Helicobacter pylori and colorectal neoplasms: a concise review

Helicobacter pylori e neoplasias colorretais: revisão concisa

Luiz Gonzaga Vaz COELHO Maria Clara Freitas COELHO About the authors

ABSTRACT

Helicobacter pylori is the main etiological agent of all malignant tumors caused by an infectious disease. It is a major, at times dominant, factor in the pathogenesis of a large spectrum of diseases such as acute and chronic gastritis, gastric and duodenal ulcers, gastric carcinoma, and lymphoma. Epidemiological and experimental studies suggest that H. pylori chronic infection may be related to different extragastric diseases, including colorectal neoplasms. This concise review aims to explore the association of H. pylori infection with colorectal cancer and adenoma, including the recent epidemiological findings, the diagnostic methods employed to detect H. pylori and virulent factors, and the potentially involved mechanisms. Furthermore, is attempted to establish the current data integration for causal inference using the Bradford-Hill causality criteria. The weak, although global, strength of the epidemiological positive association between H. pylori infection and colonic neoplasms associated to new mechanisms postulated to explain this interaction, including intestinal dysbiosis, should stimulate future studies. Prospective confirmatory studies to establish the role of H. pylori eradication in the process of carcinogenic transformation of the colonic epithelium may define its eventual role in the treatment and prevention of colonic neoplasms.

HEADINGS:
Helicobacter infections; Colorectal neoplasms; Adenoma; Epidemiologic factors

RESUMO

Helicobacter pylori é o principal agente etiológico dos tumores malignos causados por doenças infecciosas. Constitui fator importante, às vezes dominante, na patogênese de um amplo espectro de doenças como gastrite aguda e crônica, úlceras gástricas e duodenais, carcinoma gástrico e linfoma. Estudos epidemiológicos e experimentais sugerem que a infecção crônica por H. pylori pode estar relacionada a diferentes doenças extragástricas, incluindo neoplasias colorretais. Esta concisa revisão tem como objetivo explorar a associação da infecção por H. pylori com câncer colorretal e adenoma, incluindo os recentes achados epidemiológicos, os métodos de diagnóstico empregados para detectar H. pylori e seus fatores de virulência com os mecanismos potencialmente envolvidos nesta relação. Além disso, procura-se estabelecer a integração dos dados atuais na busca de inferência causal com o emprego dos critérios de causalidade de Bradford-Hill. A associação epidemiológica positiva entre infecção por H. pylori e neoplasias do cólon embora classificada como fraca - porém global - do ponto de vista epidemiológico, quando associada a mecanismos recentemente postulados para explicar essa interação, incluindo disbiose intestinal, deverá estimular a realização de investigações futuras. Estudos prospectivos confirmatórios para estabelecer o papel da erradicação do H. pylori no processo de transformação carcinogênica do epitélio do cólon são aguardados para definir seu eventual papel no tratamento e prevenção de neoplasias do cólon.

DESCRITORES:
Infecções por Helicobacter; Neoplasias colorretais; Adenoma; Fatores epidemiológicos

INTRODUCTION

It is estimated today that at least 13% of all malignant tumors are caused by an infectious agent, and Helicobacter pylori (H. pylori) is the main etiological agent and responsible for approximately 810,000 cases of gastric cancer worldwide each year11. de Martel C, Georges D, Bray F, Ferlay J, Clifford GM. Global burden of cancer attributable to infections in 2018: a worldwide incidence analysis. Lancet Glob Health. 2020;8:e180-e190.. After H. pylori was identified by Marshall and Warren in 1983 in Australia, this microorganism has been found in at least 50% of the world´s population22. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet. 1984;1:1311-5.. It is a major, at times dominant, acquired environmental factor in the pathogenesis of a large spectrum of diseases such as acute and chronic gastritis, gastric and duodenal ulcers, gastric carcinoma, and lymphoma. Epidemiological and experimental studies suggest that H. pylori chronic infection may be related to different extragastric diseases, including colorectal cancer (CRC) and precancerous lesions33. Gravina AG, Zagari RM, De Mussis C, Romano L, Loguercio C, Romano M. Helicobacter pylori and extragastric diseases. A review. World J Gastroenterol. 2018;24:3204-21.,44. Butt J, Epplein M. Helicobacter pylori and colorectal cancer - A bacterium going abroad? PLoSPathog. 2019;15:e1007861. (Figure 1).

FIGURE 1
Helicobacter pylori infection and potentially linked extragastric diseases

CRC is a multifactorial disease of global concern, being the third most commonly diagnosed cancer with nearly 1.4 million new cases in 201855. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394-424.. A majority of CRC is sporadic; both genetic and environmental factors like nutritional practices, cigarette smoking, physical activity, obesity, and heavy alcohol consumption play an important part in the etiology of CRC66. Haggar FA, Boushey RP. Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg. 2009;22:191-7.. Besides, increasing evidence has established a role for the intestinal microbiota in the development of colorectal cancer77. Lucas C, Barnich N, Nguyen HTT. Microbiota, inflammation, and colorectal cancer. Int J Mol Sci. 2017;18 pii: E1310..

This paper aims to make a concise review of the association of H. pylori infection with colorectal cancer and adenoma, including the main epidemiological findings and potentially involved mechanisms. For these purposes, a PubMed search up to May 2020 was performed using a combination of the following keywords: Helicobacter pylori, colorectal cancer, colon cancer, adenoma, and colonic polyps. Also, the reference lists of all relevant articles were reviewed.

Potential associations among H. pylori infection and colorectal neoplasms

Four recent meta-analyses demonstrated a positive association between H. pylori infection and the risk of CRC and colorectal adenoma, presenting OR (95%CI) varying from 1.27 (1.17-1.37) to 1.44 (1.26-1.65) regarding CRC and 1.49 (1.37-1.62) to 1.66 (1.39-1.97) to colorectal adenoma88. Wu Q, Yang ZP, Xu P, Gao LC, Fan DM. Association between Helicobacter pylori infection and the risk of colorectal neoplasia: a systematic review and meta-analysis. Colorectal Dis. 2013;15:e352-64.

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10. Yang F, Xu YL, Zhu RF. Helicobacter pylori infection and the risk of colorectal carcinoma: a systematic review and meta-analysis. Minerva Med. 2019;110:464-70.
-1111. Choi DS, Seo SI, Shin WG, Park CH. Risk for Colorectal Neoplasia in Patients With Helicobacter pylori Infection: A Systematic Review and Meta-analysis. Clin Transl Gastroenterol. 2020;11:e00127. (Table 1). The studies involved in these meta-analyses came from 16 countries situated in Asia (38%), Europe (33%), America (mostly the USA) (20%), Middle-East (7%), and Oceania (2%).

TABLE 1
Studies included on the meta-analyses about the association between H. pylori and colorectal cancer and colorectal adenoma.

H. pylori infection

H. pylori can be detected in the gastric mucosa by different methods, either in fragments removed during endoscopy and used for histopathological, microbiological, biochemical and molecular studies or by non-invasive tests that include searching for H. pylori anti-antibodies in a blood sample, breath tests using carbon-13 labeled urea or investigating fecal antigens1212. Megraud F, Lehours P. Helicobacter pylori detection and antimicrobial susceptibility testing. Clin Microbiol Rev. 2007;20:280-322..

Although most studies analyzed mainly the presence of serum antibodies to H. pylori, it is important to consider some factors that may contribute to the heterogeneity among the studies results and their relationship with CRC. Among them, the presence of current or previous infection and the presence or absence of bacterial virulence factors such as the cag pathogenicity island, which encodes the oncogenic effector protein cagA and the allelic variation in the vacuolating cytotoxin A (vacA) were not mentioned1313. Cover TL. Helicobacter pylori Diversity and Gastric Cancer Risk. MBio 2016;7:e01869-15.. Likewise, studies didn´t inform the presence or absence of chronic sequelae of H. pylori infection in gastric epithelium inducing pre-malignant changes (atrophic gastritis and intestinal metaplasia), the increased level of serum gastrin promoting epithelial cell growth and proliferation, and hypochlorhydria that might lead to bacterial overgrowth in the gastrointestinal tract and alterations in the colonic microenvironment of the bacterial flora1414. Coelho LG, Marinho JR, Genta R, Ribeiro LT, Passos MCF, Zaterka S, et al. IV Brazilian Consensus Conference on Helicobacter pylori infection. Arq Gastroenterol. 2018;55:97-121.,1515. Kanno T, Matsuki T, Oka M, Utsunomiya H, Inada K, Magari H, et al. Gastric acid reduction leads to an alteration in lower intestinal microflora. Biochem Biophys Res Commun. 2009;381:666-70.. All these factors may contribute to colonic carcinogenesis.

As the serological test is not able to discriminate current from past infections, one study suggests that such a distinction may be crucial because only current H. pylori infection would induce humoral and cellular immune responses that provoke or perpetuate chronic inflammatory processes in the gastrointestinal tract with potential oncogenic sequelae including metastases and mortality. The authors also suggest that H. pylori eradication might inhibit the development or delay progression of CRC and recommend large-scale studies1616. Kountouras J, Kapetanakis N, Polyzos AS, Katsinelos P, Gavalas E, Tzivras D, et al. Active Helicobacter pylori Infection Is a Risk Factor for Colorectal Mucosa: Early and Advanced Colonic Neoplasm Sequence. Gut Liver. 2017;5:733-4..

H. pylori virulence factors expressed by different bacterial strains can modulate gastric adenocarcinoma risk1717. Suerbaum S, Michetti P. Helicobacter pylori infection. N Engl J Med. 2002;347:1175-86.. To assess whether such effects may also exist in the CRC, three recent studies were carried out in Europe1818. Fernández de Larrea-Baz N, Michel A, Romero B, Perez-Gomez B, Moreno V, Martin V, et al. Helicobacter pylori Antibody Reactivities and Colorectal Cancer Risk in a Case-control Study in Spain. Front Microbiol. 2017;8:888.,1919. Butt J, Jenab M, Pawlita M, Tjønneland A, Cecilie K, Boutron-Ruault MC, et al. Antibody responses to Helicobacter pylori and risk of developing colorectal cancer in a European cohort. Cancer Epidemiol Biomarkers. 2020;29:1475-81. and USA2020. Butt J, Varga MG, Blot WJ, Teras L, Visvanathan K, Marchand LL, et al. Serological response to Helicobacter pylori proteins associate with risk of colorectal cancer among diverse populations in the United States. Gastroenterology. 2019;156:175-186.e2. using H. pylori multiplex serology, a recently developed technique able to quantify seroreactivity immune response to several different H. pylori proteins. Fernández de Larrea-Baz N et al., in Spain, in a case-control study, analyzed 1488 CRC cases and 2495 controls and found that neither H. pylori seropositivity, nor seropositivity to the virulence factor cagA is associated with higher CRC risk1818. Fernández de Larrea-Baz N, Michel A, Romero B, Perez-Gomez B, Moreno V, Martin V, et al. Helicobacter pylori Antibody Reactivities and Colorectal Cancer Risk in a Case-control Study in Spain. Front Microbiol. 2017;8:888.. The European Prospective Investigation into Cancer and Nutrition (EPIC) cohort measured antibody responses to 13 H. pylori proteins in pre-diagnostic serum samples from 485 CRC cases and 485 matched controls1919. Butt J, Jenab M, Pawlita M, Tjønneland A, Cecilie K, Boutron-Ruault MC, et al. Antibody responses to Helicobacter pylori and risk of developing colorectal cancer in a European cohort. Cancer Epidemiol Biomarkers. 2020;29:1475-81.. Specifically, Helicobacter cysteine-rich protein C (HcpC) (OR: 1.66, 95%CI: 1.19-2.30) and vacA (OR: 1.34, 95%CI: 0.99-1.82), were associated with an increased risk of developing CRC. In the study from USA, serum samples were analyzed from 4063 incident cases of CRC and 4063 controls and found serologic responses to H. pylori vacA associated with increased risk of CRC risk, particularly for African Americans (OR: 1.45, 95%CI: 1.08-1.95)2020. Butt J, Varga MG, Blot WJ, Teras L, Visvanathan K, Marchand LL, et al. Serological response to Helicobacter pylori proteins associate with risk of colorectal cancer among diverse populations in the United States. Gastroenterology. 2019;156:175-186.e2.. These two studies suggest that antibody responses to different H. pylori virulence factors, mainly vacA and cagA, were significantly associated with increased risk of developing CRC and the association could vary by race/ethnicity. Further studies are needed to investigate causality among this association and the underlying biological mechanisms involved (see below).

The sequence infection by H. pylori → chronic gastritis →glandular atrophy → intestinal metaplasia → dysplasia → gastric cancer constitutes a set of associated alterations that are very frequently observed in the development of gastric cancer since H. pylori is recognized as a class I carcinogen2121. No authors listed. Schistosomes, liver flukes, and Helicobacter pylori. IARC. Working Group on the Evaluation of Carcinogenic Risks to Humans. IARC Monogr Eval Carcinog Risks Hum. 1994;61:1-241.. The risk of gastric adenocarcinoma increases significantly with premalignant progression2222. Correa P. Human gastric carcinogenesis: a multistep and multifactorial process - First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res. 1992;52:6735-40.,2323. Ohata H, Kitauchi S, Yoshimura N, Mugitani K, Iwane M, Nakamura H, et al. Progression of chronic atrophic gastritis associated with Helicobacter pylori infection increases risk of gastric cancer. Int J Cancer. 2004;109:138-43.. To investigate the relationship between gastric mucosa histological changes induced by the bacterium and colonic neoplasms, Sonnenberg and Genta conducted a large study including 156,000 patients undergoing both colonoscopy e gastroscopy, with histological assessment of the gastric mucosa and the colon2424. Sonnenberg A, Genta RM. Helicobacter pylori is a risk factor for colonic neoplasms. Am J Gastroenterol. 2013;108:208-15.. H. pylori status was performed by a polyclonal anti-H. pylori immunohistochemical stain. Compared with normal gastric mucosa, H. pylori gastritis occurred more frequently among patients with hyperplastic polyps, adenomatous polyps, advanced adenomas, villous adenomas, or adenomas with high-grade dysplasia, and adenocarcinomas. Other gastric conditions etiologically associated with H. pylori, such as intestinal metaplasia, adenoma, lymphoma, and adenocarcinoma, were also significantly associated with an increased risk of colonic neoplasm. Similar results were also observed in a Chinese study involving 233 patients2525. Qing Y, Wang M, Lin YM, Wu D, Zhu JY, Gao L, et al. Correlation between Helicobacter pylori-associated gastric diseases and colorectal neoplasia. World J Gastroenterol . 2016;22:4576-84.. To explore whether H. pylori atrophic gastritis, a pre-malignant condition, plays some role in the relation between H. pylori infection and advanced colonic neoplasms, Lee JY et al. in a cross-sectional study investigated the relationship between the presence of serum anti-H. pylori IgG antibodies, atrophic gastritis endoscopically-diagnosed, and advanced colonic neoplasms in 6,351 consecutive asymptomatic subjects who underwent a screening colonoscopy2626. Lee JY, Park HW, Choi JY, Lee JS, Koo JE, Chung EJ, et al. Helicobacter pylori Infection with Atrophic Gastritis Is an Independent Risk Factor for Advanced Colonic Neoplasm. Gut Liver . 2016;10:902-9.. A total of 316 (5.0%) participants had advanced colonic neoplasm. The results showed that advanced colonic neoplasms occurred more frequently in H. pylori-infected patients with atrophic gastritis than without atrophic gastritis (7.3% vs 4.4%, P<0.001). A large recent study also investigated the association of gastric H. pylori presence with the risk of colorectal polyps and CRC2727. Wang M, Kong WJ, Zhang JZ, Lu JJ, Hui WJ, Liu WD, et al. Association of Helicobacter pylori infection with colorectal polyps and malignancy in China. World J Gastrointest Oncol. 2020;12:582-91.. The results confirmed that patients with H. pylori infection were 2.19 and 3.05 times more likely to develop colorectal polyps and CRC, respectively, than those without H. pylori active infection. Additionally, they found that the incidence of H. pylori infection coexisting with atrophic gastritis or intestinal metaplasia was higher in patients with colorectal polyps and CRC than in the control group. These findings reproduced Sonnenberg & Genta’s study which showed that the H. pylori-positive gastritis and intestinal metaplasia, a more easily recognizable pre-malignant lesion, increased risk for colonic neoplasms while H. pylori-negative gastritis did not2424. Sonnenberg A, Genta RM. Helicobacter pylori is a risk factor for colonic neoplasms. Am J Gastroenterol. 2013;108:208-15..

Potential mechanisms for causality

H. pylori is a pathogen restricted to primates (natural infection restricted to humans and monkeys) and, in humans, binds exclusively to the surface of the mucus-secreting cells of the stomach. In vivo, only 2-20% of the bacterial population exhibits adherence to the epithelial surface, the rest of the microorganisms remaining protected in the gastric mucus layer2828. Hessey SJ, Spencer, Wyatt JI, Sobala G, Rathbone BJ, Axon ATR, et al. Bacterial adhesion and disease activity in Helicobacter associated chronic gastritis. Gut. 1990;31:134-8.. This specific tissue tropism is partly explained by the existence of specific adhesin molecules on the bacterial surface that acts as ligands in gastric epithelium receptors. The challenge is to account any action at a distance from this unique bacteria on colonic neoplasms risks. H. pylori direct and/or indirect effects on colorectal carcinogenesis have been considered trying to explain causality2828. Hessey SJ, Spencer, Wyatt JI, Sobala G, Rathbone BJ, Axon ATR, et al. Bacterial adhesion and disease activity in Helicobacter associated chronic gastritis. Gut. 1990;31:134-8..

Regarding direct effects, studies evaluating the presence of H. pylori in the colorectal neoplastic epithelium are still scarce. Three pilot studies, two using immunohistochemical methods and a PCR technique identified H. pylori between 22-27% in samples of polyps or CRC fragments2929. Jones M, Helliwell P, Pritchard C, Tharakan J, Mathew J. Helicobacter pylori in colorectal neoplasms: is there an aetiological relationship? World J Surg Oncol. 2007;5:51.

30. Soylu A, Ozkara S, Alis H, Dolay K, Kalayci M, Yasar N, et al. Immunohistochemical testing for Helicobacter pylori existence in neoplasms of the colon. BMC Gastroenterol. 2008;8:35.
-3131. Grahn N, Hmani-Aifa M, Fransén K, Söderkvist P, Monstein H. Molecular identification of Helicobacter DNA present in human colorectal adenocarcinomas by 16S rDNA PCR amplification and pyrosequencing analysis. J Med Microbiol. 2005;54:1031-5.. Greek authors, using immunohistochemical staining technique to identify H. pylori in 50 patients with CRC, 25 patients with colorectal adenomas and 10 controls described a significantly higher prevalence of H. pylori in the adenoma (68%) and CRC (84%) groups when compared to the control group (30%)3232. Kountouras J, Kapetanakis N, Zavos C, Romiopoulos I, Polyzos AS, Tsiaousi E, et al. Impact of Helicobacter pylori infection on colon oncogenesis. Am J Gastroenterol . 2013;108:625-6.. As almost everything present in the stomach can be found in the stools, H. pylori is eliminated via this route and, although difficult, has been cultured in the stools since 19923333. Thomas JE, Gibson GR, Darboe MK, Dale A, Weaver LT. Isolation of Helicobacter pylori from human faeces. Lancet 1992;340:1194-5.. Although H. pylori or its DNA have already been identified in the colonic epithelium, it is important to note that H. pylori infects only the gastric type mucosa and, in vivo, it has never been described adhered to the colonic epithelium. Bacterial adherence to a cell can trigger a cascade of events where adhesins can act as biological effector molecules3434. Clyne M, Drum B. Adherence of Helicobacter pylori to primary human gastrointestinal cells. Infect Immun. 1993;61:4051-7.. One study showed that some components of the cell wall of H. pylori itself can be carcinogenic to the colorectal epithelial cell lining3030. Soylu A, Ozkara S, Alis H, Dolay K, Kalayci M, Yasar N, et al. Immunohistochemical testing for Helicobacter pylori existence in neoplasms of the colon. BMC Gastroenterol. 2008;8:35.. Studies are still needed to assess whether H. pylori acting directly on the colonic epithelium is capable of causing carcinogenic effects on the colon and rectum as observed in the gastric mucosa.

The mechanisms by which H. pylori virulence factors are involved in increasing the risk of developing colorectal neoplasms remain unclear. One of the major H. pylori virulent factors is the multifunctional vacA toxin. Considered a gastric cancer virulence factor, it has been speculated that it would be able to exert, outside the stomach, its effects on cellular vacuolation, cellular permeability, interference with cellular pathways, in addition to immunomodulatory and pro-inflammatory properties3535. McClain MS, Beckett AC, Cover TL. Helicobacter pylori vacuolating toxin and gastric cancer. Toxins (Basel) 2017;9.,3636. Chauhan N, Tay ACY, Marshall BJ, Jain U. Helicobacter pylori VacA, a distinct toxin exerts diverse functionalities in numerous cells: An overview. Helicobacter. 2019;24:e12544.. One recent suggestion is that vacA forms chloride channels that become inserted into the cell and mitochondrial membranes thereby reducing the membrane potential and mitochondrial energy production, interfering on cell proliferation control. Therefore, it would be biologically plausible that the vacA toxin of H. pylori could increase the risk of colon cancer, by chronically altering ionic equilibrium enterocytes exposed to the toxin3737. Ponzetto A, Figura N. Colon Cancer Risk and VacA Toxin of Helicobacter pylori. Gastroenterology. 2019;156:2356.. Regarding the virulent factor cagA, which requires direct contact between bacteria and host cells, a Japanese study3838. Shimoda A, Ueda K, Nishiumi S, Murata-Kamiya N, Mukai SA, Sawada SI, et al. Exosomes as nanocarriers for systemic delivery of the Helicobacter pylori virulence factor CagA. Sci Rep. 2016;6:18346. suggested that exosomes containing cagA were detectable in the blood of cagA-positive H. pylori-infected individuals and could facilitate the development of multiple extragastric diseases. Because cagA is a bacterial oncoprotein, exosome-mediated cagA delivery may also be involved in the development of neoplasias outside the stomach and further studies are required in this area.

Indirect mechanisms have been also hypothesized involving H. pylori infection and increased risk of colorectal neoplasms such as gastrin-17 levels and H. pylori and microbiota interactions. Gastrin-17 belongs to a subgroup of gastrin composed of 17 amino acids, being produced by G cells of the gastric antrum and indicative of the glandular integrity of the antral mucosa. Their levels are closely related to the stomach’s intraluminal pH, that is, they are reduced in acidic medium and abnormally high in case the patient has hypo or achlorhydria3939. di Mario F, Cavallaro LG. Non-invasive tests in gastric diseases. Dig Liv Dis. 2008;40:523-30.. The rationale for exploring the association between gastrin and colorectal neoplasms is the putatitve role of the hormone in epithelial cell growth and to prevent apoptosis4040. Thorburn CM, Friedman GD, Dickinson CJ, et al. Gastrin and colorectal cancer: a prospective study. Gastroenterology. 1998;115:275-80.. Experimental, in vitro, and human studies have shown discrepant results about the gastrin role to stimulate the growth of normal colonic epithelium and colorectal neoplasms4141. Chu M, Rehfeld JF, Borch K. Effects of gastric fundectomy and antrectomy on the colonic mucosa in the hamster. Digestion. 1992;53:28-34.

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48. Selgrad M, Bornschein J, Kandulski A, Hille C, Weigt J, Roessne A, et al. Helicobacter pylori but not gastrin is associated with the development of colonic neoplasms. Int J Cancer . 2014;135:1127-31.
-4949. Robertson DJ, Sandler RS, Ahnen DJ, Greenberg ER, Mott LA, Cole BF, et al. Gastrin, Helicobacter pylori, and Colorectal Adenomas. Clin Gastroenterol Hepatol. 2009;7:163-7.. In addition to H. pylori (the most common cause of hypergastrinemia), three other conditions can increase gastrin expression: use of proton pump inhibitor (PPI), autoimmune gastritis, and Zollinger-Ellison syndrome (gastrinoma). A meta-analysis performed in 2012 found no association between PPI use and the risk of CRC5050. Ahn JS, Park SM, Eom CS, Kim S, Myung SK. Use of Proton Pump Inhibitor and Risk of Colorectal Cancer: A Meta-analysis of Observational Studies. Korean J Fam Med 2012;33:272-9.. A recent nationwide cohort study performed in Taiwan involving 45,382 elegible PPI users suggests that PPIs use might increase the risk of CRC in a dose-dependent manner5151. Lei W-Y, Wang JH, Yi CH, Hung JS, Wong MW, Bair MJ, et al. Association between use of proton pump inhibitors and colorectal cancer: A nationwide population-based study. Clin Res Hepatol Gastroenterol. (2020). Available from: https://doi.org/10.1016/j.clinre.2020.02.017.
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while another USA recent nested case-control study in a large community-based integrated healthcare setting involving 18,595 CRC patients suggests that PPI use for at least two years was not associated with CRC risk (OR: 1.05, 95%CI: 0.99-1.12)5252. Lee JK, Merchant SA, Schneider JL, Jensen CD, Fireman BH, Quesenberry CP, et al. Proton Pump Inhibitor Use and Risk of Gastric, Colorectal, Liver, and Pancreatic Cancers in a Community-Based Population. Am J Gastroenterol . 2020;115:706-15.. A systematic review with meta-analysis was performed to evaluate the incidence of cancer (other than gastric cancer) in pernicious anemia (PA), a late sequel of autoimmune gastritis where hypergastrinemia is secondary to damaged oxyntic mucosa and impaired gastric secretion5353. Lahner E, Capasso M, Carabotti M, Annibale B. Incidence of cancer (other than gastric cancer) in pernicious anaemia: A systematic review with meta-analysis. Dig Liver Dis. 2018;50:780-6.. It was found that PA patients had a lower RR (0.14, 95%CI: 0.01-0.19) for CRC compared to the general population. Likewise, the long-term hypergastrinemia secondary to Zollinger-Ellison syndrome has shown no effect on colonic adenomas or CRC development5454. Orbuch M, Venzon DJ, Lubensky IA, Weber HC, Gibril F, Jensen RT. Prolonged hypergastrinemia does not increase the frequency of colonic neoplasia in patients with Zollinger-Ellison syndrome. Dig Dis Sci. 1996;41:604-13.. Some other studies included investigations related to an eventual autocrine production of gastrin by colorectal neoplasms5555. Singh P, Dai B, Wu H, Owlia A. Role of autocrine and endocrine gastrin-like peptides in colonic carcinogenesis. Curr Opin Gastroenterol. 2000;16:68-77., other forms of gastrin serum determinations and not only amidated forms5656. Watson SA, Michaeli D, Grimes S, Morris TM, Robinson G, Varro A, et al. Gastroimmune raises antibodies that neutralize amidated and glycine-extended gastrin-17 and inhibit the growth of colon cancer. Cancer Res . 1996;56:880-5., the real status of H. pylori infection5757. Kawahara Y, Kodama M, Mizukami K, Saito T, Hirashita Y, Sonoda A, et al. Endoscopic gastric mucosal atrophy as a predictor of colorectal polyps: a large scale case control study. J Clin Biochem Nutr. 2019;65:153-9., and previous information about PPI use and surgeries in the patients4848. Selgrad M, Bornschein J, Kandulski A, Hille C, Weigt J, Roessne A, et al. Helicobacter pylori but not gastrin is associated with the development of colonic neoplasms. Int J Cancer . 2014;135:1127-31., but even though, more studies to clarify the conflicting studies of hypergastrinemia and colonic neoplasms in humans are needed.

H. pylori relation to the intestinal microbiota has also been investigated. CRC results from a combination of inherited and acquired mutations in the colon’s epithelial cells and associated with different factors including the intestinal microbiota5858. Abreu MT, Peek Jr RM. Gastrointestinal Malignancy and the Microbiome. Gastroenterology. 2014;146:1534-46.. Increasing evidence shows that specific bacteria and bacterial dysbiosis can potentiate the initiation or progression of CRC. The speculated mechanisms involve damaging DNA, activating oncogenic signaling pathways, producing tumor-promoting metabolites such as secondary bile acids, and suppressing antitumor immunity5959. Garrett WS. The gut microbiota and colon cancer. Science 2019;364:1133-5.,6060. Mima K, Ogino S, Nakagawa S, Sawayamaa H, Kinoshitaa K, Krashima R, et al. The role of intestinal bacteria in the development and progression of gastrointestinal tract neoplasms. Surg Oncol. 2017:368-76.. H. pylori infection seems to span beyond gastric microbiota and affects downstream gastrointestinal microbiota1515. Kanno T, Matsuki T, Oka M, Utsunomiya H, Inada K, Magari H, et al. Gastric acid reduction leads to an alteration in lower intestinal microflora. Biochem Biophys Res Commun. 2009;381:666-70.. Experimental studies with atrophic gastritis patients demonstrate that acid secretion reduction induces colorectal microbiota changes, intestinal bacterial overgrowth, and may favor carcinogenesis6161. Dash NR, Khoder G, Nada AM, Al Bataineh MT. Exploring the impact of Helicobacter pylori on gut microbiome composition. PLoS One. 2019;14:e0218274.

62. Husebye E. The pathogenesis of gastrointestinal bacterial overgrowth. Chemotherapy. 2005;51 (Suppl 1):1-22.
-6363. Sobhani I, Tap J, Roudot-Thoraval F, Roperch JP, Letulle S, Langella P, et al. Microbial dysbiosis in colorectal cancer (CRC) patients. PLoS One . 2011;6:e16393.. The enhanced production of secondary bile acids by colonic bacterial overgrowth can also increase the risk for CRC, especially proximal colon cancer2626. Lee JY, Park HW, Choi JY, Lee JS, Koo JE, Chung EJ, et al. Helicobacter pylori Infection with Atrophic Gastritis Is an Independent Risk Factor for Advanced Colonic Neoplasm. Gut Liver . 2016;10:902-9.,6464. Giovannucci E, Colditz GA, Stampfer MJ. A meta-analysis of cholecystectomy and risk of colorectal cancer. Gastroenterology. 1993;105:130-41.. It is still unclear whether there are specific microbes that are particularly pathogenic and directly cause colorectal carcinogenesis, or whether the process requires specific interactions between host tissues and microbes5858. Abreu MT, Peek Jr RM. Gastrointestinal Malignancy and the Microbiome. Gastroenterology. 2014;146:1534-46..

Association or causation?

As the main human cancer-associated bacteria, studies continue to search for other Helicobacter species with oncogenic potential6565. de Martel C, Plummer M, Parsonnet J, Van Doorn LJ, Franceschi S. Helicobacter species in cancers of the gallbladder and extrahepatic biliary tract. Br J Cancer. 2009;100:194-9. as well as for other non-gastric tumors where it could have a causal role, such as CRC and adenomas (Table 1). The Bradford Hill criteria6666. Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965;58:295-300. (Figure 2), described in 1965 to establish a causal relationship between an agent and a disease, are still useful tools in establishing causation and also in proposing other necessary researches to confirm a potentially causal association6767. Fedak KM, Bernal A, Capshaw ZA, Gross S. Applying the Bradford Hill criteria in the 21st century: how data integration has changed causal inference in molecular epidemiology. Emerg Themes Epidemiol. 2015;12:14. and will be briefly discussed here.

FIGURE 2
Bradford-Hill causality criteria6666. Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965;58:295-300..

Strength and consistency: the positive association demonstrated between H. pylori and colorectal neoplasms is evidenced mainly by case-control studies and some prospective studies. Such observation has been consistently confirmed in different regions of the world, with some predominance in Asian countries. However, the OR found always ranges below 2, considered a weak association to the assessment of potentially causal relationships88. Wu Q, Yang ZP, Xu P, Gao LC, Fan DM. Association between Helicobacter pylori infection and the risk of colorectal neoplasia: a systematic review and meta-analysis. Colorectal Dis. 2013;15:e352-64.

9. Zhao Y, Wang X, Wang Y. Helicobacter pylori infection and colorectal carcinoma risk: A meta-analysis. J Can Res Ther. 2016;12:15-8.

10. Yang F, Xu YL, Zhu RF. Helicobacter pylori infection and the risk of colorectal carcinoma: a systematic review and meta-analysis. Minerva Med. 2019;110:464-70.
-1111. Choi DS, Seo SI, Shin WG, Park CH. Risk for Colorectal Neoplasia in Patients With Helicobacter pylori Infection: A Systematic Review and Meta-analysis. Clin Transl Gastroenterol. 2020;11:e00127.. Specificity: needless to point out that H. pylori and colorectal neoplasm association is not specific given the well-known relationship between H. pylori and gastroduodenal diseases. However, this is not uncommon in the infectious diseases field where an individual may harbor a microorganism as an asymptomatic carrier while others, in the presence of genetic or environmental factors, will develop associated diseases. In other words, the presence of H. pylori could be necessary, but not sufficient for the development of colorectal neoplasms. Temporality: the concept that an agent´s exposure must precede disease´s onset, seems to be observed in the association, since infection by H. pylori uses to be acquired in childhood, before 10 years of age, in most patients1717. Suerbaum S, Michetti P. Helicobacter pylori infection. N Engl J Med. 2002;347:1175-86.. The positivity of the association also observed in prospective studies excludes the possibility of reverse causality88. Wu Q, Yang ZP, Xu P, Gao LC, Fan DM. Association between Helicobacter pylori infection and the risk of colorectal neoplasia: a systematic review and meta-analysis. Colorectal Dis. 2013;15:e352-64.,4040. Thorburn CM, Friedman GD, Dickinson CJ, et al. Gastrin and colorectal cancer: a prospective study. Gastroenterology. 1998;115:275-80.. Biological gradient: the presence of a dose-response effect traditionally supports a causal relationship between an agent and the effect. Some studies suggest that patients infected with H. pylori strains expressing gastric cancer virulence factors such as cagA and vacA, or presenting premalignant gastric lesions have higher odds of association with CRC1919. Butt J, Jenab M, Pawlita M, Tjønneland A, Cecilie K, Boutron-Ruault MC, et al. Antibody responses to Helicobacter pylori and risk of developing colorectal cancer in a European cohort. Cancer Epidemiol Biomarkers. 2020;29:1475-81.,2020. Butt J, Varga MG, Blot WJ, Teras L, Visvanathan K, Marchand LL, et al. Serological response to Helicobacter pylori proteins associate with risk of colorectal cancer among diverse populations in the United States. Gastroenterology. 2019;156:175-186.e2.,2727. Wang M, Kong WJ, Zhang JZ, Lu JJ, Hui WJ, Liu WD, et al. Association of Helicobacter pylori infection with colorectal polyps and malignancy in China. World J Gastrointest Oncol. 2020;12:582-91.,5757. Kawahara Y, Kodama M, Mizukami K, Saito T, Hirashita Y, Sonoda A, et al. Endoscopic gastric mucosal atrophy as a predictor of colorectal polyps: a large scale case control study. J Clin Biochem Nutr. 2019;65:153-9.. Biological plausibility and coherence: these criteria seek to analyze whether the relationship between the agent and the disease is consistent with current knowledge concerning the etiology and mechanism of the disease. Although the pathophysiological mechanisms underlying the association between H. pylori and colonic neoplasms remain unclear, important progress has been recently observed in the direct and/or indirect potential actions of H. pylori infection, or even associated with intestinal dysbiosis, in colonic carcinogenesis process44. Butt J, Epplein M. Helicobacter pylori and colorectal cancer - A bacterium going abroad? PLoSPathog. 2019;15:e1007861.,2424. Sonnenberg A, Genta RM. Helicobacter pylori is a risk factor for colonic neoplasms. Am J Gastroenterol. 2013;108:208-15.,2626. Lee JY, Park HW, Choi JY, Lee JS, Koo JE, Chung EJ, et al. Helicobacter pylori Infection with Atrophic Gastritis Is an Independent Risk Factor for Advanced Colonic Neoplasm. Gut Liver . 2016;10:902-9.,6161. Dash NR, Khoder G, Nada AM, Al Bataineh MT. Exploring the impact of Helicobacter pylori on gut microbiome composition. PLoS One. 2019;14:e0218274.. Experiment: considered by Hill6767. Fedak KM, Bernal A, Capshaw ZA, Gross S. Applying the Bradford Hill criteria in the 21st century: how data integration has changed causal inference in molecular epidemiology. Emerg Themes Epidemiol. 2015;12:14. as the strongest support for causal inference, the intervention through which can be demonstrated that disease´s risk declines after a treatment or exposition cessation, still lacks definite proof in studies about the association between H. pylori and colorectal neoplasms. To assess the development of colorectal adenoma, a recent retrospective study followed 615 patients for nine years with no history of colorectal adenoma or cancer at baseline6868. Hu KC, Wu MS, Chu CH, Wang HY, Lin SC, Liu CC, et al. Decreased Colorectal Adenoma Risk After Helicobacter pylori Eradication: A Retrospective Cohort Study. Clin Infect Dis. 2019;68:2105‐13.. Patients underwent upper digestive endoscopy and colonoscopy and were classified into three groups: individuals with no H. pylori infection, successful H. pylori eradication, and persistent H. pylori infection. During follow-up, the incidence rates of colorectal adenoma progression in participants uninfected with H. pylori were similar to the eradication group while the risk seen in the persistent infection group was 3-fold higher (HR: 3.04, 95%CI: 1.905.86. Despite retrospective study limitations, the results might support a causal relationship. Analogy: the situation where for analogous exposures and outcomes an effect has already been shown, would be sometimes acceptable to “judge by analogy”. The tools diversity available today allowing the search for specific analogies such as the pattern of CRC progression, common risk factors, confounders and disease mechanisms, the modern value of the analogy seems more relevant in proposing and testing mechanistic hypotheses that confirm a causal inference6767. Fedak KM, Bernal A, Capshaw ZA, Gross S. Applying the Bradford Hill criteria in the 21st century: how data integration has changed causal inference in molecular epidemiology. Emerg Themes Epidemiol. 2015;12:14..

CONCLUSION

Although the strength of the positive association between H. pylori infection and colonic neoplasms is considered weak from an epidemiological point of view, new mechanisms have been postulated trying to explain how a bacterium acting far from its ecological niche − the gastric milieu - could directly or indirectly interfere in colonic carcinogenesis, either through its virulence factors and/or metabolites or by promoting intestinal dysbiosis. A preliminary study suggests that the colorectal adenoma ratio might decrease after successful eradication of H. pylori. Several further studies are still necessary to establish a causal relationship in a disease with complex multifactorial etiology as colorectal neoplasms. Well-designed studies to better understand the changing incidence of colorectal cancer, the prevalence of H. pylori infection, and ethnic and environmental aspects involved in CRC are warranted. Prospective confirmatory studies to establish the role of H. pylori eradication in the process of carcinogenic transformation of the colonic epithelium may define its eventual role in the treatment and prevention of colonic neoplasms.

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  • Disclosure of funding: no funding received

Publication Dates

  • Publication in this collection
    23 Apr 2021
  • Date of issue
    Jan-Mar 2021

History

  • Received
    29 June 2020
  • Accepted
    17 Sept 2020
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