Xiang Z, Chen YP, Ye YF, Ma KF, Chen SH, Zheng L, Yang YD, Jin X. Helicobacter pylori and Crohn’s disease: A retrospective single-center study from China. World J Gastroenterol 2013; 19(28): 4576-4581 [PMID: 23901235 DOI: 10.3748/wjg.v19.i28.4576]
Corresponding Author of This Article
Xi Jin, MD, Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou 310003, Zhejiang Province, China. jxfl007@hotmail.com
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Brief Article
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Zun Xiang, Yi-Peng Chen, Shao-Hua Chen, Xi Jin, Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
Yue-Fang Ye, Department of Gastroenterology, the Affiliated Hospital, College of Medicine, Hangzhou Normal University, Hangzhou 310015, Zhejiang Province, China
Kui-Fen Ma, Department of Pharmacy, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
Lin Zheng, Yi-Da Yang, Department of Infectious Disease, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
ORCID number: $[AuthorORCIDs]
Author contributions: Xiang Z, Chen YP and Ye YF performed the experiments and contributed equally to the study; Ma KF, Chen SH, Zheng L and Yang YD collected the clinical data and performed the statistical analysis; Jin X designed the study and wrote the manuscript.
Supported by The National Natural Science Foundation of China, No. 81000169, 81100277 and 81200284; the Excellent Young Investigator Foundation of Health Bureau of Zhejiang Province, No. 2010QNA011; the Excellent Young Investigator Natural Science Foundation of Zhejiang Province, No. Project R2110159; Project of Zhejiang Traditional Chinese Medicine Administration Bureau, Project 2010ZA065; and the National Technology Supporting Project, No. 2008BAI52B03
Correspondence to: Xi Jin, MD, Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou 310003, Zhejiang Province, China. jxfl007@hotmail.com
Telephone: +86-571-87236611 Fax: +86-571-87236603
Received: November 26, 2012 Revised: May 30, 2013 Accepted: June 19, 2013 Published online: July 28, 2013
Abstract
AIM: To investigate the association between Helicobacter pylori (H. pylori) infection and the prevalence of Crohn’s disease (CD).
METHODS: Subjects were selected from patients admitted the gastrointestinal (GI) department at The First Affiliated Hospital School of Medicine (Zhejiang University) for abdominal pain, hematochezia, diarrhea and other GI symptoms between January 2008 and September 2012. CD was diagnosed by endoscopy and biopsy. H. pylori infection was detected by a 14C-urea breath test and culturing of the biopsy sample. Demographic, anthropometric and serologic data were collected for each patient. H. pylori infection rate was compared between CD and control groups, followed by a subgroup analysis based on extent and severity of CD. Student’s t, Mann-Whiney U, and χ2 tests were used to analyze the data.
RESULTS: A total of 447 patients were analyzed, including 229 in the CD group and 248 in the control group. There were no significant differences in age, sex, and rates of hypertension or diabetes. However, the CD group showed significantly higher rates of smoking history (34.9% vs 18.1%), alcohol intake (17.4% vs 8.1%), white blood cell count (9.7 ± 2.9 × 109/L vs 4.3 ± 0.9 × 109/L), and C-reactive protein (36.3 ± 20.8 mg/L vs 5.5 ± 2.3 mg/L) but lower body mass index (24.5 ± 2.0 kg/m2vs 26.0 ± 2.2 kg/m2) than the control group. The H. pylori infection rate in the CD group was 27.1%, significantly lower than that of 47.9% in the control group. Furthermore, the H. pylori infection rates in patients with colonic, small intestine, ileocolonic and extensive CD were 31.1%, 28.9%, 26.8% and 25.9% respectively, all of which were significantly lower than in the control group. Finally, the H. pylori infection rates in patients with remission, moderate and severe CD were 34.3%, 30.7% and 22.0% respectively, which were also significantly lower than in the control group.
CONCLUSION: Lower H. pylori infection in CD patients suggests a correlation between bacterial infection and CD, suggesting caution when considering H. pylori eradication in CD patients.
Core tip: The association between Helicobacter pylori (H. pylori) infection and Crohn’s disease (CD) prevalence is still unclear. In this retrospective study, we collected 229 CD patients and 248 control subjects to investigate the risk factors for prevalence, extent and severity of CD. Through extensive analysis, we found significantly lower H. pylori infection rates in CD patients having different disease extent and severity, providing evidence for bacteria involvement in CD pathogenesis and serving as a reminder for clinicians to remain cautious when considering H. pylori eradication in CD patients.
Citation: Xiang Z, Chen YP, Ye YF, Ma KF, Chen SH, Zheng L, Yang YD, Jin X. Helicobacter pylori and Crohn’s disease: A retrospective single-center study from China. World J Gastroenterol 2013; 19(28): 4576-4581
Crohn’s disease (CD) is a chronic and relapsing inflammatory disease affecting any part of the intestine, most commonly involving the distal ileal, ileocecal and colonic sections[1]. CD is more common in northern Europe and America than in southern Europe and developing countries, and its prevalence has increased since the mid-1970s[2,3]. The pathogenesis of CD is unclear and increasing evidence supports the hypothesis of combinational involvement of genetic predisposition, immune response, and the environment, especially the gut bacteria and antigens[4]. Though several pathogens have been considered as infectious agents in CD, conclusive data is still lacking[5]. Therefore, identifying the correlation between a potential bacteria and CD pathogenesis is of clinical importance.
Helicobacter pylori (H. pylori) belongs to the family of curved or spiral flagellated, Gram-negative microaerophilic bacterium that is thought to have co-existed with humans for over 5000 years[6,7]. Since its discovery in 1984[8], H. pylori has been characterized as the causative agent for peptic ulceration and has been implicated in various autoimmune diseases[9]. Helicobacter are also excellent colonizers of the gastrointestinal surface for their microaerophilic metabolism, spiral shape, and peculiar motility. Considering the immune regulation, the capacity for colonization, and the nature of autoimmune-related damage in CD, it is theoretically plausible that H. pylori infection may take part in the pathogenesis of CD.
In immunodeficient rodents, Helicobacter hepaticus and Helicobacter bilis induce a persistent inflammation of the colon and cecum[10,11]. Nevertheless, the observations from human studies were confusing. Helicobacter was absent or only detected in the intestinal mucosa of a small subgroup of patients in both an English and an Australian study[12,13]. In contrast, Bohr et al[14] identified enterohepatic Helicobacter species in patients with inflammatory bowel disease (IBD). Furthermore, a meta-analysis suggested a protective role of H. pylori infection in CD pathogenesis but the heterogeneity among enrolled studies and the possibilities of publication bias limited the confidence of these results[15]. Therefore, we conducted a large-scale case control study to investigate the association between H. pylori infection and different severity and types of CD.
MATERIALS AND METHODS
Ethics statement
The protocol was approved by the institutional review board at Zhejiang University and conducted in accordance with the Declaration of Helsinki. We followed guidelines from the STROBE statement when designing the study and preparing the manuscript[16]. Written informed consent was collected from all patients.
Patients
Study subjects were selected from patients who were admitted for abdominal pain, hematochezia, diarrhea, and other GI symptoms between January 2008 and September 2012. Patients either underwent both a H. pylori test and endoscopy (gastroscopy, colonoscopy, or capsule) screen during admission or had recorded evidence of current H. pylori infection and CD. For the CD group, diagnosis was based on endoscopy manifestation and biopsy, as adopted by the Asia-Pacific consensus[17]. Exclusion criteria included previous acid inhibition or H. pylori eradication, 5-aminosalicylic administration and differential diagnosis with intestinal tuberculosis, ulcerative colitis (UC), Behçet’s disease, or ischemic colitis. The control group was comprised of patients who underwent the initial screening but were subsequently excluded by negative results for CD and other known GI diseases.
CD patients were further categorized into subgroups according to the severity and extent of disease following the Chinese IBD guidelines[18]. For convenience, we adopted the Harvey-Bradshaw index (HBI)[19], a simplified version of the Crohn’s disease activity index (CDAI), to evaluate CD severity. This index comprises general conditions, degree of abdominal pain, frequency of diarrhea, existence of abdominal mass, and complications such as arthritis, nodular erythema, gangrenous pyoderma, aphthous stomatitis, fistula, and abscess. Scores of 0-4 were appointed to each parameter according to disease severity. The HBI score was the summary of scores from each parameter, where ≤ 4 was remission, 5-8 was moderate, and ≥ 9 was severe. In addition, according to the extent revealed from radiology and endoscopy, CD was further divided into small intestinal CD, colonic CD, ileocolonic CD, and extensive CD, where the involved scale was over 100 cm.
Analysis of demographic, anthropometric and serologic data
Demographic and anthropometric data were retrieved from the medical records of enrolled patients and included age, sex, smoking history, alcohol intake history (with positive designation made according to the Chinese guideline of alcoholic liver disease[20]), hypertension (defined as a patient on antihypertensive drug for blood pressure over 140/90 mmHg), body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), and diabetes mellitus (DM; defined as fasting glucose ≥ 7.0 mmol/L or with past history of diagnosed DM). Patient blood samples were routinely gathered and tested for general condition and inflammation, including C-reactive protein (CRP) and complete blood cell counts. The main complications of CD were also recorded, including fistula and obstruction.
14C-urea blood test and biopsy sample culture
H. pylori infection was detected by a 14C-urea blood test (UBT) and biopsy sample culture. Serum H. pylori-IgG was not accepted as a diagnostic tool, as it does not reflect the current infection status. First described in 1989[21], 14C-UBT is considered a rapid diagnostic procedure for H. pylori detection for its ability to convert urea to ammonia and carbon dioxide. UBT is also recommended in leading society guidelines as a preferred non-invasive choice for H. pylori detection[22]. According to the manufacturer’s instruction (Headway, Shenzhen, China), patients were given a tablet of urea labeled with an uncommon isotope of radioactive carbon-14. In the following 30 min, the amount of isotope labeled carbon dioxide was measured in exhaled breath by scintillation. A positive result indicated the existence of H. pylori. For biopsy sample culture, samples from the gastric antrum obtained by gastroscopy were cultured for H. pylori as previously described[23].
Statistical analysis
Data were assessed for normality, and log-transformed as needed. Quantitative variants were expressed as mean ± SD, and analyzed by Student’s t test or Mann-Whiney U test. For qualitative variants, percentages or frequencies were calculated and a χ2 test was used for comparison. SPSS 17.0 software (Chicago, IL, United States) was used for all statistical analyses, and a P value < 0.05 was considered statistically significant.
RESULTS
Characteristics of study subjects
Following careful review of medical records, we identified 1563 patients that had been admitted to our ward for abdominal pain, hematochezia, diarrhea, and other GI symptoms over the past five years. Among these patients, 1231 were selected according to their having undergone both endoscopy and H. pylori test. The endoscopic diagnosis of CD was given to 921 patients by colonoscopy, 603 by gastroscopy, and 105 by capsule endoscopy. Furthermore, many of the patients had received more than one type of endoscopy. For the H. pylori infection test, 603 patients were investigated by biopsy sample culturing and 628 patients were investigated by 14C-UBT. Among these 1231 subjects, 287 were diagnosed as CD by endoscopy and/or biopsy confirmation, with 18 of these patients having already received 5-aminosalicylic therapy, 11 being under proton pump inhibitor (PPI) therapy for reflux symptoms, and 21 having achieved H. pylori eradication. Among the remaining patients, 8 were further excluded due to positive serum H. pylori-IgG but negative 14C-UBT or biopsy sample culture results. Finally, a total of 229 patients were enrolled into the CD group. Among them, 132 and 97 patients had 14C-UBT and biopsy sample culture, respectively.
Among 1231 subjects, 251 were diagnosed with UC, 279 with different degrees of hemorrhoids, 41 with ischemic colitis, 7 with antibiotic-associated colitis, 5 with radiation enterocolitis, 11 with intestinal tuberculosis, 71 with sigmoiditis and proctitis, and 2 with Behçet’s disease. The remaining 277 patients had GI symptoms but normal endoscopy and biopsy results. Nevertheless, there were still 14 patients under anti-acid therapy (10 with PPI and 4 with H2 receptor antagonist) and 15 patients in which H. pylori had been eradicated. Finally, there were 248 patients enrolled into control group. Among them, 147 and 101 patients had 14C-UBT and biopsy sample cultures, respectively.
Demographic, anthropometric and serologic data of enrolled patients
The average age and sex distribution of patients were balanced between two groups (Table 1). Differences in the rates of hypertension and DM between the two groups were not significant. However, BMI was significantly lower in the CD group than that in the control group, while the rate of smoking history was approximately twice that of the CD group (P < 0.01), reinforcing a correlation between smoking history and CD pathogenesis. In addition, percentage of alcohol intake was also significantly higher in the CD group. Finally, the two inflammation-associated markers, CRP and white blood cell (WBC) count, were significantly higher in the CD group, supporting the potential involvement of inflammation in CD.
Table 1 Demographic, anthropometric and serologic data of enrolled patients.
Group
CD (n = 229)
Control (n = 248)
P value
Age (yr)
46.2 ± 10.2
46.8 ± 9.4
0.79
Sex (male/female)
133/96
141/107
0.07
Smoking history
34.90%
18.10%
< 0.01
Alcohol intake
17.40%
8.10%
< 0.01
BMI (kg/m2)
24.5 ± 2.0
26.0 ± 2.2
< 0.01
Hypertension
14.80%
16.10%
0.09
Diabetes,
7.90%
6.90%
0.13
CRP (mg/L)
36.3 ± 20.8
5.5 ± 2.3
< 0.01
WBC (× 109/L)
9.7 ± 2.9
4.3 ± 0.9
< 0.01
Association between CD and H. pylori infection
Total H. pylori infection rate in the CD group was 27.1%, significantly lower than that of 47.9% in the control group. In the CD group, there were 45 patients with colonic CD, 28 with small intestine CD, 112 with ileocolonic CD, and 34 with extensive CD. In a subgroup analysis, all of the above-mentioned CD subgroups had significantly lower H. pylori infection rate than that in the control group, but the differences among these subgroups did not reach statistical significance (Table 2). We further divided the CD group into three subgroups according to severity determined by endoscopic appearance. Briefly, there were 32, 88 and 109 patients in the CD subgroups of remission, moderate CD, and severe CD, with corresponding H. pylori-positive rates of 34.3%, 30.7% and 22.0% respectively (Table 3). All three subgroups had significantly lower H. pylori infection rates than the control group. Nevertheless, though there was a decrease trend in H. pylori infection rate from the CD remission group to the severe CD group, there was no significant difference among these three groups.
Table 2Helicobacter pylori infection rate between different Crohn’s disease types n (%).
Group
H. pylori-positive
H. pylori-negative
P value
CD
62 (27.1)
167 (72.9)
< 0.01
Colonic CD
14 (31.1)
31 (68.9)
< 0.01
Small intestine CD
11 (28.9)
27 (71.1)
< 0.01
Ileocolonic CD
30 (26.8)
82 (73.2)
< 0.01
Extensive CD
7 (25.9)
27 (74.1)
< 0.01
Control
119 (47.9)
129 (52.1)
Table 3Helicobacter pylori infection between different severity of Crohn’s disease and control n (%).
Crohn’s disease can affect the entire digestive system from mouth to anus, but it is most commonly seen in the final segment of the small bowel and the first part of the colon. The frequency of CD has significantly increased in the last century, becoming a heavy economic burden[24]. The etiology of CD is still not completely understood[25], although NOD2/CARD15 was the first CD susceptibility gene to be discovered[26]. Oxidative stress, autophagy, endoplasmic reticulum stress and other molecular pathways have been correlated with CD prevalence[27,28]. Moreover, an infectious organism might be the initiating factor for CD pathogenesis. This hypothesis was supported by evidence from animal models showing that spontaneous colitis did not develop in a germ-free environment[29]. Nevertheless, none of suggested bacterial causes have been conclusively proven[5].
The role of H. pylori in IBD pathogenesis has been enticing. Generally, H. pylori had two main subgroups: gastric Helicobacter that preferentially colonize the stomach, and enterohepatic Helicobacter that infect the intestinal or hepatobiliary system[30]. Accumulating evidence from gene knockout rodents indicate that the presence of enterohepatic helicobacter worsens the severity or hastens the development of colitis[31,32]. A more causative role was suggested by the observation that Helicobacter muridarum can provoke CD in severe combined immunodeficiency mice upon receipt of T cells[33]. In addition, lower H. pylori infection rate in CD patients was not influenced by antibiotic use[34]. However, the results from human studies are confusing. The largest study examining the association between H. pylori infection and CD was conducted in the Netherlands by Wagtmans et al[35], which enrolled 386 CD patients and 277 controls. Though their results supported the positive association between H. pylori infection and CD prevalence, the credibility of these findings was weakened by the use of serum H. pylori-IgG as the diagnostic tool. A meta-analysis was conducted that supported the involvement of H. pylori infection in CD, but study heterogeneity and publication bias decreased its credibility[15]. In contrast, two independent studies found higher H. pylori infection in CD patients than in controls (12% vs 4% and 14.0% vs 1.4%, respectively)[14,36]. Furthermore, other studies investigating Helicobacter species in human colon also failed to find any correlation with CD[37,38].
To tackle this discordancy, we retrospectively investigated the association between H. pylori infection and CD in a large case control study of Chinese patients. The initial results showed a significantly lower H. pylori infection rate in the CD group, which is in accordance with the previous meta-analysis[15]. The 14C-UBT and biopsy sample culture had higher sensitivity and specificity than the serum H. pylori-IgG test, increasing the credibility of these findings. The significantly lower BMI in CD patients may be due to malnutrition caused by diarrhea and other GI symptoms. Based on subgroup analysis (Tables 2 and 3), we found significantly lower H. pylori infection in each CD subgroup and a trend of decreased H. pylori infection paralleling with increased CD severity, increasing the correlation between H. pylori infection and CD. Theoretically, it is possible for a protective role of H. pylori infection in CD[39]. In detail, H. pylori is able to decrease immune-mediated intestinal injury by triggering Th1 dominated cell defense[40] and inhibit other bacterially-induced mucosal damage by inducing antibacterial peptide production[41].
Several limitations of this study should be acknowledged. First, H. pylori infection in colon biopsy was not detected, which may decrease disease occurrence rate. Furthermore, other members of the Helicobacter family are associated with the development of gut inflammation and some are found more commonly in people with IBD when compared to healthy controls. However, these members colonize the lower gut, rather than having a location limited to the stomach. Therefore, while these data are convincing, it would be helpful to detect them in another independent experiment. Second, it is better to use 13C-UBT instead of 14C-UBT, since the former has no radiation and is safer for patients[42]. We have plans to implement this technique in our laboratory in the future. Third, wireless capsule endoscopy was used to detect small intestine CD. Though the effect of capsule endoscopy in small intestine CD diagnosis has been recognized[43], the lack of biopsy results may decrease its credibility. It would be helpful to include double balloon small bowel endoscopy. Fourth, the trend of decreased H. pylori infection paralleling with increased CD severity should be repeated in a larger clinical trial for statistical significance. Fifth, it is better to report H. pylori infection rate in IBD, where H. pylori in UC should be reported. We found a 30.5% H. pylori infection rate in UC patients and are currently preparing these data for submission. Finally, the causative effect of H. pylori infection in CD cannot be established through case control studies and further prospective clinical trial data are necessary.
In conclusion, our results provide evidence for the involvement of H. pylori in CD prevalence. These findings should serve as an important reminder to clinicians when considering H. pylori eradication in CD patients.
COMMENTS
Background
Crohn’s disease (CD) is a chronic and relapsing inflammatory disease affecting any part of the intestine, with distal ileal, ileocecal and colonic regions most commonly involved. CD is more common in Northern Europe and America than in Southern Europe and developing countries, with increased incidence since the mid-1970s and unknown etiologies.
Research frontiers
Increasing evidence supports the combinational involvement of genetic predisposition, immune response, and environment, especially gut bacteria and antigens. Though some pathogens have been considered as infectious agents in CD, conclusive data is still lacking. Considering the immune regulation and colonization capacity of Helicobacter pylori (H. pylori) and the nature of autoimmune-related damage in CD, it is plausible that H. pylori infection may take part in the etiology of CD. However, results in humans remain unclear and contradictory. While Helicobacter was absent or only detected in the intestinal mucosa of a few patients in English and Australian studies, another study identified enterohepatic Helicobacter species in patients with inflammatory bowel disease. Furthermore, a meta-analysis suggested a protective role of H. pylori infection in CD pathogenesis. However, the heterogeneity among enrolled studies and the possibilities of publication bias limited the confidence of those results.
Innovations and breakthroughs
The authors conducted a large-scale case control study to investigate the association between H. pylori infection and different severity and type of CD. These findings are the first example of a significant correlation between H. pylori infection rate in CD patients and different subtypes.
Applications
Lower H. pylori infection in CD patients provides evidence for bacterial involvement in the pathogenesis of CD and reminds clinicians remain cautious when considering H. pylori eradication in CD patients.
Peer review
Their results supported the potential involvement of H. pylori infection in CD pathogenesis and raised concern for the necessity of H. pylori eradication in CD patients. This manuscript provides some key information, and builds on the published literature. The authors should be able to enhance this by extensive revisions.
Footnotes
P- Reviewer Day AS S- Editor Zhai HH L- Editor A E- Editor Zhang DN
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