Abstract
The etiologic link between H. pylori infection and gastric chronic inflammation and related complications has been well established, but pathogenic pathways are still widely discussed and not sufficiently clear. The introduction of culture-independent molecular techniques has allowed better understanding of the gastric microbiota and has revealed that, when present, H. pylori represents the main colonizer but is part of a far more complex and dynamic microbiota than previously thought. This conceptual shift has made way for new pathogenic theories, focused on the interrelations between H. pylori and other gastric microbiota. Main factors that affect the gastric microbiota are gastric acidity, inflammation, and environmental factors, such as diet and drugs. Previous studies have made progress in explaining the complex interactions between gastric microorganisms in healthy individuals and their role in the development of related gastroduodenal (peptic ulcers and gastric cancer (GC)) and extraintestinal diseases, but more scientific proof is needed. This review presents current knowledge on gastric microbiota and its role in health and in the development of gastroduodenal diseases.
Keywords
- gastric microbiota
- H. pylori
- pathogenesis
- chronic inflammation
- peptic ulcers
- gastric cancer
1. Introduction
The first isolation of
2. The hostile gastric environment
Compared to other gastrointestinal (GI) segments, the stomach has a physiological environment that is significantly more hostile to bacterial colonization and is a crucial part of the dynamics of the gastric microbiota. Primary reason for this is the gastric juice, which is composed of two main components—proteolytic enzymes and hydrochloric acid (HCl). The hydrochloric acid creates a strong acidic environment by maintaining a pH of 1–2 in the gastric lumen, which together with the proteolytic features of the gastric enzymes creates an intragastric environment that serves both digestive and protective roles. This environment facilitates the denaturation of proteins and nutrient absorption but also severely limits bacterial colonization and survival, preventing infection by pathogens [4]. The low pH value is the main restrictive component of the gastric juice [5]. To prevent damage to the mucosa from the acid and enzymes, neck cells of the gastric glands secrete mucus on the surface of the gastric epithelium. This mucus layer establishes a pH gradient that increases the pH up to 6–7 at the surface of the mucosa [6]. This is due to the unique properties of the mucus which permit acid to flow from parietal cells into crypts which communicate with the lumen, but do not allow acid at pH <4 from penetrating the mucus layer [6]. The mucus layer consists of several different mucin molecules, including MUC1, MUC5AC, MUC5AB, and MUC6, and forms two sublayers, an inner mucus layer that is firmly attached to the epithelia and a loose mucus layer, which is in direct contact with the lumen [7, 8]. Additional factors that contribute to the strong antimicrobial environment of the stomach are the accidental bile reflux and the gastric peristalsis.
3. H. pylori
In 1982
4. Other non-H. pylori microbiota
4.1 Culture-dependent identification of gastric microbiota
Initial studies on the bacteria present in the stomach, using culture-based techniques, such as gastric juice cultures and mucosal biopsies were reported even before the isolation of
4.2 Culture-independent identification of gastric microbiota
Culture-independent studies use a variety of molecular methods based on 16S rRNA gene sequencing. A multitude of reasons define these methods as far superior to those which are culture-dependent. These include:
16S rRNA is present in almost all bacteria.
The function of the 16S rRNA gene has remained unchanged over time, suggesting that random sequence changes are a more accurate measure of time (evolution).
The 16S rRNA gene is large enough for computational purposes [24].
A variety of 16S rRNA based methods exist, including:
Fluorescent in situ hybridization (FISH) [25]
Dot-blot hybridization with rRNA-targeted probes [26]
Targeted qPCR [27]
Traditional or sequence-aided community fingerprinting [28]
Temperature gradient gel electrophoresis (TGGE) [29]
Terminal restriction fragment length polymorphism (T-RFLP) [30]
Sequencing of cloned 16S rDNA [29]
Microarrays (PhyloChip) [31]
Next-generation sequencing (NGS) [32]
In an extensive review of eight culture-independent studies, Sheh A. and Fox J. concluded that the most prominent phyla in the stomach are
5. Interrelations between H. pylori and other gastric microbiota
Numerous studies have shown significant variability of the gastric microbial communities with respect to
Several mouse model studies have also shown clear differences in the composition of the gastric microbiota with respect to
A few studies have also examined
A few studies have given insight on how other microbial species can affect
As previously described
6. Factors affecting the gastric microbiota
As described,
6.1 Gastric acidity
The human gastric juice has an interprandial pH of between 1 and 2 in the gastric lumen, whereas with food ingestion it can reach up to pH 5. pH also varies in the different anatomical regions of the stomach, with most acidic being the fundus and the least being the antrum. The mucus lining the gastric mucosa establishes also a pH gradient from the lumen to the surface of the epithelium. This mucus consists of two sublayers—an inner mucus layer that is firmly attached to the epithelium and a variable mucus layer directly interacting with the lumen [7, 8]. Thus, across the mucus layer, the pH ranges from about 5.5 to 6.8 or even 7 at the surface of the gastric epithelial cells [5, 6]. It was already discussed that the low pH, caused by the hydrochloric acid, restricts the quantity of microorganisms and reduces the risk of infection by pathogens. Hence, sites with higher pH are significantly more hospitable to colonization and have a higher microbial density. Considerable fluctuations in the microbial density have been described with respect to the pH in the stomach, whereby both the quantity and the proportion of genera also fluctuate [43, 44]. Bacteria and bacterial DNA, which are isolated from gastric juice, differ from bacterial isolates adhering to the mucosa. During abnormal conditions, this balance may be different.
6.2 Dietary habits
While many studies document the effects of diet on the gut microbiota composition in humans, [45, 46, 47, 48, 49] there are only a few, mainly animal model studies, addressing the influence of diet on the gastric microbiota. An example is an in vivo study that compared the gastric microbiota of mice fed a non-purified diet (natural source-derived food) to mice fed a purified diet (refined food) and found higher levels of total aerobes, total anaerobes, and
6.3 Use of medications
The long-term use of proton pump inhibitors (PPIs) and H2 antagonists affects the composition of the gastric microbiota by inducing a non-
Antibiotics are well known to have suppressive effects on the gastrointestinal microflora.
7. Gastric microbiota and gastroduodenal diseases
7.1 Chronic gastritis and peptic ulcer disease
The isolation of
Nevertheless, there is arising evidence that non-
7.2 Gastric cancer
Each year approximately 990,000 people are diagnosed with gastric cancer (GC) worldwide, of whom about 738,000 die from this disease, making GC the fourth most common incident cancer and the second most common cause of cancer death. Both incidence and mortality rates are about twice as high in males as in females. Over 70% of cases occur in developing nations, concentrated in Eastern Asia, Eastern Europe, and Central and South America. Approximately 90% of gastric cancers are adenocarcinomas, with the other 10% shared between mucosa-associated lymphoid tissue (MALT) lymphomas, gastrointestinal stromal tumors (GIST), leiomyosarcomas, and other more rare types of cancer. Adenocarcinomas are histologically classified into two major types: diffuse and intestinal. These two types not only look different under the microscope but also differ in gender ratio, age at diagnosis, and other epidemiologic features. Anatomically, gastric cancers are categorized as proximal and distal. Proximal adenocarcinomas are more similar to esophageal adenocarcinomas and may be associated with the absence of
However,
Studies with INS-GAS mice have revealed that male mice with intestinal microbiota developed gastric pathology from chronic gastritis to atrophy and dysplasia independent of
A study by Wang et al. found a similar number of bacterial species in the microbiota between gastric cancer and chronic gastritis, but by using a method to explore and visualize similarities or dissimilarities of the data, a pattern suggesting the presence of a diversified microbiota in gastric cancer was found [68]. Moreover, a 16S rRNA gene sequencing analysis of gastric mucosa of patients with gastric cancer showed a prevalence of the genera
It is possible that non-
8. Gastric microbiota and extra-gastric diseases
The stomach is part of the GI tract, and as such, possible relations between the gastric microbiota’s composition and diseases of other parts of the GI tract, such as the esophagus (esophagitis and esophageal cancer), small intestines, and colon cannot be overlooked [72]. One study, using 16S rDNA analyses of duodenal aspirates, demonstrated lower diversity in irritable bowel syndrome patients compared to controls with significant alterations in 12 genera [73]. An increased risk for colorectal neoplasia in
Other studies have addressed the association between autoimmune hepatitis and altered microbiome of the upper GI tract and found this to be linked to increased intestinal permeability [76].
Regarding the extra-gastrointestinal involvement of gastric microbiota (especially
Nevertheless, research in this field is far from sufficient to be conclusive.
9. Discussion
It is undeniable that
Conflict of interest
There are no conflicts of interest.
References
- 1.
Warren JR, Marshall BJ. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet. 1983; 1 :1273-1275. DOI: 10.1016/S0140-6736(83)92719-8 - 2.
Wang F, Meng W, Wang B, Qiao L. Helicobacter pylori -induced gastric inflammation and gastric cancer. Cancer Letters. 2014;345 (2):196-202. DOI: 10.1016/j.canlet.2013.08.016 - 3.
Delgado S, Cabrera-Rubio R, Mira A, Suárez A, Mayo B. Microbiological survey of the human gastric ecosystem using culturing and pyrosequencing methods. Microbial Ecology. 2013; 65 (3):763-772. DOI: 10.1007/s00248-013-0192-5 - 4.
Martinsen TC, Bergh K, Waldum HL. Gastric juice: A barrier against infectious diseases. Basic & Clinical Pharmacology & Toxicology. 2005; 96 :94-102. DOI: 10.1111/j.1742-7843.2005.pto960202.x - 5.
Manson JM, Rauch M, Gilmore MS. The commensal microbiology of the gastrointestinal tract. Advances in Experimental Medicine and Biology. 2008; 635 :15-28. DOI: 10.1007/978-0-387-09550-9_2 - 6.
Bhaskar KR, Garik P, Turner BS, Bradley JD, Bansil R, Stanley HE, et al. Viscous fingering of HCl through gastric mucin. Nature. 1992; 360 :458-461. DOI: 10.1038/360458a0 - 7.
Corfield AP, Carroll D, Myerscough N, Probert CS. Mucins in the gastrointestinal tract in health and disease. Frontiers in Bioscience. 2001; 6 :D1321-D1357. DOI: 10.2741/Corfield - 8.
Atuma C, Strugala V, Allen A, Holm L. The adherent gastrointestinal mucus gel layer: Thickness and physical state in vivo. American Journal of Physiology. Gastrointestinal and Liver Physiology. 2001; 280 :G922-G929. DOI: 10.1152/ajpgi.2001.280.5.G922 - 9.
Kusters JG, van Vliet AH, Kuipers EJ. Pathogenesis of Helicobacter pylori infection. Clinical Microbiology Reviews. 2006;19 (3):449-490. DOI: 10.1128/CMR.00054-05 - 10.
Bik EM, Eckburg PB, Gill SR, et al. Molecular analysis of the bacterial microbiota in the human stomach. Proceedings of the National Academy of Sciences of the United States of America. 2006; 103 (3):732-737. DOI: 10.1073/pnas.0506655103 - 11.
Schulz C, Schütte K, Koch N, et al. The active bacterial assemblages of the upper GI tract in individuals with and without Helicobacter infection. Gut. 2016;67 (2):216-225. DOI: 10.1136/gutjnl-2016-312904 - 12.
Llorca L, Pérez-Pérez G, Urruzuno P, et al. Characterization of the gastric microbiota in a pediatric population according to Helicobacter pylori status. The Pediatric Infectious Disease Journal. 2017;36 (2):173-178. DOI: 10.1097/INF.0000000000001383 - 13.
Williams SM, Chen YT, Andermann TM, Carter JE, McGee DJ, Ottemann KM. Helicobacter pylori chemotaxis modulates inflammation and bacterium-gastric epithelium interactions in infected mice. Infection and Immunity. 2007;75 :3747-3757. DOI: 10.1128/IAI.00082-07 - 14.
Croxen MA, Sisson G, Melano R, Hoffman PS. The Helicobacter pylori chemotaxis receptor TlpB (HP0103) is required for pH taxis and for colonization of the gastric mucosa. Journal of Bacteriology. 2006;188 :2656-2665. DOI: 10.1128/JB.188.7.2656-2665.2006 - 15.
Saha A, Backert S, Hammond CE, Gooz M, Smolka AJ. Helicobacter pylori CagL activates ADAM17 to induce repression of the gastric H, K-ATPase alpha subunit. Gastroenterology. 2010;139 :239-248. DOI: 10.1053/j.gastro.2010.03.036 - 16.
O’Keeffe J, Moran AP. Conventional, regulatory, and unconventional T cells in the immunologic response to Helicobacter pylori . Helicobacter. 2008;13 :1-19. DOI: 10.1111/j.1523-5378.2008.00559.x - 17.
Savage DC. Microbial ecology of the gastrointestinal tract. Annual Review of Microbiology. 1977; 31 :107-133. DOI: 10.1146/annurev.mi.31.100177.000543 - 18.
Stockbruegger RW. Bacterial overgrowth as a consequence of reduced gastric acidity. Scandinavian Journal of Gastroenterology. Supplement. 1985; 111 :7-16. DOI: 10.3109/00365528509093749 - 19.
Hu Y, He LH, Xiao D, Liu GD, Gu YX, Tao XX, et al. Bacterial flora concurrent with Helicobacter pylori in the stomach of patients with upper gastrointestinal diseases. World Journal of Gastroenterology. 2012;18 :1257-1261. DOI: 10.3748/wjg.v18.i11.1257 - 20.
Zilberstein B, Quintanilha AG, Santos MA, Pajecki D, Moura EG, Alves PR, et al. Clinics (São Paulo, Brazil). 2007; 62 :47-54. DOI: 10.1590/S1807-59322007000100008 - 21.
Sharma BK, Santana IA, Wood EC, Walt RP, Pereira M, Noone P, et al. Intragastric bacterial activity and nitrosation before, during, and after treatment with omeprazole. British Medical Journal. 1984; 289 :717-719. DOI: 10.1136/bmj.289.6447.717 - 22.
Adamsson I, Nord CE, Lundquist P, Sjöstedt S, Edlund C. Comparative effects of omeprazole, amoxycillin plus metronidazole versus omeprazole, clarithromycin plus metronidazole on the oral, gastric and intestinal microflora in Helicobacter pylori -infected patients. The Journal of Antimicrobial Chemotherapy. 1999;44 :629-640. DOI: 10.1093/jac/44.5.629 - 23.
Sjöstedt S, Heimdahl A, Kager L, Nord CE. Microbial colonization of the oropharynx, esophagus and stomach in patients with gastric diseases. European Journal of Clinical Microbiology. 1985; 4 :49-51. DOI: 10.1007/BF02148660 - 24.
Janda JM, Abbott SL. 16S rRNA gene sequencing for bacterial identification in the diagnostic laboratory: Pluses, perils, and pitfalls. Journal of Clinical Microbiology. 2007; 45 (9):2761-2764. DOI: 10.1128/JCM.01228-07 - 25.
Langendijk PS, Schut F, Jansen GJ, Raangs GC, Kamphuis GR, Wilkinson MH, et al. Quantitative fluorescence in situ hybridization of Bifidobacterium spp. with genus-specific 16S rRNAtargeted probes and its application in fecal samples. Applied and Environmental Microbiology. 1995;61 :3069-3075 - 26.
Aebischer T, Fischer A, Walduck A, Schlötelburg C, Lindig M, Schreiber S, et al. Vaccination prevents Helicobacter pylori -induced alterations of the gastric flora in mice. FEMS Immunology and Medical Microbiology. 2006;46 :221-229. DOI: 10.1111/rp10.1016-j.femsim.2004.05.008 - 27.
Lertpiriyapong K, Whary MT, Muthupalani S, Lofgren JL, Gamazon ER, Feng Y, et al. Gastric colonisation with a restricted commensal microbiota replicates the promotion of neoplastic lesions by diverse intestinal microbiota in the Helicobacter pylori INS-GAS mouse model of gastric carcinogenesis. Gut. 2013;63 :54-63. DOI: 10.1136/gutjnl-2013-305178 - 28.
Heilig HG, Zoetendal EG, Vaughan EE, Marteau P, Akkermans AD, de Vos WM. Molecular diversity of Lactobacillus spp. and other lactic acid bacteria in the human intestine as determined by specific amplification of 16S ribosomal DNA. Applied and Environmental Microbiology. 2002;68 :114-123. DOI: 10.1128/AEM.68.1.114-123.2002 - 29.
Monstein HJ, Tiveljung A, Kraft CH, Borch K, Jonasson J. Profiling of bacterial flora in gastric biopsies from patients with Helicobacter pylori -associated gastritis and histologically normal control individuals by temperature gradient gel electrophoresis and 16SrDNA sequence analysis. Journal of Medical Microbiology. 2000;49 :817-822. DOI: 10.1099/0022-1317-49-9-817 - 30.
Dicksved J, Lindberg M, Rosenquist M, Enroth H, Jansson JK, Engstrand L. Molecular characterization of the stomach microbiota in patients with gastric cancer and in controls. Journal of Medical Microbiology. 2009; 58 :509-516. DOI: 10.1099/jmm.0.007302-0 - 31.
Rolig AS, Cech C, Ahler E, Carter JE, Ottemann KM. The degree of Helicobacter pylori -triggered inflammation is manipulated by preinfection host microbiota. Infection and Immunity. 2013;81 :1382-1389. DOI: 10.1128/IAI.00044-13 - 32.
Lofgren JL, Whary MT, Ge Z, Muthupalani S, et al. Lack of commensal flora in Helicobacter pylori -infected INS-GAS mice reduces gastritis and delays intraepithelial neoplasia. Gastroenterology. 2011;140 :210-220. DOI: 10.1053/j.gastro.2010.09.048 - 33.
Sheh A, Fox JG. The role of the gastrointestinal microbiome in Helicobacter pylori pathogenesis. Gut Microbes. 2013;4 (6):505-531. DOI: 10.4161/gmic.26205 - 34.
Andersson AF, Lindberg M, Jakobsson H, Bäckhed F, Nyrén P, Engstrand L. Comparative analysis of human gut microbiota by barcoded pyrosequencing. PLoS One. 2008; 3 :e2836. DOI: 10.1371/journal.pone.0002836 - 35.
Li XX, Wong GL, To KF, Wong VW, Lai LH, Chow DK, et al. Bacterial microbiota profiling in gastritis without Helicobacter pylori infection or non-steroidal anti-inflammatory drug use. PLoS One. 2009;4 :e7985. DOI: 10.1371/journal.pone.0007985 - 36.
Stearns JC, Lynch MD, Senadheera DB, Tenenbaum HC, Goldberg MB, Cvitkovitch DG, et al. Bacterial biogeography of the human digestive tract. Scientific Reports. 2011; 1 :170. DOI: 10.1038/srep00170 - 37.
Osaki T, Matsuki T, Asahara T, Zaman C, Hanawa T, Yonezawa H, et al. Comparative analysis of gastric bacterial microbiota in Mongolian gerbils after long-term infection with Helicobacter pylori . Microbial Pathogenesis. 2012;53 (1):12-18 - 38.
Tan MP, Kaparakis M, Galic M, Pedersen J, Pearse M, Wijburg OL, et al. Chronic Helicobacter pylori infection does dot significantly alter the microbiota of the murine stomach. Applied and Environmental Microbiology. 2007;73 (3):1010-1013 - 39.
Maldonado-Contreras A, Goldfarb KC, Godoy-Vitorino F, et al. Structure of the human gastric bacterial community in relation to Helicobacter pylori status. The ISME Journal. 2010;5 (4):574-579. DOI: 10.1038/ismej.2010.149 - 40.
Lemke LB, Ge Z, Whary MT, et al. Concurrent Helicobacter bilis infection in C57BL/6 mice attenuates proinflammatoryH. pylori -induced gastric pathology. Infection and Immunity. 2009;77 (5):2147-2158. DOI: 10.1128/IAI.01395-08 - 41.
Ge Z, Feng Y, Muthupalani S, et al. Infection and Immunity. 2011; 79 (10):3861-3871. DOI: 10.1128/IAI.05357-11 - 42.
Nagai S, Mimuro H, Yamada T, et al. Role of Peyer's patches in the induction of Helicobacter pylori -induced gastritis. Proceedings of the National Academy of Sciences of the United States of America. 2007;104 (21):8971-8976. DOI: 10.1073/pnas.0609014104 - 43.
Draser BS, Shiner M, McLeod GM. Studies of the intestinal flora 1. The bacterial flora of the gastrointestinal tract in healthy and achlorhydric patients. Gastroenterology. 1969; 56 :71-79 - 44.
Milton-Thompson GJ, Lightfoot NF, Ahmet Z, et al. Intragastric acidity, bacteria, nitrite, and N-nitroso compounds before, during, and after cimetidine treatment. Lancet. 1982; 1 (8281):1091-1095 - 45.
Goldsmith JR, Sartor RB. The role of diet on intestinal microbiota metabolism: Downstream impacts on host immune function and health, and therapeutic implications. Journal of Gastroenterology. 2014; 49 (5):785-798. DOI: 10.1007/s00535-014-0953-z - 46.
Korpela K, Flint HJ, Johnstone AM, et al. Gut microbiota signatures predict host and microbiota responses to dietary interventions in obese individuals. PLoS One. 2014; 9 (6):e90702. DOI: 10.1371/journal.pone.0090702 - 47.
David LA, Maurice CF, Carmody RN, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2013; 505 (7484):559-563. DOI: 10.1038/nature12820 - 48.
Chan YK, Estaki M, Gibson DL. Clinical consequences of diet-induced dysbiosis. Annals of Nutrition and Metabolism. 2013; 63 (suppl 2):28-40. DOI: 10.1159/000354902 - 49.
Fan W, Huo G, Li X, et al. Impact of diet in shaping gut microbiota revealed by a comparative study in infants during the six months of life. Journal of Microbiology and Biotechnology. 2014; 24 (2):133-143 - 50.
Wu GD, Chen J, Hoffmann C, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011; 334 :105-108. DOI: 10.1126/science. 1208344 - 51.
Sanduleanu S, Jonkers D, De Bruine A, Hameeteman W, Stockbrügger RW. Non- Helicobacter pylori bacterial flora during acid-suppressive therapy: Differential findings in gastric juice and gastric mucosa. Alimentary Pharmacology & Therapeutics. 2001;15 (3):379-388. DOI: 10.1046/j.1365-2036.2001.00888.x - 52.
Williams C, McColl KEL. Review article: Proton pump inhibitors and bacterial overgrowth. Alimentary Pharmacology & Therapeutics. 2006; 23 (1):3-10. DOI: 10.1111/j.1365-2036.2006.02707.x - 53.
Meuwissen SG, Craanen ME, Kuipers EJ. Gastric mucosal morphological consequences of acid suppression: A balanced view. Best practice & research. Clinical Gastroenterology. 2001; 15 (3):497-510. DOI: 10.1053/bega.2001.0189 - 54.
Mason KL, Erb Downward JR, Falkowski NR, Young VB, Kao JY, Huffnagle GB. Interplay between the gastric bacterial microbiota and Candida albicans during postantibiotic recolonization and gastritis. Infection and Immunity. 2012;80 (1):150-158. DOI: 10.1128/IAI.05162-11 - 55.
Zhang X, Zhang J, Lin Y, Xu K, Li N, Chen H, et al. Analysis of the relationship between invasive capability of Helicobacter pylori and gastroduodenal diseases. Journal of Medical Microbiology. 2015 May;64 (Pt 5):498-506. DOI: 10.1099/jmm.0.000049 - 56.
Blaser MJ, Atherton JC. Helicobacter pylori persistence: Biology and disease. The Journal of Clinical Investigation. 2004;113 (3):321-333. DOI: 10.1172/JCI20925 - 57.
Correa P, Piazuelo MB. Helicobacter pylori infection and gastric adenocarcinoma. US Gastroenterology and Hepatology Review. 2011;7 (1):59-64 - 58.
Ford AC, Gurusamy KS, Delaney B, Forman D, Moayyedi P. Eradication therapy for peptic ulcer disease in Helicobacter pylori -positive people. Cochrane Database of Systematic Reviews. 2016;4 :CD003840. DOI: 10.1002/14651858.CD003840.pub5 - 59.
Engstrand L, Lindberg M. Helicobacter pylori and the gastric microbiota. Best Practice & Research. Clinical Gastroenterology. 2013;27 :39-45. DOI: 10.1016/j.bpg.2013.03.016 - 60.
Khosravi Y, Dieye Y, Poh BH, et al. Culturable bacterial microbiota of the stomach of Helicobacter pylori positive and negative gastric disease patients. The Scientific World Journal. 2014;2014 :610421. DOI: 10.1155/2014/610421 - 61.
Karimi P, Islami F, Anandasabapathy S, Freedman ND, Kamangar F. Gastric cancer: Descriptive epidemiology, risk factors, screening, and prevention. Cancer Epidemiology, Biomarkers & Prevention. 2014; 23 (5):700-713. DOI: 10.1158/1055-9965.EPI-13-1057 - 62.
Forman D, Newell DG, Fullerton F, et al. Association between infection with Helicobacter pylori and risk of gastric cancer: Evidence from a prospective investigation. BMJ. 1991;302 (6788):1302-1305 - 63.
Nomura A, Stemmermann GN, Chyou PH, Kato I, Perez-Perez GI, Blaser MJ. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. The New England Journal of Medicine. 1991;325 (16):1132-1136. DOI: 10.1056/NEJM199110173251604 - 64.
Hsu PI, Lai KH, Hsu PN, et al. Helicobacter pylori infection and the risk of gastric malignancy. The American Journal of Gastroenterology. 2007;102 (4):725-730. DOI: 10.1111/j.1572-0241.2006.01109.x - 65.
Malfertheiner P, Megraud F, O’Morain CA, et al. Management of Helicobacter pylori infection--the Maastricht IV/ Florence consensus report. Gut. 2012;61 (5):646-664. DOI: 10.1136/gutjnl-2012-302084 - 66.
Sheu BS, Wu MS, Chiu CT, et al. Consensus on the clinical management, screening-to-treat, and surveillance of Helicobacter pylori infection to improve gastric cancer control on a nationwide scale. Helicobacter. 2017;22 (3):e12368. DOI: 10.1111/hel.12368 - 67.
Lee CW, Rickman B, Rogers AB, et al. Combination of sulindac and antimicrobial eradication of Helicobacter pylori prevents progression of gastric cancer in hypergastrinemic INS-GAS mice. Cancer Research. 2009;69 (20):8166-8174. DOI: 10.1158/0008-5472.CAN-08-3856 - 68.
Wang L, Zhou J, Xin Y, Geng C, Tian Z, Yu X, et al. Bacterial overgrowth and diversification of microbiota in gastric cancer. European Journal of Gastroenterology & Hepatology. 2016; 28 (3):261-266. DOI: 10.1097/MEG.0000000000000542 - 69.
Eun CS, Kim BK, Han DS, Kim SY, Kim KM, Choi BY, et al. Differences in gastric mucosal microbiota profiling in patients with chronic gastritis, intestinal metaplasia, and gastric cancer using pyrosequencing methods. Helicobacter. 2014; 19 :407-416. DOI: 10.1111/hel.12145 - 70.
Walker MM, Talley NJ. Review article: Bacteria and pathogenesis of disease in the upper gastrointestinal tract–beyond the era of Helicobacter pylori . Alimentary Pharmacology & Therapeutics. 2014;39 (8):767-779. DOI: 10.1111/apt.12666 - 71.
Alarcon T, Lorca L, Pereze-Perez G. Impact of microbiota and gastric disease development by Helicobacter pylori . Current Topics in Microbiology and Immunology. 2017;400 :253-275. DOI: 10.1007/978-3-319-50520-6_11 - 72.
Ianiro G, Molina-Infante J, Gasbarrini A. Gastric microbiota. Helicobacter. 2015; 20 (Suppl. 1):68-71. DOI: 10.1111/hel.12260 - 73.
Giamarellos-Bourboulis E, Tang J, Pyleris E, Pistiki A, Barbatzas C, Brown J, et al. Molecular assessment of differences in the duodenal microbiome in subjects with irritable bowel syndrome. Scandinavian Journal of Gastroenterology. 2015; 50 (9):1076-1087. DOI: 10.3109/00365521.2015.1027261 - 74.
Zhang Y, Hoffmeister M, Weck MN, Chang-Claude J, Brenner H. Helicobacter pylori infection and colorectal cancer risk: Evidence from a large population-based case-control study in Germany. American Journal of Epidemiology. 2012;175 (5):441-450. DOI: 10.1093/aje/kwr331 - 75.
Kim TJ, Kim ER, Chang DK, et al. Helicobacter pylori infection is an independent risk factor of early and advanced colorectal neoplasm. Helicobacter. 2017;22 (3):e12377. DOI: 10.1111/hel.12377 - 76.
Lin R, Zhou L, Zhang J, Wang B. Abnormal intestinal permeability and microbiota in patients with autoimmune hepatitis. International Journal of Clinical and Experimental Pathology. 2015; 8 (5):5153-5160 - 77.
Franchini M, Vescovi PP, Garofano M, Veneri D. Helicobacter pylori -associated idiopathic thrombocytopenic purpura: A narrative review. Seminars in Thrombosis and Hemostasis. 2012;38 (5):463-468. DOI: 10.1055/s-0032-1305781 - 78.
Cardenas VM, Mulla ZD, Ortiz M, Graham DY. Iron deficiency and Helicobacter pylori infection in the United States. American Journal of Epidemiology. 2006;163 (2):127-134. DOI: 10.1093/aje/kwj018 - 79.
Nam SY, Park BJ, Ryu KH, Nam JH. Effect of Helicobacter pylori eradication on the regression of gastric polyps in National Cancer Screening Program. The Korean Journal of Internal Medicine. 2017;33 (3):506-511. DOI: 10.3904/kjim.2016.286 - 80.
Suwarnalata G, Tan AH, Isa H, et al. Augmentation of autoantibodies by Helicobacter pylori in Parkinson's disease patients may be linked to greater severity. PLoS One. 2016;11 (4):e0153725. DOI: 10.1371/journal.pone.0153725 - 81.
Wang F, Liu J, Lv Z. Association of Helicobacter pylori infection with diabetes mellitus and diabetic nephropathy: A meta-analysis of 39 studies involving more than 20,000 participants. Scandinavian Journal of Infectious Diseases. 2013;45 (12):930-938. DOI: 10.3109/00365548.2013.844351