the results of all existing relevant studies.

Methods

Identification of studies and data extraction

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 (inflammatory bowel disease OR ulcerative colitis OR Crohn’s 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 ((“inflammatory bowel diseases” (MeSH Terms) OR (“inflammatory” (All Fields) AND “bowel” (All Fields) AND “diseases” (All Fields)) OR “inflammatory bowel diseases” (All Fields) OR (“inflammatory” (All Fields) AND “bowel” (All Fields) AND “disease” (All Fields)) OR “inflammatory 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 (“crohn’s” (All Fields) AND “disease” (All Fields)) OR “crohn’s 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 predefined 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

Selection criteria

Inclusion and exclusion criteria were defined 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 confirmed 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.

Statistical analysis

The risk ratio (RR, 95 % confidence 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 fixed-model (Mantel and Haenszel) method,17 unless significant heterogeneity was present or if the design of the studies was considered to be different enough, in which case the random-effects 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 Q-test 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 effect sizes, were meta-analyzed by choosing the most suitable data entry option for the meta-analysis software used (Comprehensive Meta-Analysis, version 2; Biostat Inc, Englewood, NJ, USA).

Sensitivity analyses/publication bias

In the presence of significant statistical heterogeneity, apart from the random-effects model, we performed sensitivity analyses to evaluate the consistency of our results. Firstly, to evaluate any possible excessive influence 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 effect of the exclusion on the pooled RRs.22 Secondly, as different study designs and populations may incorporate different biases, we performed subgroup analyses, stratifying by factors that could potentially influence the results. These factors were established a priori to the analysis. Where needed, we further explored heterogeneity by performing meta-regression 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 Egger’s 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 Tweedie’s nonparametric “trim and fill” rank-based method.27

Results

Descriptive assessment and study characteristics

A flowchart 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.28–60 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 different parts of the world and contained a total of 4400 IBD patients and 4763 controls.

Figure 1.

Figure 1.

Open in a new tab

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

Table 1.

The main characteristics of the included studies

First author (reference) Publication/ Year Country Study design IBD pts (n) (CD/UC) Controls (n) (group composition) IBD diagnosis H.pylori diagnostic method
el-Omar28 1994 UK Prospective (cohort) 110 (63/47) 100 (Hospital patients for elective surgery) Chart review Serology
Mantzaris29 1995 Greece Prospective (cohort) 90 (0/90) 120 (Healthy individuals) Not reported Serology/RUT
Halme30 1996 Finland Prospective (cohort) 200 (100/100) 100 (Patients with acute bacterial diarrhea) Not reported Serology
Meining31 1997 Germany Prospective (case control) 36 (36/0) 36 (Healthy individuals) Histology Histology
Oberhuber32 1997 Germany Prospective (cohort) 75(75/0) 200 (Crohn's disease-free controls) Histology Histology
Parente33 1997 Italy Prospective (cross-sectional) 216 (123/93) 216 (Blood donors) Chart review Serology
Wagtmans34 1997 Netherlands Retrospective (cohort) 386 (386/0) 277 (Blood donors) Chart review Serology
D’Inca35 1998 Italy Prospective (cohort) 108 (67/41) 43 (Non-IBD patients) Chart review Histology
Duggan36 1998 UK Prospective (case control) 323 (110/213) 337 (Hospital patients for elective surgery) Chart review Serology
Pearce37 2000 UK Prospective (cohort) 93 (42/51) 40 (Patients with IBS) Radiology and/or histology Serology, UBT
Parente38 2000 Italy Prospective (cohort) 220 (141/79) 141(CD- and UC-free controls) Chart review UBT, histology
Matsumura39 2001 Japan Prospective (cohort) 90 (90/0) 525 (Dyspeptic patients) Not reported Histology
Parlak40 2001 Turkey Prospective (cohort) 111 (45/66) 77 (Patients with non-organic dyspepsia) Not reported Histology
Vare41 2001 Finland Prospective (cohort) 279 (94/185) 70 (Healthy individuals) Chart review/face to face interview Serology
Feeney42 2002 UK Prospective (case-control) 276 (139/137) 276 (Outpatient controls) Conventional clinical criteria Serology
Furusu43 2002 Japan Prospective (cohort) 50 (25/25) 25 (patients without IBD) Histology Serology, histology
Guslandi44 2002 Italy Not reported (cohort) 60 (60/0) 30 (Irritable bowel syndrome) Not reported Serology
Pascasio45 2003 US Retrospective (cohort) 56 (56/0) 382 (Non-CD patients) Histology Histology
Piodi46 2003 Italy Prospective (cohort) 72 (30/42) 72 (Non-CD patients) Chart review UBT
Triantafillidis47 2003 Greece Prospective (cohort) 116 (39/77) 127 (Healthy controls) Chart review Serology
Oliveira48 2004 Brazil Prospective (cohort) 42 (0/42) 74 (Non-IBD patients) Histology Serology, UBT
Pronai49 2004 Italy Prospective (cohort) 133 (51/82) 200 (Non-IBD patients) Histology UBT
Oliveira50 2006 Brazil Prospective (cohort) 43 (43/0) 74 (Non-IBD patients) Histology UBT
Sładek51 2007 Poland Not reported (cohort) 94 (50/44) 194 (Non-IBD patients) Clinical criteria/histology RUT, histology
Ando52 2008 Japan Prospective (cohort) 38 (38/0) 12 (Healthy individuals) Not reported UBT
Lidar53 2009 Israel Prospective (cohort) 119 (80/39) 98 (Non-IBD patients) Not reported Serology
Song54 2009 Korea Prospective (case control) 316 (147/169) 316 (Non-IBD patients) Chart review/personal interview UBT
Garza-González55 2010 Mexico Prospective (cohort) 44 (21/23) 75 (Non-IBD patients) Not reported Serology
Pellicano56 2010 Italy Prospective (case-control) 20 (12/8) 29 (Patients with idiopathic constipation) Not reported UBT, histology
Varas-Lorenzo57 2010 Spain Prospective (cohort) 60 (30/30) 20 (Non-IBD patients) Chart review UBT
Zhang58 2011 China Prospective (case-control) 208 (104/104) 416 (Healthy individuals) Clinical presentation, endoscopic, histological, radiological findings UBT
Jin59 2013 China Prospective (cohort) 153 (0/153) 121 (Non-UC patients) Endoscopic, histological, findings UBT
Xiang60 2013 China Prospective (cohort) 229 (229/0) 248 (Non-CD patients) Endoscopy manifestation and biopsy, as adopted by Asia-Pacific consensus UBT, culture, histology
Open in a new tab

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

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 (25.2–27.8)), compared to 44.7% (43.3–46.1) of individuals in the control group (2129/4763). There was significant heterogeneity in the included studies (Q = 137.2, degree of freedom (df) (Q) = 32, I2 = 77%, p < 0.001) and therefore the random-effects model of meta-analysis was used. The obtained pool RR estimation was 0.62 (95% CI (0.55–0.71), test for overall effect 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 Egger’s regression test) (Figure 2(b)).

Figure 2.

Figure 2.

Open in a new tab

(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.

Subgroup analyses/sensitivity analyses

Due to significant heterogeneity, apart from using the random-effects 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 significant results for both diseases, with a trend toward a greater effect for CD (0.38 (0.31–0.47), Z = −8.98, p < 0.001) when compared to UC (0.53 (0.42–0.67), Z = −5.39, p < 0. 001). However, there was significant 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 stratified 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 different study designs and populations may incorporate different 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 significant results (z = −0.48, p = 0.63) (Figure 4(c)).

Figure 3.

Figure 3.

Open in a new tab

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: Crohn’s disease; UC: ulcerative colitis.

Table 2.

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

RR (95% CI) Z value p value Heterogeneity
Q value df(Q) I2 % p value
Study design
Case control 0.59 (0.43–0.82) −3.12 0.002 29.15 5 82.85 <0.001
Cohort 0.62 (0.53–0.72) −6.04 <0.001 100.41 25 75.10 <0.001
H. pylori diagnosis
Histology 0.61 (0.45–0.83) −3.15 0.002 29.48 6 79.65 <0.001
Serology 0.62 (0.51–0.76) −4.72 <0.001 58.99 14 76.27 <0.001
Urea breath test 0.63 (0.50–0.79) −3.93 <0.001 42.85 10 76.66 <0.001
Open in a new tab

RR: risk ratio; CI: confidence interval.

Figure 4.

Figure 4.

Open in a new tab

(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.

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 effect 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 meta-analysis pooled all data from eligible relevant studies and showed a statistically significant inverse relationship between H. pylori infection and IBD (both CD and UC), which may suggest a possible protective effect of H. pylori against the development of IBD. These results confirmed 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 findings 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 influence 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 influence on H. pylori status in IBD patients.64

Nonetheless, the notion that the immunomodulatory properties of H. pylori may confer protection against allergic and chronic inflammatory disorders has been addressed and recently reviewed.65,66 Toward this notion there is laboratory evidence illustrating H. pylori’s role in the regulation of the immune system. Thus, a proposed model of H. pylori’s effect 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 proinflammatory 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 inflammatory Th1/Th17 pathway.67–71 Furthermore, in mice evidence has emerged proving protective effects of H. pylori infection against Salmonella typhimurium-induced colitis.72 Thus in co-infection with both bacteria, H. pylori suppressed Salmonella-specific Th17 responses in the cecum, reducing cecal inflammation. These protective effects 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 differentiation and/or activity of Th17 cells. In addition it is speculated that the protective effect of H. pylori on colitis may be associated with H. pylori’s 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-effects model used and the sensitivity analyses performed, the persisting significant heterogeneity found among the studies may call the results into question. An additional drawback is that the possible role of confounders, which could influence 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-effect relationships.

In the future, in order to overcome problems that may contribute to significant heterogeneity, relevant prospective studies should address all the related confounders, stratifying by factors that could potentially influence the results, such as the method of H. pylori diagnosis, method of IBD diagnosis, study origin and study population age. Ideally, controls who are age- and 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 naïve for IBD treatment, which potentially could influence H. pylori status. Furthermore, in H. pylori-positive patients the presence of cagA should be considered, as it is claimed that the possible protective effects 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 defined. 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 effect 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 specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest

None declared.

References

  • 1.Loftus EV. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology 2004; 126: 1504–1517. [DOI] [PubMed] [Google Scholar]
  • 2.Thia KT, Loftus EV, Sandborn WJ, et al. An update on the epidemiology of inflammatory bowel disease in Asia. Am J Gastroenterol 2008; 103: 3167–3182. [DOI] [PubMed] [Google Scholar]
  • 3.Baumgart DC, Bernstein CN, Abbas Z, et al. IBD Around the world: Comparing the epidemiology, diagnosis, and treatment: Proceedings of the World Digestive Health Day 2010—Inflammatory Bowel Disease Task Force meeting. Inflamm Bowel Dis 2011; 17: 639–644. [DOI] [PubMed] [Google Scholar]
  • 4.Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012; 142: 46–54. [DOI] [PubMed] [Google Scholar]
  • 5.Bloomfield SF, Stanwell-Smith R, Crevel RW, et al. Too clean, or not too clean: The hygiene hypothesis and home hygiene. Clin Exp Allergy 2006; 36: 402–425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Koloski NA, Bret L, Radford-Smith G. Hygiene hypothesis in inflammatory bowel disease: A critical review of the literature. World J Gastroenterol 2008; 14: 165–173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Valle J, Kekki M, Sipponen P, et al. Long-term course and consequences of Helicobacter pylori gastritis. Results of a 32-year follow-up study. Scand J Gastroenterol 1996; 31: 546–550. [DOI] [PubMed] [Google Scholar]
  • 8.Sonnenberg A. Review article: Historic changes of Helicobacter pylori-associated diseases. Aliment Pharmacol Ther 2013; 38: 329–342. [DOI] [PubMed] [Google Scholar]
  • 9.Smythies LE, Waites KB, Lindsey JR, et al. Helicobacter pylori-induced mucosal inflammation is Th1 mediated and exacerbated in IL-4, but not IFNgamma, gene-deficient mice. J Immunol 2000; 165: 1022–1029. [DOI] [PubMed] [Google Scholar]
  • 10.Di Tommaso A, Xiang Z, Bugnoli M, et al. Helicobacter pylori-specific CD4+ T-cell clones from peripheral blood and gastric biopsies. Infect Immun 1995; 63: 1102–1106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Meyer F, Wilson KT, James SP. Modulation of innate cytokine responses by products of Helicobacter pylori. Infect Immun 2000; 68: 6265–6272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.van Amsterdam K, van Vliet AH, Kusters JG, et al. Of microbe and man: Determinants of Helicobacter pylori-related diseases. FEMS Microbiol Rev 2006; 30: 131–156. [DOI] [PubMed] [Google Scholar]
  • 13.Ram M, Barzilai O, Shapira Y, et al. Helicobacter pylori serology in autoimmune diseases—fact or fiction? Clin Chem Lab Med 2013; 51: 1075–1082. [DOI] [PubMed] [Google Scholar]
  • 14.Chen Y, Blaser MJ. Helicobacter pylori colonization is inversely associated with childhood asthma. J Infect Dis 2008; 198: 553–560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Reibman J, Marmor M, Filner J, et al. Asthma is inversely associated with Helicobacter pylori status in an urban population. PLoS One 2008; 2: e4060–e4060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: Explanation and elaboration. J Clin Epidemiol 2009; 62: e1–e34. [DOI] [PubMed] [Google Scholar]
  • 17.Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Nat Cancer Inst 1959; 22: 719–748. [PubMed] [Google Scholar]
  • 18.DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177–188. [DOI] [PubMed] [Google Scholar]
  • 19.Cochran WG. The combination of estimates from different experiments. Biometrics 1954; 8: 101–129. [Google Scholar]
  • 20.Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21: 1539–1558. [DOI] [PubMed] [Google Scholar]
  • 21.Higgins JP, Thompson SG, Deeks JJ. Measuring inconsistency in meta-analysis. BMJ 2003; 327: 557–560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Sutton AJ, Abrams KR, Jones DR, et al. In: Methods for meta-analysis in medical research. New York: John Wiley & Sons Ltd, 2000.
  • 23.Borenstein M, Hedges LV, Higgins JPT, et al. Introduction to meta-analysis, New York: John Wiley & Sons Ltd, 2009. [Google Scholar]
  • 24.Copas JB, Shi JQ. A sensitivity analysis for publication bias in systematic reviews. Stat Methods Med Res 2001; 10: 251–265. [DOI] [PubMed] [Google Scholar]
  • 25.Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994; 50: 1088–1101. [PubMed] [Google Scholar]
  • 26.Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple graphical test. BMJ 1997; 315: 29–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Duval S, Tweedie R. Trim and fill: A simple funnel-plot-based method of testing and in meta-analysis. Biometrics 2000; 56: 455–463. [DOI] [PubMed] [Google Scholar]
  • 28.el-Omar E, Penman I, Cruikshank G, et al. Low prevalence of Helicobacter pylori in inflammatory bowel disease: Association with sulfasalazine. Gut 1994; 35: 1385–1388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Mantzaris GJ, Archavlis E, Zografos C, et al. Low prevalence of Helicobacter pylori in inflammatory bowel disease: Association with sulfasalazine. Am J Gastroenterol 1995; 90: 1900–1900. [PubMed] [Google Scholar]
  • 30.Halme L, Rautelin H, Leidenius M, et al. Inverse correlation between Helicobacter pylori infection and inflammatory bowel disease. J Clin Pathol 1996; 49: 65–67. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Meining A, Bayerdorffer E, Bastlein E, et al. Focal inflammatory infiltrations in gastric biopsy specimens are suggestive of Crohn’s disease. Scand J Gastroenterol 1997; 32: 813–818. [DOI] [PubMed] [Google Scholar]
  • 32.Oberhuber G, Püspök A, Oesterreicher C, et al. Focally enhanced gastritis: A frequent type of gastritis in patients with Crohn’s disease. Gastroenterology 1997; 112: 698–706. [DOI] [PubMed] [Google Scholar]
  • 33.Parente F, Molteni P, Bollani S, et al. Prevalence of Helicobacter pylori infection and related upper gastrointestinal lesions in patients with inflammatory bowel disease. A cross-sectional study with matching. Scand J Gastroenterol 1997; 32: 1140–1146. [DOI] [PubMed] [Google Scholar]
  • 34.Wagtmans MJ, Witte AMC, Taylor DR, et al. Low seroprevalence of Helicobacter pylori antibodies in historical sera of patients with Crohn’s disease. Scand J Gastroenterol 1997; 32: 712–718. [DOI] [PubMed] [Google Scholar]
  • 35.D’Inca R, Sturniolo G, Cassaro M, et al. Prevalence of upper gastrointestinal lesions and Helicobacter pylori infection in Crohn’s disease. Dig Dis Sci 1998; 43: 988–992. [DOI] [PubMed] [Google Scholar]
  • 36.Duggan AE, Usmani I, Neal KR, et al. Appendicectomy, childhood hygiene, Helicobacter pylori status, and risk of inflammatory bowel disease: A case control study. Gut 1998; 43: 494–498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Pearce CB, Duncan HD, Timmis L, et al. Assessment of the prevalence of infection with Helicobacter pylori in patients with inflammatory bowel disease. Eur J Gastroenterol Hepatol 2000; 12: 439–443. [DOI] [PubMed] [Google Scholar]
  • 38.Parente F, Cucino C, Bollani S, et al. Focal gastric inflammatory infiltrates in inflammatory bowel diseases: Prevalence, immunohistochemical characteristics and diagnostic role. Am J Gastroenterol 2000; 95: 705–711. [DOI] [PubMed] [Google Scholar]
  • 39.Matsumura M, Matsui T, Hatakeyama S, et al. Prevalence of Helicobacter pylori infection and correlation between severity of upper gastrointestinal lesions and H. pylori infection in Japanese patients with Crohn's disease. J Gastroenterol 2001; 36: 740–747. [DOI] [PubMed]
  • 40.Parlak E, Ulker A, Dişibeyaz S, et al. There is no significant increase in the incidence of Helicobacter pylori infection in patients with inflammatory bowel disease in Turkey. J Clin Gastroenterol 2001; 33: 87–88. [DOI] [PubMed] [Google Scholar]
  • 41.Vare PO, Heikius B, Silvennoinen R, et al. Seroprevalence of Helicobacter pylori infection in inflammatory bowel disease: Is Helicobacter pylori infection a protective factor? Scand J Gastroenterol 2001; 36: 1295–1300. [DOI] [PubMed] [Google Scholar]
  • 42.Feeney MA, Murphy F, Clegg AJ, et al. A case-control study of childhood environmental risk factors for the development of inflammatory bowel disease. Eur J Gastroenterol Hepatol 2002; 14: 529–534. [DOI] [PubMed] [Google Scholar]
  • 43.Furusu H, Murase K, Nishida Y, et al. Accumulation of mast cells and macrophages in focal active gastritis of patients with Crohn’s disease. Hepatogastroenterology 2002; 49: 639–643. [PubMed] [Google Scholar]
  • 44.Guslandi M, Fanti L, Testoni PA. Helicobacter pylori seroprevalence in Crohn’s disease: Lack of influence by pharmacological treatment. Hepatogastroenterology 2002; 49: 1296–1297. [PubMed] [Google Scholar]
  • 45.Pascasio JM, Hammond S, Qualman SJ. Recognition of Crohn disease on incidental gastric biopsy in childhood. Pediatr Dev Pathol 2003; 6: 209–214. [DOI] [PubMed] [Google Scholar]
  • 46.Piodi LP, Bardella M, Rocchia C, et al. Possible protective effect of 5-aminosalicylic acid on Helicobacter pylori infection in patients with inflammatory bowel disease. J Clin Gastroenterol 2003; 36: 22–25. [DOI] [PubMed] [Google Scholar]
  • 47.Triantafillidis JK, Tzourmakliotis D, Peros G, et al. Serum gastrin levels in patients with inflammatory bowel disease. Hepatogastroenterology 2003; 50(Suppl 2): cccxv–cccxvii. [PubMed] [Google Scholar]
  • 48.Oliveira AG, Sanna MGP, Rocha GA, et al. Helicobacter species in the intestinal mucosa of patients with ulcerative colitis. J Clin Microbiol 2004; 42: 384–386. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Prónai L, Schandl L, Orosz Z, et al. Lower prevalence of Helicobacter pylori infection in patients with inflammatory bowel disease but not with chronic obstructive pulmonary disease—antibiotic use in the history does not play a significant role. Helicobacter 2004; 9: 278–283. [DOI] [PubMed] [Google Scholar]
  • 50.Oliveira AG, Rocha GA, Rocha AMC, et al. Isolation of Helicobacter pylori from the intestinal mucosa of patients with Crohn’s disease. Helicobacter 2006; 11: 2–9. [DOI] [PubMed] [Google Scholar]
  • 51.Sładek M, Jedynak-Wasowicz U, Wedrychowicz A, et al. The low prevalence of Helicobacter pylori gastritis in newly diagnosed inflammatory bowel disease children and adolescent [article in Polish]. Przegl Lek 2007; 64(Suppl 3): 65–67. [PubMed] [Google Scholar]
  • 52.Ando T, Watanabe O, Ishiguro K, et al. Relationships between Helicobacter pylori infection status, endoscopic, histopathological findings, and cytokine production in the duodenum of Crohn’s disease patients. J Gastroenterol Hepatol 2008; 23(Suppl 2): S193–S197. [DOI] [PubMed] [Google Scholar]
  • 53.Lidar M, Langevitz P, Barzilai O, et al. Infectious serologies and autoantibodies in inflammatory bowel disease: Insinuations at a true pathogenic role. Ann N Y Acad Sci 2009; 1173: 640–648. [DOI] [PubMed] [Google Scholar]
  • 54.Song MJ, Park DI, Hwang SJ, et al. The prevalence of Helicobacter pylori infection in Korean patients with inflammatory bowel disease, a multicenter study [article in Korean]. Korean J Gastroenterol 2009; 53: 341–347. [DOI] [PubMed] [Google Scholar]
  • 55.Garza-González E, Pérez-Pérez GI, Mendoza-Ibarra SI, et al. Genetic risk factors for inflammatory bowel disease in a North-eastern Mexican population. Int J Immunogenet 2010; 37: 355–359. [DOI] [PubMed] [Google Scholar]
  • 56.Pellicano R, Bresso F, Demarchi B, et al. Prevalence of Helicobacter pylori infection in patients with inflammatory bowel disease: Pilot study. Rev Esp Enferm Dig 2010; 102: 675–666; author reply 676. [DOI] [PubMed] [Google Scholar]
  • 57.Varas-Lorenzo MJ, Muñoz-Agel F. Is Helicobacter pylori active infection increased or decreased in Crohn’s disease? [article in Spanish]. Rev Esp Enferm Dig 2010; 102: 509–510. [DOI] [PubMed] [Google Scholar]
  • 58.Zhang S, Zhong B, Chao K, et al. Role of Helicobacter species in Chinese patients with inflammatory bowel disease. J Clin Microbiol 2011; 49: 1987–1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Jin X, Chen YP, Chen SH, et al. Association between Helicobacter pylori infection and ulcerative colitis—a case control study from China. Int J Med Sci 2013; 10: 1479–1484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Xiang Z, Chen YP, Ye YF, et al. Helicobacter pylori and Crohn’s disease: A retrospective single-center study from China. World J Gastroenterol 2013; 19: 4576–4581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Atherton JC, Blaser MJ. Helicobacter pylori infections. Harrison’s principles of internal medicine, 16th ed New York: McGraw-Hill, 2005, pp. 886–886. [Google Scholar]
  • 62.Luther J, Dave M, Higgins PD, et al. Association between Helicobacter pylori infection and inflammatory bowel disease: A meta-analysis and systematic review of the literature. Inflamm Bowel Dis 2010; 16: 1077–1084. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Sonneberg A, Genta RM. Low prevalence of Helicobacter pylori infection among patients with inflammatory bowel disease. Aliment Pharmacol Ther 2012; 35: 469–476. [DOI] [PubMed] [Google Scholar]
  • 64.Triantafillidis JK, Gikas A, Merikas E. Treatment of inflammatory bowel disease patients with anti-TNF-α factors and immunosuppressives do not influence the prevalence of Helicobacter pylori infection. Indian J Gastroenterol 2014; 33: 383–384. [DOI] [PubMed] [Google Scholar]
  • 65.Arnold IC, Hitzler I, Müller A. The immunomodulatory properties of Helicobacter pylori confer protection against allergic and chronic inflammatory disorders. Front Cell Inf Microbiol 2012; 2: 10–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Papamichael K, Konstantopoulos P, Mantzaris GI. Helicobacter pylori infection and inflammatory bowel disease: Is there a link? World J Gastroenterol 2014; 20: 6374–6385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Kao JY, Rathinavelu S, Eaton KA. Helicobacter pylori-secreted factors inhibit dendritic cell IL-12 secretion: A mechanism of ineffective host defense. Am J Physiol Gastrointest Liver Physiol 2006; 291: G73–G81. [DOI] [PubMed] [Google Scholar]
  • 68.Paziak-Domańska B, Chmiela M, Jarosińska A, et al. Potential role of CagA in the inhibition of T cell reactivity in Helicobacter pylori infections. Cell Immunol 2000; 202: 136–139. [DOI] [PubMed] [Google Scholar]
  • 69.Gerbert B, Fischer W, Haas R. The Helicobacter pylori vacuolating cytotoxin: From cellular vacuolation to immunosuppressive activities. Rev Physiol Biochem Pharmacol 2004; 152: 205–202. [DOI] [PubMed] [Google Scholar]
  • 70.Rad R, Brenner L, Bauer S, et al. CD25+/Foxp3+ T cells regulate gastric inflammation and Helicobacter pylori colonization in vivo. Gastroenterology 2006; 131: 525–537. [DOI] [PubMed] [Google Scholar]
  • 71.Lundgren A, Suri-Payer E, Enarsson K, et al. Helicobacter pylori-specific CD4+ CD25+ high regulatory T cells suppress memory T-cell responses to H. pylori in infected individuals. Infect Immun 2003; 1: 1755–1762. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Higgins PD, Johnson LA, Luther J, et al. Prior Helicobacter pylori infection ameliorates Salmonella typhimurium-induced colitis: Mucosal crosstalk between stomach and distal intestine. Inflamm Bowel Dis 2011; 17: 1398–1408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Luther J, Owyang SY, Takeuchi T, et al. Helicobacter pylori DNA decreases pro-inflammatory cytokine production by dendritic cells and attenuates dextran sodium sulphate-induced colitis. Gut 2011; 60: 1479–1486. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Chen Y, Blaser MJ. Inverse associations of Helicobacter pylori with asthma and allergy. Arch Intern Med 2007; 167: 821–827. [DOI] [PubMed] [Google Scholar]
  • 75.Cover TL, Blaser MJ. Helicobacter pylori in health and disease. Gastroenterology 2009; 136: 1863–1873. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from United European Gastroenterology Journal are provided here courtesy of Wiley

RESOURCES