Is <i>Helicobacter pylori</i> Infection Associated With Ulcerative Colitis Activity?

Ayoung Lee; Jung Wan Choe; Sung Woo Jung; Jae Youn Park; Ik Yoon; Seung Young Kim

doi:10.7704/kjhugr.2023.0045

Korean J Helicobacter Up Gastrointest Res > Volume 24(1); 2024 > Article

Lee, Choe, Jung, Park, Yoon, and Kim: Is Helicobacter pylori Infection Associated With Ulcerative Colitis Activity?

Original Article

The Korean Journal of Helicobacter and Upper Gastrointestinal Research 2024;24(1):52-57.

Published online: March 8, 2024

DOI: https://doi.org/10.7704/kjhugr.2023.0045

Is Helicobacter pylori Infection Associated With Ulcerative Colitis Activity?

Ayoung Lee

, Jung Wan Choe

, Sung Woo Jung

, Jae Youn Park, Ik Yoon, Seung Young Kim

Division of Gastroenterology, Department of Internal Medicine, Korea University College of Medicine, Ansan, Korea

Corresponding author Sung Woo Jung, MD, PhD Division of Gastroenterology, Department of Internal Medicine, Korea University Ansan Hospital, 123 Jeokgeum-ro, Danwon-gu, Ansan 15355, Korea E-mail: sungwoojung@korea.ac.kr

Received August 24, 2023; Revised November 3, 2023; Accepted November 15, 2023;

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objectives

Epidemiological studies have shown an inverse association between Helicobacter pylori infection and ulcerative colitis (UC). In this study, we investigated the protective effects of H. pylori infection on the severity of UC.

Methods

This single-center study included 316 patients with newly diagnosed UC based on findings of colonoscopy and upper endoscopy for H. pylori evaluation between January 1994 and December 2015. Patients’ medical records were retrospectively reviewed, and severity of UC was assessed based on endoscopic findings, clinical symptoms, treatment regimens, and Mayo scores.

Results

The prevalence of H. pylori infection in patients with UC was 74/316 (23.4%). Based on upper endoscopic findings, the percentage of patients with duodenal ulcers was significantly higher in the H. pylori positive group than that in the H. pylori negative group (27.0% vs. 11.6%, p=0.022). Disease extent and endoscopic severity showed no significant intergroup difference (p=0.765 and p=0.803, respectively). Endoscopic severity was unaffected by the H. pylori infection status, based on the extent of endoscopically documented disease and endoscopic findings. Furthermore, UC-related symptom severity assessed on the basis of stool frequency, rectal bleeding severity, and rate of admission necessitated by UC aggravation was not associated with H. pylori infection (p=0.185, 0.144, and 0.182, respectively). Use of steroids as induction therapy for severe UC did not differ with regard to H. pylori infection (p=0.327). No intergroup difference was observed in disease severity of UC classified using the Mayo score (p=0.323).

Conclusions

H. pylori infection was detected in approximately 25.0% of patients with UC. However, the H. pylori infection status was not associated with the severity of UC based on endoscopic disease activity, patients’ symptoms, steroid use, or the Mayo clinic score.

Key words: Helicobacter pylori; Inflammatory bowel disease; Ulcerative colitis

INTRODUCTION

Inflammatory bowel disease (IBD), a relapsing disorder characterized by chronic idiopathic gastrointestinal (GI) tract inflammation, is categorized into ulcerative colitis (UC) and Crohn’s disease [1]. Although environmental and genetic factors contribute to IBD progression, the exact etiology of the disease remains unclear. Currently, it is hypothesized that GI microbes may trigger a deregulated immune response in genetically predisposed individuals, resulting in chronic inflammation [2,3]. As mediators of a chronic immune response, these microbes may play a key role in the pathogenesis of autoimmune diseases, such as asthma, vasculitic diseases, and IBD [4]. The Helicobacter genus is implicated as a potential pathogenetic contributor to IBD5 and reportedly triggers IBD-like colitis in an immunocompromised murine model [5].

However, many epidemiological studies have suggested a negative association between H. pylori infection and UC [6]. Korean studies have reported an increase in the prevalence of UC with a simultaneous decrease in that of H. pylori [7]. Based on the inverse prevalence between H. pylori infection and UC, recent studies suggest a protective role of H. pylori infection against UC [8-10]. However, epidemiological studies can only suggest associations and do not establish cause-and-effect relationships. Assuming a potential protective effect of H. pylori in UC, it is reasonable to conclude that the severity of UC may be lesser in patients with than in those without H. pylori infection. However, few studies have discussed the clinical association between H. pylori infection and severity of UC.

In this study, we investigated the association, if any, between severity of UC and H. pylori infection.

METHODS

Patients

In this study, we performed a retrospective analysis of data obtained from medical records of all patients with newly diagnosed UC, who were evaluated at Korea University Ansan Hospital for H. pylori infection between January 1994 and December 2015. No patient had previously received H. pylori eradication treatment. Patients were categorized as follows: patients with H. pylori infection (HP[+] group) and those without H. pylori infection (HP[-] group). This study was approved by the Institutional Review Board of the Korea University College of Medicine (AS 16046). Informed consent was obtained from subjects.

Diagnosis of H. pylori infection

During upper endoscopy, a rapid urease test (Campylobacterlike organism test; Kimberly-Clark Ballard Medical Products, Roswell, GA, USA) or histological examination of biopsy specimens obtained from the antrum and body was performed. The biopsied tissues were fixed and stained using crystal violet for histological evaluation. A positive result on either test was diagnosed as H. pylori infection.

Assessment of disease activity of UC

The severity of UC was assessed using the following methods: 1) endoscopic severity was assessed based on endoscopic extent and endoscopic findings. Endoscopic extent was defined based on the maximum extent of the disease and was classified according to the Montreal classification [11] as follows: proctitis (inflammatory changes from the anal verge to >15 cm proximally), left colitis (extending from the rectum to the splenic flexure), and pancolitis (inflammatory changes proximal to the splenic flexure). Endoscopic findings were classified as mild (erythema, decreased vascular pattern, and mild friability), moderate (pronounced erythema, absence of vascularity, friability, and erosion), and severe (spontaneous bleeding and ulceration). 2) Symptom severity was assessed based on stool frequency, rectal bleeding severity, and a history of admission necessitated by UC aggravation. Stool frequency was classified into three groups using the Truelove-Witts score as follows [12]: mild (1–3 stools/day), moderate (4–6 stools/day), and severe (>7 stools/day). Rectal bleeding severity was classified based on the frequency of hematochezia as follows: minimum (no blood visible in stool), mild (blood-streaked stool <50% of the time), moderate (clearly visible blood in stool most of the time), and severe (passage of blood alone). 3) Review of details of induction therapy using sulfasalazine, 5-aminosalicylic acid (mesalazine), steroids, azathioprine, and infliximab. We concluded that patients with UC who received steroids, azathioprine, or infliximab as induction therapy had more severe UC than those who received sulfasalazine and 5-aminosalicylic acid. 4) We evaluated the severity of UC based on the Mayo score [13], which includes the following variables: stool frequency, rectal bleeding, endoscopic findings, and physician’s global assessment (Table 1). The estimated Mayo scores were categorized as mild disease (scores 3–5), moderate disease (scores 6–10), and severe disease (scores 11–12).

Statistical analysis

All statistical analyses were performed using the IBM SPSS Statistics for Windows, version 21.0 (IBM Corp., Armonk, NY, USA). Patients’ mean ages were compared using the t-test, and differences in sex and endoscopic findings were compared using the chi-square test, which was also used to determine the association between H. pylori status and severity of UC. A pvalue of <0.05 was considered statistically significant.

RESULTS

Of the 668 patients newly diagnosed with UC at our institution, 344 underwent upper GI endoscopy during the study period, and among these, 28 were excluded (10 did not undergo H. pylori testing, 6 had a history of H. pylori eradication therapy, 2 had received a proton pump inhibitor [which affects H. pylori test results] within 4 weeks, and 10 patients underwent gastroscopy after UC induction therapy). Finally, 316 patients eligible for this study underwent both upper GI and colonic endoscopic examinations. The study population was categorized into the HP(-) (n=242) and the HP(+) group (n=74) based on the results of H. pylori testing (Fig. 1). Available data showed that the H. pylori infection rate in the UC group was 23.4%.

Patients’ clinical characteristics

Table 2 illustrates the clinical characteristics of groups included in this study. Patients’ mean ages were 44.6 and 46.5 years in the HP(-) and HP(+) groups, respectively. The HP(-) and HP(+) groups comprised 140 (57.8%) and 54 (72.9%) men, respectively, and men outnumbered women in both groups; however, the difference was statistically insignificant. With regard to upper endoscopic findings, the percentage of patients with duodenal ulcers was significantly higher in the HP(+) than that in the HP(-) group (27.0% vs. 11.6%, p=0.022). We observed no statistically significant intergroup differences in other endoscopic findings (reflux esophagitis, chronic gastritis, gastric ulcers, and duodenitis).

Endoscopic severity of UC

The endoscopic extent of the disease did not show a significant intergroup difference (Table 3). The proctitis rates in the HP(-) and HP(+) groups were 28.9% and 35.2%, respectively; these differences were statistically insignificant (p=0.472). The left-sided colitis rates in the HP(-) and HP(+) groups were 46.3% and 43.2% (p=0.745), respectively, and the pancolitis rates were 24.8% and 21.6%, respectively (p=0.693).

We observed no significant intergroup difference in endoscopic findings of UC involving the colonic mucosa (Table 3). Mild disease rates in the HP(-) and HP(+) groups were 20.7% and 24.3%, respectively; these differences were statistically insignificant (p=0.635). The moderate disease rates in the HP(-) and HP(+) groups were 47.1% and 48.6% (p=0.870), and the severe disease rates were 32.2% and 27.1% (p=0.549), respectively.

Clinical symptom severity

The frequency of defecation and severity of rectal bleeding showed no significant association with H. pylori infection. Rates of admission necessitated by UC aggravation in the HP(-) and HP(+) groups were 57.9% and 59.5%, respectively, and no significant association with H. pylori infection was observed (p=0.182) (Table 4).

Induction therapy

The percentage of patients who received initial systemic steroid induction therapy in the HP(-) group was higher than that in the HP(+) group (52.5% vs. 45.9%); however, the intergroup difference was statistically insignificant (p=0.327). The percentage of patients who received azathioprine or infliximab was not statistically significantly different (Table 5).

The Mayo score

Disease severity estimated using the Mayo score did not show a significant intergroup difference (Table 6). The mild disease rates in the HP(-) and HP(+) groups were 23.1% and 21.6%, respectively; these differences were statistically insignificant (p=0.847). Moderate and severe disease rates in the HP(-) and HP(+) groups were also not statistically significantly different (56.2% vs. 45.9%, p=0.315 and 20.7% vs. 32.5%, p=0.139, respectively).

DISCUSSION

In this study, the H. pylori infection rate in patients with newly diagnosed UC was 23.4%; disease prevalence was significantly lower than that observed in the general Korean population (41.5%–66.9%) [14,15] throughout the duration similar to our study period. This result was consistent with findings reported by previous studies, which indicates a negative association between H. pylori infection and UC [2,6,16]. Notably, the H. pylori infection status did not affect the severity of UC, including the severity of endoscopic findings, clinical symptoms, treatment regimen, and Mayo scores.

Numerous studies have investigated the effect of H. pylori infection on UC; however, these studies have reported conflicting results. Some studies suggest a protective effect of H. pylori infection against autoimmune diseases such as asthma, type 1 diabetes mellitus, and IBD [2,9,10]. Laboratory evidence, which highlights the role of H. pylori infection in immune system dysregulation, supports this impression. This finding indicates that H. pylori, through its interaction with dendritic cells, can upregulate regulatory T cells, with decreased production of pro-inflammatory cytokines, which consequently may downregulate the systemic immune response and suppress autoimmunity [2]. Another potential mechanism underlying the protective role of H. pylori infection is the differential expression of an acute and/or chronic local mucosal inflammatory response [17,18]. H. pylori may induce the production of antibacterial peptides that counteract potentially harmful bacteria implicated in the pathogenesis of IBD [17,18]. Several clinical studies have investigated the association between H. pylori infection and UC progression, which reflects disease activity [19-21]. The results of these studies show that H. pylori positivity rates were lower in patients with UC who present with pancolitis than in those with more limited disease. Reportedly, H. pylori colonization has an independent protective effect against UC disease activity.

Some other studies have reported that H. pylori infection does not protect against UC and is not associated with UC activity [1,22-24]. In these studies, the incidence of H. pylori in patients with IBD was the same as that observed in the normal population, and H. pylori infection was not significantly associated with disease extent, stool frequency, rate of admission necessitated by disease aggravation, and treatment regimen (oral or intravenous steroid therapy), which indicates a severe disease status [24,25]. However, it is important to consider the limitations of the small-scale study (42 patients) [23] and that detailed categorization for evaluation of UC activity was not reported.

In our study, we investigated the association between UC activity and H. pylori infection in a relatively large number of patients with newly diagnosed UC. Disease activity was classified in detail using various indices, including endoscopic findings, patient symptoms, treatment regimen, and Mayo scores. Endoscopically, UC is characterized by inflammatory changes observed immediately above the anorectal junction that extend proximally in a confluent and continuous manner [26]. Therefore, disease localization is easy in patients with UC. Estimation of endoscopic extent and findings is widely used to evaluate IBD severity because endoscopic severity correlates with symptom severity and is significantly correlated with histopathological findings. Stool frequency and rectal bleeding were also evaluated because these symptoms can be easily assessed and are more objective parameters compared with the patient’s or physician’s global assessment. Disease activity was estimated on the basis of the induction treatment regimen. We concluded that administration of steroid, azathioprine, or infliximab as induction therapy was common in patients with severe UC and that sulfasalazine and 5-aminosalicylic acid therapy was primarily used in those with less severe disease. To avoid the possibility of spontaneous eradication of H. pylori following antibiotic therapy (particularly metronidazole), sulfasalazine, and other aminosalicylic compounds commonly used for management of UC, we only enrolled patients with newly diagnosed treatment-naïve UC and without H. pylori eradication treatment history.

Interestingly, in this study, we observed an inverse association between H. pylori infection and UC, which concurs with the findings of many epidemiological studies that have reported a low incidence of H. pylori infection in patients with IBD. In this study, we did not observe a protective effect of H. pylori against UC, which suggests that the inverse association may be ascribed to a coincident phenomenon and does not indicate a cause-and-effect relationship. Therefore, the lower incidence of H. pylori infection in patients with UC may be attributable to the role of other confounders such as inherent genetic or environmental factors that favor H. pylori infection in some patients and the development of IBD in some others.

Following are the limitations of this study. First, we could not address the role of potential confounders that may have affected our results. For example, low socioeconomic status may be a strong common confounder that could account for both the higher prevalence of H. pylori infection and lower prevalence of IBD observed in the study. Second, we did not investigate the effects of H. pylori eradication therapy on UC activity. Follow-up of the disease course without treatment for UC after H. pylori eradication is difficult in patients with UC, and further prospective studies are warranted to conclusively determine the exact effect of H. pylori eradication on UC disease activity. Third, we evaluated the gastric H. pylori infection status but not the H. pylori status throughout the colonic mucosa; therefore, we could not compare disease activity based on colonic H. pylori infection. Future clinical studies should investigate the effects of H. pylori on disease activity in the intestinal mucosa of patients with UC. Fourth, a selection bias cannot be excluded; H. pylori testing was not performed in all patients with newly diagnosed UC. We evaluated H. pylori infection at the physician’s discretion in patients who presented with dyspepsia, a history of gastric cancer, and endoscopic findings, including peptic ulcers, gastric polyps, and atrophic gastritis. Further research, including prospective cohort studies, is warranted.

In conclusion, the H. pylori infection rate in our study (23.4%) was lower in patients with UC than in the general population. Moreover, H. pylori infection did not affect endoscopic severity, symptom severity, induction therapy, or the Mayo score classification, which suggests that H. pylori infection is not associated with UC disease activity. Further prospective studies are required to conclusively establish whether H. pylori infection affects UC onset and produces chronic effects on the natural course of the disease.

Notes

Availability of Data and Material

The datasets generated or analyzed during the study are available from the corresponding author on reasonable request.

Conflicts of Interest

The authors have no financial conflicts of interest.

Authors’ Contribution

Conceptualization: Sung Woo Jung. Data curation: Jae Youn Park, Ik Yoon. Formal analysis: Jae Youn Park, Jung Wan Choe. Investigation: Jae Youn Park, Ik Yoon. Methodology: Sung Woo Jung. Project administration: Sung Woo Jung, Seung Young Kim. Resources: Jae Youn Park, Ik Yoon. Software: Jung Wan Choe. Supervision: Jung Wan Choe, Sung Woo Jung. Validation: Ayoung Lee, Jung Wan Choe. Visualization: Ayoung Lee, Jung Wan Choe. Writing—original draft: Ayoung Lee. Writing—review & editing: Seung Young Kim, Sung Woo Jung. Approval of final manuscript: all authors.

Funding Statement

None

Acknowledgements

None

Fig. 1.

Flowchart of study enrollment. UC, ulcerative colitis; GI, gastrointestinal; HP, Helicobacter pylori; PPI, proton pump inhibitor; HP(-), patients without HP infection; HP(+), patients with HP infection.

Table 1.

Components of the Mayo clinic score (an index of the disease severity of ulcerative colitis)

Variables	Criteria
Stool frequency	0	Normal number of stool
	1	1–2 Stools more than normal
	2	3–4 Stools more than normal
	3	≥5 Stools more than normal
Rectal bleeding	0	No blood seen
	1	Streaks of blood with stool less than half of the time
	2	Obvious blood with stool most of the time
	3	Blood alone passed
Endoscopic finding	0	Normal or inactive disease
	1	Erythema, decreased vascular pattern, mild friability
	2	Marked erythema, absent vascular pattern, friability, erosion
	3	Spontaneous bleeding, ulceration
Physician’s global assessment	0	Normal
	1	Mild
	2	Moderate
	3	Severe

Table 2.

Demographic and baseline characteristics of the study population

Characteristics	HP(-) group (n=242)	HP(+) group (n=74)	p-value
Age (yr)	44.6±13.5	46.5±9.2	0.935
Sex, male/female	140/102	54/20	0.098
Upper endoscopic finding
Esophageal reflux	68 (28.0)	16 (22.0)	0.435
Chronic gastritis	180 (74.4)	60 (81.1)	0.404
Gastric ulcer	18 (7.4)	12 (16.2)	0.111
Duodenitis	16 (6.6)	8 (11.8)	0.399
Duodenal ulcer	28 (11.6)	20 (27.0)	0.022
HP diagnosis
HP biopsy (H&E staining)	228	66
CLOtest	14	8

Data are presented as mean±standard deviation, n, or n (%).

HP(-), patients without HP infection; HP(+), patients with HP infection; HP, Helicobacter pylori; H&E, hematoxylin and eosin; CLOtest, Campylobacter-like organism test (a rapid urease test).

Table 3.

Assessment of endoscopic disease activity

Endoscopic finding	HP(-) group (n=242)	HP(+) group (n=74)	p-value
Extents			0.765
Ulcerative proctitis	70 (28.9)	26 (35.2)	0.472
Left-sided UC (distal UC)	112 (46.3)	32 (43.2)	0.745
Extensive UC (pancolitis)	60 (24.8)	16 (21.6)	0.693
Endoscopic severity			0.803
Mild	50 (20.7)	18 (24.3)	0.635
Moderate	114 (47.1)	36 (48.6)	0.870
Severe	78 (32.2)	20 (27.1)	0.549

Data are presented as n (%).

HP(-), patients without HP infection; HP(+), patients with HP infection; HP, Helicobacter pylori; UC, ulcerative colitis.

Table 4.

Assessment of clinical disease activity

	HP(-) group (n=242)	HP(+) group (n=74)	p-value
Stool frequency			0.185
Mild (1–3 times/day)	126 (52.0)	34 (45.9)	0.515
Moderate (4–6 times/day)	66 (27.3)	32 (43.2)	0.066
Severe (≥ 7 times/day)	50 (20.7)	8 (10.9)	0.176
Rectal bleeding			0.144
Minimum	36 (14.9)	16 (21.6)	0.333
Mild	108 (44.6)	21 (28.4)	0.146
Moderate	76 (31.4)	28 (37.8)	0.466
Severe	22 (9.1)	12 (16.3)	0.221
Admission due to aggravation	140 (57.9)	44 (59.5)	0.182

Data are presented as n (%).

HP(-), patients without HP infection; HP(+), patients with HP infection; HP, Helicobacter pylori.

Table 5.

Primary drugs used for induction therapy in patients with ulcerative colitis

	HP(-) group (n=242)	HP(+) group (n=74)	p-value
Patients who took medicine			0.686
Sulfasalazine, 5-ASA	96 (39.7)	35 (47.3)	0.242
Systemic steroid	127 (52.5)	34 (45.9)	0.327
Azathioprine	16 (6.6)	4 (5.4)	0.711
Infliximab	3 (1.2)	1 (1.4)	0.936

Data are presented as n (%).

HP(-), patients without HP infection; HP(+), patients with HP infection; HP, Helicobacter pylori; 5-ASA, 5-aminosalicylic acid.

Table 6.

Classification of disease severity of ulcerative colitis based on the Mayo clinic score

	HP(-) group (n=242)	HP(+) group (n=74)	p-value
Patients			0.323
Mild UC	28 (23.1)	8 (21.6)	0.847
Moderate UC	68 (56.2)	17 (45.9)	0.315
Severe UC	25 (20.7)	12 (32.5)	0.139

Data are presented as n (%).

HP(-), patients without HP infection; HP(+), patients with HP infection; HP, Helicobacter pylori; UC, ulcerative colitis.

REFERENCES

1. Yu Q, Zhang S, Li L, et al. Enterohepatic Helicobacter species as a potential causative factor in inflammatory bowel disease: a meta-analysis. Medicine (Baltimore) 2015;94:e1773.

2. Rokkas T, Gisbert JP, Niv Y, O’Morain C. The association between Helicobacter pylori infection and inflammatory bowel disease based on meta-analysis. United European Gastroenterol J 2015;3:539–550.

3. Guarner F, Malagelada JR. Gut flora in health and disease. Lancet 2003;361:512–519.

4. Jørgensen T, Jensen KH. Polyps in the gallbladder. A prevalence study. Scand J Gastroenterol 1990;25:281–286.

5. Segawa K, Arisawa T, Niwa Y, et al. Prevalence of gallbladder polyps among apparently healthy Japanese: ultrasonographic study. Am J Gastroenterol 1992;87:630–633.

6. Sonnenberg A, Genta RM. Low prevalence of Helicobacter pylori infection among patients with inflammatory bowel disease. Aliment Pharmacol Ther 2012;35:469–476.

7. Song MJ, Park DI, Hwang SJ, et al. The prevalence of Helicobacter pylori infection in Korean patients with inflammatory bowel disease, a multicenter study. Korean J Gastroenterol 2009;53:341–347.

8. Gasbarrini A, Franceschi F, Armuzzi A, et al. Extradigestive manifestations of Helicobacter pylori gastric infection. Gut 1999;45(Suppl 1): I9–I12.

9. Luther J, Dave M, Higgins PD, Kao JY. Association between Helicobacter pylori infection and inflammatory bowel disease: a meta-analysis and systematic review of the literature. Inflamm Bowel Dis 2010;16:1077–1084.

10. Wu XW, Ji HZ, Yang MF, Wu L, Wang FY. Helicobacter pylori infection and inflammatory bowel disease in Asians: a meta-analysis. World J Gastroenterol 2015;21:4750–4756.

11. Silverberg MS, Satsangi J, Ahmad T, et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a working party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol 2005;19(Suppl A): 5A–36A.

12. Seo M, Okada M, Yao T, Okabe N, Maeda K, Oh K. Evaluation of disease activity in patients with moderately active ulcerative colitis: comparisons between a new activity index and Truelove and Witts’ classification. Am J Gastroenterol 1995;90:1759–1763.

13. Choi CH, Jung SA, Lee BI, Lee KM, Kim JS, Han DS. Diagnostic guideline of ulcerative colitis. Korean J Gastroenterol 2009;53:145–160.

14. Do MY, Lee YC, Choi CH, et al. The changes in prevalence and the related factors of Helicobacter pylori infection in Korean health checkup subjects during 8 years. Korean J Gastroenterol 2009;53:76–83.

15. Lim SH, Kim N, Kwon JW, et al. Trends in the seroprevalence of Helicobacter pylori infection and its putative eradication rate over 18 years in Korea: a cross-sectional nationwide multicenter study. PLoS One 2018;13:e0204762.

16. Halme L, Rautelin H, Leidenius M, Kosunen TU. Inverse correlation between Helicobacter pylori infection and inflammatory bowel disease. J Clin Pathol 1996;49:65–67.

17. Sonnenberg A. Protective role of Helicobacter pylori against inflammatory bowel disease: a hypothesis. Pract Gastroenterol 2009;33:23–33.

18. Wehkamp J, Fellermann K, Herrlinger KR, Bevins CL, Stange EF. Mechanisms of disease: defensins in gastrointestinal diseases. Nat Clin Pract Gastroenterol Hepatol 2005;2:406–415.

19. Sładek M, Jedynak-Wasowicz U, Wedrychowicz A, Kowalska-Duplaga K, Pieczarkowski S, Fyderek K. [The low prevalence of Helicobacter pylori gastritis in newly diagnosed inflammatory bowel disease children and adolescent]. Przegl Lek 2007;64(Suppl 3): 65–67.

20. Väre PO, Heikius B, Silvennoinen JA, 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.

21. Caner S, Altinbaş A, Yeşıl Y, Beyazit Y, Yilmaz B, Yüksel O. The relation between Helicobacter pylori and ulcerative colitis. Turk J Med Sci 2014;44:820–823.

22. Monceaux CP, Testerman TL, Boktor M, et al. Helicobacter infection decreases basal colon inflammation, but increases disease activity in experimental IBD. Open J Gastroenterol 2013;3:177–189.

23. Oliveira AG, das Graças Pimenta Sanna M, Rocha GA, et al. Helicobacter species in the intestinal mucosa of patients with ulcerative colitis. J Clin Microbiol 2004;42:384–386.

24. Parlak E, Ulker A, Dişibeyaz S, Alkim C, Dağli U. 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.

25. Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet 2007;369:1641–1657.

26. Fefferman DS, Farrell RJ. Endoscopy in inflammatory bowel disease: indications, surveillance, and use in clinical practice. Clin Gastroenterol Hepatol 2005;3:11–24.