ISSN: 0973-7510
E-ISSN: 2581-690X
, Soumia Cherif1,3, Souad Sellami2, Maria Dref2, Khadija Krati4, Meftah Elkhir Meriem1, Said Elantri1, Abdessamad Amine1 and Hanane Rais2Observational studies regarding the correlation between colorectal carcinoma, inflammatory bowel disease and Helicobacter pylori infection are inconsistent. The present study aims to investigate the association between colorectal adenocarcinoma (CRA) and inflammatory bowel disease (IBD) with H. pylori status in 100 patients who have inflammatory bowel disease and colorectal carcinoma was confirmed disease by histological approach. Besides, a meta-analysis was performed of published studies, to evaluate the link between H. pylori infection and an increased risk of CRC and IBD. Among 67 cases with CRA and 33 cases with IBD, 59.7% and 51.5% were H. pylori positive; respectively. In the meta-analysis, thirty-nine articles were included, involving 13 231 cases with CRC and 2477 with IBD. The pooled odds ratio for CRC and IBD was 1.16 (95%CI = 0.73-1.82) and 0.42 (95%CI = 0.32-0.56); respectively. Our meta-analysis indicates that H. pylori is not associated with CRC.
Colorectal adenocarcinoma, colorectal cancer, Helicobacter pylori, IBD, immunohistochemistry, meta-analysis
Colorectal carcinoma (CRC) is the third most diagnosed cancer and the second most lethal cancer worldwide.1,2 In Morocco, colorectal cancer is classified as the first digestive cancer and remains a burden in the country, as 2484 new cases are diagnosed and account for ~14.8% of deaths annually.4,5 Additionally, it´s well known that colorectal cancer is sporadic. However, genetic and environmental risk factors are regarded as the most important.6,7 Furthermore, inflammatory bowel disease (IBD) related to Crohn’s disease (CD) and ulcerative colitis (UC); were associated positively with the occurrence of CRC.8-10
Despite the long-standing associations between bacterial infection and carcinogenesis, researchers have recently highlighted, the implication of Helicobacter pylori (H. pylori) in the initiation of colorectal carcinogenesis and the progression of CRC.11 H. pylori is a well-known cause of gastroduodenal disease.12 Beside gastric cancer, H. pylori infection has been correlated with other digestive tract cancers such as CRC.13 However, the cause and effect relationship of H. pylori with colorectal carcinogenesis, is still under debate; several studies have detected Helicobacter spp. in IBD, colonic adenoma and colonic adenocarcinoma.14-19 Nevertheless, the results were conflicting. In Morocco, there is no study linking H. pylori to colorectal adenocarcinoma and IBD.
To better evaluate the association of H. pylori infection with the risk of developing colorectal cancer, we aim to detect the presence of H. pylori in cases with IBD and colorectal adenocarcinomas (CRA).20 We also aim to update and review systematically current information regarding H. pylori in CRC and IBD.
Histological study
It is a prospective study, conducted at the department of pathological anatomy in Mohammed VI University Hospital Center in Marrakech. The biopsies were obtained by colonoscopy in the gastroenterology department in the University Hospital Center of Marrakech and examined histopathologically at the anatomy-pathology department in the Arrazi hospital CHU Mohammed VI in Marrakech. This study included 100 cases (67 colorectal adenocarcinoma, 23 ulcerative colitis and 10 Crohn’s disease cases) over 2 years (May 2018-May 2020). Medical and pathology records of the included cases were retrieved. The histopathological aspect of the study was performed by pathologists in accordance with the World Health Organisation (WHO) pathology and genetics (2010). After formalin fixation and paraffin embedding, the samples were sectioned and stained with Hematoxylin and eosine (H&E), and then analyzed by optical microscopy. The study protocol was approved by the local ethics committee of the Marrakech University Hospital Center. Patient consent was signed before the colonoscopy. In the case of illiterate or semi-illiterate consenters the written consent was explained by the investigator.
Data such as: sex, age, macroscopic aspect, anatomical location, degree of infiltration, histological type and degree of tumor differentiation were collected prospectively from the medical records of the included cases.
The detection for Helicobacter pylori was performed by histological Stains: modified Giemsa, Warthin-Starry and immunohistochemical staining were used to detect Helicobacter pylori, as previously described.13,21
The statistical analysis was performed using the software SPSS v26. The ҳ2 test was used to evaluate the association between the presence of H. pylori and the variable collected, p <0.05 was considered statistically significant.
Meta-analysis
Literature search
We followed PRISMA guidelines to conduct the meta-analysis. A systematic search was conducted from 1998 to 2019 using EMBASE, Web of Science, PubMed, and Cochrane Database. Two researchers (S.C and K.E) conducted literature searches independently, using the following terms: “H. pylori” or “Helicobacter pylori” and “Inflammatory bowel disease” or” IBD” or “Colorectal cancer” or “CRC” or “Crohn disease” or “ulcerative colitis” or “colitis”.
Inclusion criteria
The inclusion criteria were: i) observational studies including case-control studies, ii) detection of H. pylori by PCR, fast urease test, immunohistochemistry, specific staining (Giemsa and Warthin Starry) and ELISA, and iii) studies limited to humans.
Data extraction
The following information was extracted: I) the first author’s name, ii) the year of publication, iii) the study design, iv) the country where the study was conducted, v) the method used to detect H. pylori, vi) diagnosis; and vii) sample size.
Statistical analysis
Calculations were carried out by generating odds ratio “OR” with their 95% CIs using a random-effects model. Assessment of heterogeneity was performed using the Chi-square test and the I2statistic. If I2 statistic value is >50%, then the level of heterogeneity is considered as high.
Publication bias detection was performed by using Begg’s rank correlation test and Egger’s test. A two-sided P-value of less than 0.05 was considered as statistically significant. All analyses were performed using the software Rstudio version 1.3.1093 (USA).
As shown in Table 1, the median age of patients with IBD is 29.99±8.77 years, and that of patients with adenocarcinomas is 64.5 ±15.933 years. The male to female ratios for IBD and CRA were 0.73:1 and 1.31:1, respectively. In the CRA group, the tumour is frequently located in the left colon and the rectum (40.3% each), while 19.4% of tumours are located in the right colon. Macroscopically, in the CRA group, ulcerative-burgeoning tumours were the most common type (86.5%). The Lieberkuhnian adenocarcinoma was the most common histologic type (98.5%), followed by Mucinous CRA (1.5%). And according to the degree of tumour differentiation, 74.6% of adenocarcinomas are moderately differentiated, 19.4% are poorly differentiated and 5.9% are well differentiated. Depending on the degree of locoregional invasion, 97% of adenocarcinomas are infiltrated into the sub-serosa followed by 1.5% that is infiltrated into the serosa.
Table (1):
Clinical and histopathological characteristics of patients with CRA and IBD (N= 100).
| Categories | Variables | CRA (N=67) | IBD (N=33) |
|---|---|---|---|
| Sex | Female (48/100) | 29 (43%) | 19 (57,57%) |
| Male (52/100) | 38 (57%) | 14 (42,42%) | |
| Age (median) | 64,5 ±15,933 | 29,99±8,77 | |
| Anatomical localisation of the disease | Right colon | 13 (19,4%) | 10 (30,30%) |
| Left colon | 27 (40,3%) | 15 (45,46%) | |
| Rectum | 27 (40,3%) | 8 (24,24%) | |
| Macroscopic aspect of CRA | bourgeoning | 9 (15.5%) | – |
| ulcero-bourgeoning | 58 (86,5%) | – | |
| Histological types of CRA | Lieberkuhnien ACR | 66 (98,5%) | – |
| Mucinous ACR | 1 (1,5%) | – | |
| Degree of differentiation | Well-differentiated | 4 (5.9%) | – |
| Moderately differentiated | 50 (74.6%) | – | |
| Poorly differentiated | 13 (19.4%) | – | |
| Infiltration of CRA | Infiltrating the muscularis | 1 (1.5%) | – |
| Infiltrating the serosal surface | 1 (1.5%) | – | |
| Infiltrating the subserosal | 65 (97%) | – | |
CRA: colorectal adenocarcinoma, IBD: Inflammatory bowel disease
Special stainings and the immunohistochemistry revealed that H. pylori was present in 59.7% of CRA and 51.5% of IBD (Fig. 1, Table 2). 41.3% of women with CRA were H. pylori positive vs 73.6% of men (p≤0.05). Also, a positive association was found between H. pylori presence and the anatomical location of the diseases and the macroscopic aspect of the tumour. No association was found between H. pylori positivity and age, histological type, degree of differentiation and infiltration of the tumour (Table 2).
Table (2):
Characteristics of the patients linked with H. pylori infection (N=100) Chi square (χ2) test
| Categories | Variables | H. pylori positive n (%) | H. pylori negative n (%) | P-value | |
|---|---|---|---|---|---|
| Sex | IBD | Female | 12 (36.36%) | 5 (15.15%) | 0.16 |
| Male | 7 (21.21%) | 9 (27.27%) | |||
| CRA | Female | 12 (17.91%) | 17 (25.37%) | 0.01 | |
| Male | 28 (41.79%) | 10 (14.92%) | |||
| Age | IBD | A<50 | 15 (45.45%) | 11 (33.33%) | 0.67 |
| A≥51 | 5 (15.15%) | 2 (6.06%) | |||
| CRA | A<50 | 7 (10.44%) | 33 (49.25%) | 0.001 | |
| A≥51 | 15 (22.38%) | 12 (17.91%) | |||
| Anatomical location of IBD | Right colon | 4 (12.12%) | 6 (18.18%) | 0.36 | |
| Left colon | 7 (21.21%) | 8 (24.24%) | |||
| Rectum | 6 (18.18%) | 2 (6.06%) | |||
| Anatomical location of CRA | Right colon | 4 (5.97%) | 9 (13.43%) | 0.0007 | |
| Left colon | 23 (34.32%) | 4 (5.97%) | |||
| Rectum | 13 (19.4%) | 14 (20.89%) | |||
| Macroscopic aspect of CRA | Bourgeoning | 3 (4.47%) | 6 (8.95%) | 0.015 | |
| ulcero-bourgeoning | 37 (55.22%) | 11 (16.42%) | |||
| Histological types of CRA | Lieberkuhnian | 40 (59.7%) | 26 (38.8%) | 0.40 | |
| Mucinos | 0 (0%) | 1 (1.49%) | |||
| Differentiation | Well differentiated | 2 (2.98%) | 2 (2.98%) | 0.68 | |
| Moderately differentiated | 28 (41.79%) | 22 (32.83%) | |||
| Poorly differentiated | 10 (14.92%) | 13 (19.4%) | |||
Fig. 1. Detection of Helicobacter pylori by histological staining techniques: (A) by immunohistochemistry (× 100) B) Giemsa (× 1000) and (C) by Warthin starry (× 1000).
For the meta-analysis, a flow chart of study selection is reported in Fig. 2. The initial search identified 650 articles. Of these, 39 articles fulfilled the inclusion criteria and were retrieved for detailed evaluation. Twenty of these studies included 13231 patients with CRC, while nineteen articles were about 2477 patients with IBD.
Fig. 2. Flow Diagram of the literature research.
In the included articles (Table 3), 22 were performed in Europe, 12 in Asia, 3 in America and two in Turkey. In terms of H. pylori detection methods, 24 studies used serological tests (ELISA), 8 used C-urea breath tests, 8 performed histological techniques (IHC, special staining), 3 used H. pylori culture used PCR. A combination of 2 to 3 detection techniques was used in 3 studies.
Table (3):
Characteristics of the studies included in the meta-analysis.
Study |
Country |
Detection methods |
Type of malignancy |
Positivity in cases group(n/N) |
Positivity in control group(n/N) |
|---|---|---|---|---|---|
Wang et al22 |
China |
histology |
CRC |
189/3044 |
890/2362 |
Butt et al23 |
USA |
serology |
CRC |
1665/4063 |
1625/4063 |
Blase et al24 |
Gemany |
serology |
CRC |
213/392 |
121/774 |
Zhang et al25 |
China |
serology |
CRC |
265/569 |
205/569 |
Roka et al26 |
Greece |
Histology+ culture+ UBT |
IBD |
2/34 UC 3/66 CD 1/ 59 unspecified |
190/1443 |
Hansen et al27 |
Scotland |
histology |
IBD |
0/29 CD 0/13 UC 0/2 unspecified |
4/42 |
Jin et al28 |
China |
UBT+culture |
UC |
46/153 |
69/121 |
Nam et al29 |
Korea |
serology |
CRC |
6/9 |
248/470 |
Xiang et al30 |
China |
UBT +culture |
CD |
62/229 |
119/248 |
Zhang et al31 |
Germany |
serology |
CRC |
790/1712 |
669/1669 |
Strofilas et al32 |
Greece |
serology |
CRC |
66/93 |
13/20 |
Engin et al33 |
Turkey |
serology |
CRC |
77/110 |
71/116 |
Garza-Gonzalez et al34 |
Mexico |
serology |
IBD |
12/23 UC 12/21 CD |
51/75 |
Hong et al35 |
Korea |
histology |
IBD |
26/80 |
22/41 |
Lidar et al36 |
Italy |
serology |
IBD |
11/80 CD 5/39 UC |
27/98 |
Song et al37 |
Korea |
UBT |
IBD |
54/169 UC 26/147 CD |
165/316 |
Ando et al38 |
Japan |
UBT |
CD |
3/38 |
5/12 |
Bulajic et al39 |
Serbia |
PCR (ureA) |
CRC |
1/83 |
5/40 |
D’Onghia et al40 |
Italy |
serology |
CRC |
13/29 |
19/50 |
Jones et al41 |
UK |
histology |
CRC |
10/59 |
1/58 |
Montani et al42 |
Japan |
serology |
CRC |
74/113 |
145/226 |
Zumkeller et al43 |
Germany |
serology |
CRC |
195/384 |
204/467 |
Georgopoulos et al44 |
Greece |
serology |
CRC |
62/78 |
53/78 |
Moriyama et al45 |
Japan |
UBT |
CD |
3/29 |
5/7 |
Pronai et al46 |
Hungary |
UBT |
IBD |
10/82 UC 7/51 CD |
78/200 |
Piodi et al47 |
Italy |
UBT |
IBD |
17/32 CD 17/40 UC |
44/72 |
Limburg et al48 |
Finland |
serology |
CRC |
89/118 |
184/236 |
Furusu et al49 |
Japan |
Serology+ histology |
IBD |
0/25 UC 14/25 CD |
0/25 |
Siddheshwar et al50 |
Uk |
serology |
CRC |
110/189 |
110/179 |
Matsumura et al51 |
Japan |
serology |
CD |
15/90 |
211/525 |
Hartwick et al17 |
Poland |
serology |
CRC |
34/40 |
96/160 |
Vare et al52 |
Finland |
serology |
IBD |
55/185 UC 8/94 CD 3/17 Unspecified |
26/70 |
Parlak et al53 |
Turkey |
histology |
IBD |
46/66 UC 28/45 CD |
48/77 |
Pearce et al54 |
England |
Serology+UBT |
IBD |
11/51 UC 5/42 CD |
10/40 |
Breuer-Katschinski et al18 |
Germany |
serology |
CRC |
62/98 |
55/98 |
Thorburn et al55 |
USA |
serology |
CRC |
159/233 |
158/233 |
D´inca et al56 |
Italy |
histology |
IBD |
25/41 UC 33/67 CD |
54/43 |
Duggan et al57 |
England |
serology |
IBD |
59/213 UC 29/110 CD |
63/223 |
CRC: colorectalcancer, IBD: Inflammatory bowl disease, CD: Crohn s disease, UC: ulcerative colitis, UBT: 13C urease breath test, PCR: Polymerase Chain Reaction
The overall meta-analysis revealed no significant association between H. pylori and CRC (OR 1.16, 95%CI 0.73 to 1.82, p-value 0.74), and a negative association was found between H. pylori and IBD (OR 0.42, 95 % CI 0.32 to 0.56, p-value ≤0.0001) (Fig. 3, 4). However, heterogeneity was observed (p < 0.0001, I2 = 95%) (p < 0.0001, I2 = 69%) in CRC and IBD; respectively. As shown in Fig. 5, the funnel plots of publication bias appears asymmetric. Thus, we can assume the possibility of publication bias.
Fig. 3. Forest plot for the pooled OR of H.pylori infection and CRC.
Fig. 4. Forest plot for the pooled OR of H.pylori infection and IBD.
Fig. 5. Funnel plots of the published studies evaluating the association between H.pylori infection and the risk of CRC (A) and IBD (B).
CRC accounts for 8% of cancer deaths worldwide.4 This malignancy is asymptomatic until it reaches an advanced stage.58 Nowadays, it is known that IBD has a high relationship with CRC.59 The pathogenesis of CRC and IBD is still under debate. However, several pathways, have been proposed including TNF-α activation, which activates the transcription factor NF-kB. Besides, IL6 might also activate signal transducer and activator of transcription 3 (STAT), followed by the activation of JAKs (Janus kinase).5,59-61
Brackmann et al.,18 mentioned that patients with CRC related to IBD are affected at a younger age. In our study, the median age of patients with IBD was 29 years old. Besides, the median age in patients with CRC was 64.5 years in the present study. A comparable result was reported in a retrospective study conducted in Rabat.4
CRC is influenced by sex and gender, with males having significantly higher mortality rates.60,61 This might be due to several behavioural and gender-related factors such as a diet with red meat, alcohol consumption, and smoking. In our study, 57% of the cases were male.
Depending on the CRC anatomical position, the disease progression and the overall survival of CRCs will differ. The difference between these tumours is due to different cancerogenic factors and to the developmental origin of the tumour.62 Besides, a slight decrease in the incidence of the right-sided CRC was observed worldwide That can be explained by the progress of diagnostic, treatment and by the prevention of these cancers by ablation of the adenomatous polyps in the right part of the colon. An increase was reported in the left colon CRC.9 In a study conducted in Morocco, 60.3% of tumours were located in the rectum, 23.2% were located in the left colon, and 16.5% of tumours were located in the right colon.63 In our study, 19.4% of tumours are right-sided, 40.3% are left-sided and 40% are located in the rectum.
Regarding a probable correlation between colorectal carcinoma and H. pylori infection, several mechanisms have been proposed; such as the increasing release of gastrin that acts as a mitogen, the changing of gut microbiota and IBD induced during the migration of H. pylori from the mucosa to the light of the colon by faecal excretions.11,64,65 Besides, H. pylori virulence factors, like Cag A and Vac A that are associated with gastric adenocarcinoma, might have the same effect on CRC.66
In addition, an in-vitro study demonstrated that H. pylori lipopolysaccharides, can intervene with the DNA repair system of the colonic epithelial cells, promoting genotoxicity and then colon carcinogenesis.67 Also, it was shown that H. pylori lipopolysaccharides induce the production of nitric oxide, by inhibition of DNA repair enzymes and pro-apoptotic effector proteins resulting from the nitrosylation of their tyrosine and cysteine residues, causing chronic inflammation and then cancer.68,69
Several epidemiological studies have associated H. pylori infection with CRC and precancerous lesions like IBD, while others failed to establish a statistical association.11,70 Therefore, a quantitative evaluation of a possible association between CRC, IBD and H. pylori is required. In the current meta-analysis, 39 studies, with 13231 CRC cases and 2477 IBD cases, fit the selection criteria. The overall analyses showed no significant association between H. pylori and CRC (OR 1.16, 95%CI 0.73 to 1.82, p-value 0.74), and a negative association between H. pylori and IBD (OR 0.42, 95% CI 0.32 to 0.56, p-value ≤0.0001). Moreover, in the present prospective study, no correlation between H. pylori and IBD was addressed. Consistently, this study has shown a negative association between H. pylori and IBD The mechanism of the protective effect is the production of IL-18 by the suppressive T cells.71 Another immunoregulatory mechanism has been proposed involving the production of H. pylori neutrophil-activating protein, that decreases inflammation by agonist ligation of toll-like receptor 2, and H. pylori DNA, that averts sodium dextran sulfate-included colitis in mice.72
However, an association was found between sex, age, anatomical location, macroscopic aspect of the tumour in CRA patients and H. pylori (P≤0.05). These findings, plus the fact that very few studies have used PCR and histology to identify H. pylori in colorectal tissues, lead to the necessity to use more sensitive techniques to detect H. pylori in CRC subjects.
Our study presented had several limitations. First, several studies included in our meta-analysis used serological tests that can’t distinguish the exact location of H. pylori. Second, few have reported the exclusion of patients who have been administrated an H. pylori eradication treatment. Third, significant heterogeneity was found across studies, which might be explained by the geographic distribution and detection methods used.73,74
To the best of our knowledge, this is the first study that assesses the association between IBD and CRC with H. pylori infection in Morocco. Our results assert a possible association between H. pylori and sex, age, anatomical location and macroscopic aspect of the tumour in CRA patients. In the present meta-analysis, no association between H. pylori and CRC was established. Moreover, a negative association between H. pylori and IBD was addressed. However, more studies are needed to investigate the association of H. pylori with CRC risk using molecular techniques.
ACKNOWLEDGMENTS
None.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interest.
AUTHORS’ CONTRIBUTION
SC and KB conceptualize and designed the study. KB, SC, SS, MD, KK, MEM, SE, AA and HR collected, generated, assembled, analyzed and interpreted the data and drafted the manuscript. All authors read and approved the final manuscript for publication.
FUNDING
None.
ETHICS STATEMENT
This study was apporved by the Ethics Committees of the Arrazi Hospital CHU Mohammed VI of Marrakech, Morocco.
AVAILABILITY OF DATA
Not applicable.
INFORMED CONSENT
Informed consent was obtained from all individual participants included in the study.
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