Helicobacter pylori infection and colorectal carcinoma: is there a causal association?

To the Editor,

We would like to thank Dr. Kapetanakis and his colleagues for their interest in our article (1). We specifically appreciate the attention they brought to the importance of environmental factors, particularly Helicobacter pylori (H. pylori) infection, in the development of sporadic colorectal carcinoma (CRC). While the focus of our article was on the pathologic aspects (2), we would like to take this opportunity to extend our discussion to H. pylori as a potential etiopathogenetic factor in colorectal tumorigenesis.

As mentioned by Dr. Kapetanakis and his colleagues, the development of sporadic CRC is associated with a variety of environmental factors including diet and lifestyle. Given that the colon harbors the largest number of microorganisms in the body, it is natural to assume that certain microbial species may play a role in colorectal tumorigenesis. The first reports connecting intestinal microflora with CRC were published back in the early 1950s. Streptococcus bovis septicemia was reported to be associated with carcinoma of the sigmoid colon (3). This association was subsequently supported by several publications (4-6). Animal studies have shown that S. bovis or its cell wall antigens promote the formation of hyperproliferative aberrant colonic crypts, enhance the expression of proliferation markers, and increase IL-8 production in the colonic mucosa (7). IL-8 is a proinflammatory cytokine that has been shown to promote the growth, angiogenesis and metastasis of colon cancer cells (8-11). Taken together, these observations suggest that S. bovis acts as a promoter of colorectal tumorigenesis.

Later on in the mid-1970s, experiments with germ-free rats further showed that intestinal microflora played a modifying role in colorectal tumorigenesis. Germ-free rats developed much fewer colonic tumors compared to conventional rats when challenged with carcinogens (12,13). Since then, a number of commensal bacteria have been linked to CRC, including Escherichia coli, Enterococcus faecalis, Bacteroides spp. (B. fragilis, B. vulgatus, B. stercoris), Eubacterium limosum, and Clostridium septicum (14-22).

Ever since the oncogenic properties of H. pylori were firmly established in the stomach, studies on its oncogenicity have extended to other parts of the gastrointestinal tract, particularly the colon (23). To date, the link between H. pylori infection and CRC remains inconclusive, with some reports showing an association (24-32) while others none (33-37). The results of two meta-analyses published in 2006 and 2008 both suggested a possible small increased risk of CRC in association with H. pylori infection (38,39).

Several hypotheses have been proposed to explain the possible link between H. pylori infection and CRC. These include: (I) hypergastrinemia, (II) change in colorectal microflora, (III) toxin production, and (IV) chronic inflammation secondary to direct H. pylori colonization in the colon.

Hypergastrinemia

Gastrin and gastrin-like peptides received considerable attention in the 1980s and 1990s because of their growth-promoting properties. Early in vitro studies demonstrated that gastrins had a direct mitogenic effect on cultured normal and neoplastic colonic cells (40-42). Later researches reported that induced hypergastrinemia resulted in hyperproliferation of colonic mucosa in transgenic mice (43-45). In addition, gastrin gene knock-out mice showed decreased proliferation of the colonic mucosa (46). Furthermore, several case-control studies observed elevated serum/plasma gastrin levels in patients with colorectal adenomatous polyps and/or adenocarcinoma (47-50). These observations suggest that hypergastrinemia in the setting of H. pylori-associated atrophic gastritis promotes colorectal tumorigenesis.

However, the link between hypergastrinemia and CRC has been in question from the beginning. Animal studies showed that drug-induced hypergastrinemia had no stimulatory effect on the growth of colonic mucosa or CRC progression (51-53). In fact, omeprazole was found to inhibit colorectal tumorigenesis induced by azoxymethane in rats despite causing hypergastrinaemia (54). In humans, chronic hypergastrinemia caused by proton pump inhibitors also showed no effect on the development of colonic adenomas (55). Patients with Zollinger-Ellison syndrome does not show an increased risk of developing CRC despite prolonged and marked plasma elevation of all forms of gastrin (56). Several studies demonstrated that serum/plasma gastrin levels were not significantly different between subjects with and without colorectal neoplasia, and thus unlikely to play a significant role in colorectal tumorigenesis (57-61). It is interesting to note that some studies have demonstrated that CRC tumor cells express gastrins that may function as autocrine growth factors (62-66). In that scenario, gastrin secretion by tumor cells is likely the source of hypergastrinemia observed in CRC patients. In support of this notion, several studies demonstrated a fall in serum/plasma gastrin values in CRC patients following surgical resections of the tumors (48,67,68). While these data may further support a role of hypergastrinemia in colorectal tumorigenesis, they argue against a direct association with H. pylori infection.

Change in colorectal microflora

Gastric acid barrier is an important regulator of the population and composition of the intestinal microflora (69-72). Atrophic gastritis secondary to H. pylori infection is associated with reduced acid production, which permits a greater number and variety of microbial species to enter and colonize the intestinal tract. It has been proposed that shifts in the composition of colorectal microflora resulted from H. pylori atrophic gastritis may facilitate selective growth of bacteria such as B. fragilis, E. faecalis, and others that are linked to the development of CRC (14-16,18-20). Supporting this hypothesis are studies showing an increased CRC risk following gastric surgery for benign peptic ulcer disease (73,74). However, other studies failed to confirm the association between gastrectomy and subsequent CRC development (75-78).

Toxin production

There are different H. pylori strains, some of which are more virulent and more carcinogenic than the others. For instance, patients infected with H. pylori organisms that express cagA gene are more likely to develop gastric cancer than those infected with cagA-negative strains (79,80). Shmuely et al. tested patients with various malignancies for serum antibodies against H. pylori and CagA protein and found that CagA seropositivity was associated with an increased risk not only for gastric adenocarcinoma but also for colonic adenocarcinoma, when compared with CagA-seronegative controls (81). However, as the authors pointed out, the findings should be interpreted with caution because the tests for H. pylori and CagA were performed at the same time of cancer diagnosis, which raised the question about the temporal relationship between the two conditions. The conclusions of the study were drawn under the assumption that H. pylori infection occurred before CRC development, as for gastric adenocarcinoma. A reasonable argument would be that CRC patients may have an altered immune status, which allows H. pylori organisms, especially the more virulent strains, to have a greater chance to successfully establish infection in these patients.

If infection by cagA-positive H. pylori strains does in fact precede and contribute to the development of CRC, the underlying mechanisms remains elusive. It has been shown that infection by cagA-positive strains is associated with higher levels of gastrin than that by cagA-negative strains (82,83). Overproduction of IL-8, which is known to be a growth factor for human colon carcinoma cells (8-11), may also be implicated (81,84,85). In addition, infection with cagA-positive H. pylori strains is associated with an increased likelihood of developing atrophic gastritis (86-88), which would be expected to sustain a more drastic disruption of the gastric acid barrier function to allow for an abnormal bacterial colonization in the lower intestinal tract as discussed above.

Chronic inflammation secondary to direct H. pylori colonization in the colon

Chronic mucosal inflammation is believed to be a predisposing factor for CRC development, as evidenced by inflammatory bowel disease. Given H. pylori’s well-established proinflammatory and carcinogenic effect in the stomach, a “chronic inflammation → dysplasia → neoplasia” sequence, similar to that for inflammatory bowel disease, may occur in the colon initiated by direct H. pylori colonization.

In this regard, Kapetanakis et al. reported detection of H. pylori organisms in malignant tissues from 34 of 41 (82.9%) CRC patients by cresyl violet staining and immunohistochemistry (32). Using the same staining methods, the authors recently extended their study to 50 patients with CRC and 25 patients with colonic polyps and found that H. pylori organisms were present in 84% CRC tissues and 64% polyps (1). It is unclear, however, whether the authors have also included nonneoplastic colonic tissues for comparison in their studies, where the organisms were located in the tissues, and what staining characteristics they have observed for the organisms. Soylu et al. examined 51 colonic polyps (39 tubular adenomas, 3 tubulovillous adenomas, 5 villous adenomas, and 4 adenocarcinomas) by immunohistochemistry and demonstrated positive staining in 11 (21.6%) polyps. In 10 (90.9%) polyps, however, the positive staining was interpreted as equivocal and appeared nonspecific (89). Again, no nonneoplastic colonic mucosa was included for comparison. In the study by Jones et al., a total of 176 colorectal specimens (normal 58, adenoma 59, adenocarcinoma 59) were examined by H. pylori immunohistochemistry. Positive staining was seen in 1 (1.7%) normal sample, 9 (15.3%) adenomas, and 
10 (16.9%) adenocarcinomas (90). However, all the positive cases showed granular and dot-like staining patterns; none of the positive cases demonstrated an unequivocal spiral form of H. pylori organisms as typically seen in the stomach. It is thus difficult to determine whether the positive staining represents deformed (dead or partially degraded) organisms or simply staining artifact.

Employing a Helicobacter species-specific 16S rDNA PCR assay combined with pyrosequencing analysis, Grahn et al. detected the presence of Helicobacter DNA sequences in 21 of 77 (27%) CRC biopsy specimens (91). No nonneoplastic colorectal tissues were examined in the study because the authors did not have access to normal colorectal biopsy specimens according to the authors. However, in a different study using the same techniques, the researchers were able to detect H. pylori DNA in 5 of 19 colon samples biopsied from 3 patients with microscopic colitis. No H. pylori DNA was detected in 12 rectal biopsies that were histologically normal (92).

Although the exact route of H. pylori transmission has not been fully understood, person-to-person transmission via either oral-to-oral or fecal-to-oral route is most common. Since H. pylori organisms are shed in stools from infected individuals (93-95), it is not surprising that the organisms, which may just simply pass through the intestinal tract with digested contents, can be detected in colonic tissue samples. It should also be noted that H. pylori-associated gastric cancer is known to be the consequence of chronic active gastritis that leads to mucosal atrophy, intestinal metaplasia and dysplasia. However, there have been no reports of chronic or active colitis resulted from direct H. pylori infection in the colon. Based on our experience, the colonic mucosa in patients with H. pylori gastritis shows normal histology unless other medical conditions are present. Thus, simply identifying H. pylori organisms in colorectal tumor samples does not prove a causal relationship.

Conclusions

While the etiopathogenetic role of H. pylori in gastric cancer is well-established, its role in colorectal tumorigenesis remains controversial. H. pylori infection of the stomach may promote colorectal tumorigenesis indirectly in a variety of ways such as modulating intestinal microflora, enhancing cytokine production and increasing gastrin secretion. These effects may be more pronounced when infected by more virulent H. pylori strains. Detection of H. pylori antigens and/or DNA in colonic tissue samples does not necessarily mean colonic colonization by the organisms, and should not be viewed as direct evidence of causal association with colorectal tumorigenesis.

Acknowledgements

Disclosure: The authors declare no conflict of interest.

References

1. Kapetanakis N, Kountouras J, Zavos C, et al. Helicobacter pylori infection and colorectal carcinoma: pathologic aspects. J Gastrointest Oncol 2012;3:377-9.
2. Fleming M, Ravula S, Tatishchev SF, et al. Colorectal carcinoma: Pathologic aspects. J Gastrointest Oncol 2012;3:153-73. [PubMed]
3. McCoy WC, Mason JM 3rd. Enterococcal endocarditis associated with carcinoma of the sigmoid; report of a case. J Med Assoc State Ala 1951;21:162-6. [PubMed]
4. Klein RS, Recco RA, Catalano MT, et al. Association of Streptococcus bovis with carcinoma of the colon. N Engl J Med 1977;297:800-2. [PubMed]
5. Murray HW, Roberts RB. Streptococcus bovis bacteremia and underlying gastrointestinal disease. Arch Intern Med 1978;138:1097-9. [PubMed]
6. Gold JS, Bayar S, Salem RR. Association of Streptococcus bovis bacteremia with colonic neoplasia and extracolonic malignancy. Arch Surg 2004;139:760-5. [PubMed]
7. Ellmerich S, Schöller M, Duranton B, et al. Promotion of intestinal carcinogenesis by Streptococcus bovis. Carcinogenesis 2000;21:753-6. [PubMed]
8. Li A, Varney ML, Singh RK. Expression of interleukin 8 and its receptors in human colon carcinoma cells with different metastatic potentials. Clin Cancer Res 2001;7:3298-304. [PubMed]
9. Lee YS, Choi I, Ning Y, et al. Interleukin-8 and its receptor CXCR2 in the tumour microenvironment promote colon cancer growth, progression and metastasis. Br J Cancer 2012;106:1833-41. [PubMed]
10. Fox SH, Whalen GF, Sanders MM, et al. Angiogenesis in normal tissue adjacent to colon cancer. J Surg Oncol 1998;69:230-4. [PubMed]
11. Brew R, Erikson JS, West DC, et al. Interleukin-8 as an autocrine growth factor for human colon carcinoma cells in vitro. Cytokine 2000;12:78-85. [PubMed]
12. Reddy BS, Weisburger JH, Narisawa T, et al. Colon carcinogenesis in germ-free rats with 1,2-dimethylhydrazine and N-methyl-n’-nitro-N-nitrosoguanidine. Cancer Res 1974;34:2368-72. [PubMed]
13. Reddy BS, Narisawa T, Wright P, et al. Colon carcinogenesis with azoxymethane and dimethylhydrazine in germ-free rats. Cancer Res 1975;35:287-90. [PubMed]
14. Cuevas-Ramos G, Petit CR, Marcq I, et al. Escherichia coli induces DNA damage in vivo and triggers genomic instability in mammalian cells. Proc Natl Acad Sci U S A 2010;107:11537-42. [PubMed]
15. Wu S, Morin PJ, Maouyo D, et al. Bacteroides fragilis enterotoxin induces c-Myc expression and cellular proliferation. Gastroenterology 2003;124:392-400. [PubMed]
16. Toprak NU, Yagci A, Gulluoglu BM, et al. A possible role of Bacteroides fragilis enterotoxin in the aetiology of colorectal cancer. Clin Microbiol Infect 2006;12:782-6. [PubMed]
17. Sears CL, Islam S, Saha A, et al. Association of enterotoxigenic Bacteroides fragilis infection with inflammatory diarrhea. Clin Infect Dis 2008;47:797-803. [PubMed]
18. Sobhani I, Tap J, Roudot-Thoraval F, et al. Microbial dysbiosis in colorectal cancer (CRC) patients. PLoS One 2011;6:e16393. [PubMed]
19. Wang X, Allen TD, May RJ, et al. Enterococcus faecalis induces aneuploidy and tetraploidy in colonic epithelial cells through a bystander effect. Cancer Res 2008;68:9909-17. [PubMed]
20. Moore WE, Moore LH. Intestinal floras of populations that have a high risk of colon cancer. Appl Environ Microbiol 1995;61:3202-7. [PubMed]
21. Sungkanuparph S, Chansirikarnjana S, Vorachit M. Eubacterium bacteremia and colon cancer. Scand J Infect Dis 2002;34:941-3. [PubMed]
22. Dylewski J, Luterman L. Septic arthritis and Clostridium septicum: a clue to colon cancer. CMAJ 2010;182:1446-7. [PubMed]
23. Selgrad M, Bornschein J, Rokkas T, et al. Helicobacter pylori Gastric Cancer and Extragastric Intestinal Malignancies. Helicobacter 2012;17:30-5. [PubMed]
24. Meucci G, Tatarella M, Vecchi M, et al. High prevalence of Helicobacter pylori infection in patients with colonic adenomas and carcinomas. J Clin Gastroenterol 1997;25:605-7. [PubMed]
25. Aydin A, Karasu Z, Zeytinoglu A, et al. Colorectal adenomateous polyps and Helicobacter pylori infection. Am J Gastroenterol 1999;94:1121-2. [PubMed]
26. Fujimori S, Kishida T, Kobayashi T, et al. Helicobacter pylori infection increases the risk of colorectal adenoma and adenocarcinoma, especially in women. J Gastroenterol 2005;40:887-93. [PubMed]
27. Lin YL, Chiang JK, Lin SM, et al. Helicobacter pylori infection concomitant with metabolic syndrome further increase risk of colorectal adenomas. World J Gastroenterol 2010;16:3841-6. [PubMed]
28. Mizuno S, Morita Y, Inui T, et al. Helicobacter pylori infection is associated with colon adenomatous polyps detected by high-resolution colonoscopy. Int J Cancer 2005;117:1058-9. [PubMed]
29. Inoue I, Mukoubayashi C, Yoshimura N, et al. Elevated risk of colorectal adenoma with Helicobacter pylori-related chronic gastritis: a population-based case-control study. Int J Cancer 2011;129:2704-11. [PubMed]
30. Hong SN, Lee SM, Kim JH, et al. Helicobacter pylori infection increases the risk of colorectal adenomas: cross-sectional study and meta-analysis. Dig Dis Sci 2012;57:2184-94. [PubMed]
31. Zhang Y, Hoffmeister M, Weck MN, et al. Helicobacter pylori infection and colorectal cancer risk: evidence from a large population-based case-control study in Germany. Am J Epidemiol 2012;175:441-50. [PubMed]
32. Kapetanakis N, Kountouras J, Zavos C, et al. Re: helicobacter pylori infection and colorectal cancer risk: evidence from a large population-based case-control study in Germany. Am J Epidemiol 2012;176:566-7. [PubMed]
33. Moss SF, Neugut AI, Garbowski GC, et al. Helicobacter pylori seroprevalence and colorectal neoplasia: evidence against an association. J Natl Cancer Inst 1995;87:762-3. [PubMed]
34. Siddheshwar RK, Muhammad KB, Gray JC, et al. Seroprevalence of Helicobacter pylori in patients with colorectal polyps and colorectal carcinoma. Am J Gastroenterol 2001;96:84-8. [PubMed]
35. Bae RC, Jeon SW, Cho HJ, et al. Gastric dysplasia may be an independent risk factor of an advanced colorectal neoplasm. World J Gastroenterol 2009;15:5722-6. [PubMed]
36. Abbass K, Gul W, Beck G, et al. Association of Helicobacter pylori infection with the development of colorectal polyps and colorectal carcinoma. South Med J 2011;104:473-6. [PubMed]
37. Robertson DJ, Sandler RS, Ahnen DJ, et al. Gastrin, Helicobacter pylori, and colorectal adenomas. Clin Gastroenterol Hepatol 2009;7:163-7. [PubMed]
38. Zumkeller N, Brenner H, Zwahlen M, et al. Helicobacter pylori infection and colorectal cancer risk: a meta-analysis. Helicobacter 2006;11:75-80. [PubMed]
39. Zhao YS, Wang F, Chang D, et al. Meta-analysis of different test indicators: Helicobacter pylori infection and the risk of colorectal cancer. Int J Colorectal Dis 2008;23:875-82. [PubMed]
40. Sirinek KR, Levine BA, Moyer MP. Pentagastrin stimulates in vitro growth of normal and malignant human colon epithelial cells. Am J Surg 1985;149:35-9. [PubMed]
41. Watson SA, Durrant LG, Morris DL. Growth-promoting action of gastrin on human colonic and gastric tumour cells cultured in vitro. Br J Surg 1988;75:342-5. [PubMed]
42. Watson S, Durrant L, Morris D. Gastrin: growth enhancing effects on human gastric and colonic tumour cells. Br J Cancer 1989;59:554-8. [PubMed]
43. Wang TC, Koh TJ, Varro A, et al. Processing and proliferative effects of human progastrin in transgenic mice. J Clin Invest 1996;98:1918-29. [PubMed]
44. Wang TC, Dockray GJ. Lessons from genetically engineered animal models. I. Physiological studies with gastrin in transgenic mice. Am J Physiol 1999;277:G6-11. [PubMed]
45. Koh TJ, Dockray GJ, Varro A, et al. Overexpression of glycine-extended gastrin in transgenic mice results in increased colonic proliferation. J Clin Invest 1999;103:1119-26. [PubMed]
46. Koh TJ, Goldenring JR, Ito S, et al. Gastrin deficiency results in altered gastric differentiation and decreased colonic proliferation in mice. Gastroenterology 1997;113:1015-25. [PubMed]
47. Smith JP, Wood JG, Solomon TE. Elevated gastrin levels in patients with colon cancer or adenomatous polyps. Dig Dis Sci 1989;34:171-4. [PubMed]
48. Wong K, Beardshall K, Waters CM, et al. Postprandial hypergastrinaemia in patients with colorectal cancer. Gut 1991;32:1352-4. [PubMed]
49. Seitz JF, Giovannini M, Gouvernet J, et al. Elevated serum gastrin levels in patients with colorectal neoplasia. J Clin Gastroenterol 1991;13:541-5. [PubMed]
50. Thorburn CM, Friedman GD, Dickinson CJ, et al. Gastrin and colorectal cancer: a prospective study. Gastroenterology 1998;115:275-80. [PubMed]
51. Pinson DM, Havu N, Sztern MI, et al. Drug-induced hypergastrinemia: absence of trophic effects on colonic carcinoma in rats. Gastroenterology 1995;108:1068-74. [PubMed]
52. Hurwitz A, Sztern MI, Looney GA, et al. Effects of omeprazole on cell kinetics of carcinogen-induced colon tumours in rats. Cell Prolif 1995;28:525-31. [PubMed]
53. Graffner H, Singh G, Chaudry I, et al. Omeprazole-induced hypergastrinemia does not influence growth of colon carcinoma. Dig Dis Sci 1992;37:485-9. [PubMed]
54. Penman ID, el-Omar E, McGregor JR, et al. Omeprazole inhibits colorectal carcinogenesis induced by azoxymethane in rats. Gut 1993;34:1559-65. [PubMed]
55. Singh M, Dhindsa G, Friedland S, et al. Long-term use of proton pump inhibitors does not affect the frequency, growth, or histologic characteristics of colon adenomas. Aliment Pharmacol Ther 2007;26:1051-61. [PubMed]
56. Orbuch M, Venzon DJ, Lubensky IA, et al. Prolonged hypergastrinemia does not increase the frequency of colonic neoplasia in patients with Zollinger-Ellison syndrome. Dig Dis Sci 1996;41:604-13. [PubMed]
57. Lamberts R, Wartenberg T, Creutzfeldt W. Role of circulating gastrin in colorectal adenomas and carcinomas. Digestion 1999;60:101-9. [PubMed]
58. Suzuki H, Matsumoto K, Terashima H. Serum levels of gastrin in patients with colorectal neoplasia. Dis Colon Rectum 1988;31:716-7. [PubMed]
59. Penman ID, el-Omar E, Ardill JE, et al. Plasma gastrin concentrations are normal in patients with colorectal neoplasia and unaltered following tumor resection. Gastroenterology 1994;106:1263-70. [PubMed]
60. Kikendall JW, Glass AR, Sobin LH, et al. Serum gastrin is not higher in subjects with colonic neoplasia. Am J Gastroenterol 1992;87:1394-7. [PubMed]
61. Vanderstraeten EF, De Vos MM, Versieck JM, et al. Serum gastrin levels and colorectal neoplasia. Dis Colon Rectum 1995;38:172-6. [PubMed]
62. Baldwin GS, Zhang QX. Measurement of gastrin and transforming growth factor alpha messenger RNA levels in colonic carcinoma cell lines by quantitative polymerase chain reaction. Cancer Res 1992;52:2261-7. [PubMed]
63. Monges G, Biagini P, Cantaloube JF, et al. Detection of gastrin mRNA in fresh human colonic carcinomas by reverse transcription-polymerase chain reaction. J Mol Endocrinol 1993;11:223-9. [PubMed]
64. Finley GG, Koski RA, Melhem MF, et al. Expression of the gastrin gene in the normal human colon and colorectal adenocarcinoma. Cancer Res 1993;53:2919-26. [PubMed]
65. Xu Z, Dai B, Dhruva B, et al. Gastrin gene expression in human colon cancer cells measured by a simple competitive PCR method. Life Sci 1994;54:671-8. [PubMed]
66. Singh P, Dai B, Wu H, et al. Role of autocrine and endocrine gastrin-like peptides in colonic carcinogenesis. Curr Opin Gastroenterol 2000;16:68-77. [PubMed]
67. Bombski G, Gasiorowska A, Orszulak-Michalak D, et al. Elevated plasma gastrin, CEA, and CA 19-9 levels decrease after colorectal cancer resection. Int J Colorectal Dis 2003;18:148-52. [PubMed]
68. Charnley RM, Thomas WM, Stanley J, et al. Serum gastrin concentrations in colorectal cancer patients. Ann R Coll Surg Engl 1992;74:138-40; discussion 141. [PubMed]
69. Kanno T, Matsuki T, Oka M, et al. Gastric acid reduction leads to an alteration in lower intestinal microflora. Biochem Biophys Res Commun 2009;381:666-70. [PubMed]
70. Macfarlane GT, Macfarlane LE. Acquisition, evolution and maintenance of the normal gut microbiota. Dig Dis 2009;27:90-8. [PubMed]
71. Husebye E. The pathogenesis of gastrointestinal bacterial overgrowth. Chemotherapy 2005;51:1-22. [PubMed]
72. Batt RM, Rutgers HC, Sancak AA. Enteric bacteria: friend or foe? J Small Anim Pract 1996;37:261-7. [PubMed]
73. Stemmermann GN, Nomura AM, Chyou PH. Cancer incidence following subtotal gastrectomy. Gastroenterology 1991;101:711-5. [PubMed]
74. Bundred NJ, Whitfield BC, Stanton E, et al. Gastric surgery and the risk of subsequent colorectal cancer. Br J Surg 1985;72:618-9. [PubMed]
75. Toftgaard C. Risk of colorectal cancer after surgery for benign peptic ulceration. Br J Surg 1987;74:573-5. [PubMed]
76. Thiruvengadam R, Hench V, Melton LJ 3rd, et al. Cancer of the nongastric hollow organs of the gastrointestinal tract after gastric surgery. Arch Intern Med 1988;148:405-7. [PubMed]
77. Lundegårdh G, Adami HO, Helmick C, et al. The risk of large bowel cancer after partial gastrectomy for benign ulcer disease. Ann Surg 1990;212:714-9. [PubMed]
78. Fisher SG, Davis F, Nelson R, et al. Large bowel cancer following gastric surgery for benign disease: a cohort study. Am J Epidemiol 1994;139:684-92. [PubMed]
79. Parsonnet J, Friedman GD, Orentreich N, et al. Risk for gastric cancer in people with CagA positive or CagA negative Helicobacter pylori infection. Gut 1997;40:297-301. [PubMed]
80. Wu AH, Crabtree JE, Bernstein L, et al. Role of Helicobacter pylori CagA+ strains and risk of adenocarcinoma of the stomach and esophagus. Int J Cancer 2003;103:815-21. [PubMed]
81. Shmuely H, Passaro D, Figer A, et al. Relationship between Helicobacter pylori CagA status and colorectal cancer. Am J Gastroenterol 2001;96:3406-10. [PubMed]
82. Parente F, Imbesi V, Maconi G, et al. Influence of bacterial CagA status on gastritis, gastric function indices, and pattern of symptoms in H. pylori-positive dyspeptic patients. Am J Gastroenterol 1998;93:1073-9. [PubMed]
83. Konturek PC, Konturek SJ, Bielanski W, et al. Role of gastrin in gastric cancerogenesis in Helicobacter pylori infected humans. J Physiol Pharmacol 1999;50:857-73. [PubMed]
84. Konturek SJ, Starzynska T, Konturek PC, et al. Helicobacter pylori and CagA status, serum gastrin, interleukin-8 and gastric acid secretion in gastric cancer. Scand J Gastroenterol 2002;37:891-8. [PubMed]
85. Eftang LL, Esbensen Y, Tannæs TM, et al. Interleukin-8 is the single most up-regulated gene in whole genome profiling of H. pylori exposed gastric epithelial cells. BMC Microbiol 2012;12:9. [PubMed]
86. Kuipers EJ, Pérez-Pérez GI, Meuwissen SG, et al. Helicobacter pylori and atrophic gastritis: importance of the cagA status. J Natl Cancer Inst 1995;87:1777-80. [PubMed]
87. Sozzi M, Valentini M, Figura N, et al. Atrophic gastritis and intestinal metaplasia in Helicobacter pylori infection: the role of CagA status. Am J Gastroenterol 1998;93:375-9. [PubMed]
88. Pilotto A, Rassu M, Bozzola L, et al. Cytotoxin-associated gene A-positive Helicobacter pylori infection in the elderly. Association with gastric atrophy and intestinal metaplasia. J Clin Gastroenterol 1998;26:18-22. [PubMed]
89. Soylu A, Ozkara S, Alis H, et al. Immunohistochemical testing for Helicobacter Pylori existence in neoplasms of the colon. BMC Gastroenterol 2008;8:35. [PubMed]
90. Jones M, Helliwell P, Pritchard C, et al. Helicobacter pylori in colorectal neoplasms: is there an aetiological relationship? World J Surg Oncol 2007;5:51. [PubMed]
91. Grahn N, Hmani-Aifa M, Fransén K, et al. 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. [PubMed]
92. Monstein HJ, Olsson C, Nilsson I, et al. Multiple displacement amplification of DNA from human colon and rectum biopsies: bacterial profiling and identification of Helicobacter pylori-DNA by means of 16S rDNA-based TTGE and pyrosequencing analysis. J Microbiol Methods 2005;63:239-47. [PubMed]
93. Kelly SM, Pitcher MC, Farmery SM, et al. Isolation of Helicobacter pylori from feces of patients with dyspepsia in the United Kingdom. Gastroenterology 1994;107:1671-4. [PubMed]
94. Kabir S. Detection of Helicobacter pylori in faeces by culture, PCR and enzyme immunoassay. J Med Microbiol 2001;50:1021-9. [PubMed]
95. Parsonnet J, Shmuely H, Haggerty T. Fecal and oral shedding of Helicobacter pylori from healthy infected adults. JAMA 1999;282:2240-5. [PubMed]