OBJECTIVE: Gastrointestinal microbiota may be involved in Helicobacter pylori-associated gastric cancer development. The aim of this study was to explore the possible microbial mechanisms in gastric carcinogenesis and potential dysbiosis arising from H. pylori infection. DESIGN: Deep sequencing of the microbial 16S ribosomal RNA gene was used to investigate alterations in paired gastric biopsies and stool samples in 58 subjects with successful and 57 subjects with failed anti-H. pylori treatment, relative to 49 H. pylori negative subjects. RESULTS: In H. pylori positive subjects, richness and Shannon indexes increased significantly (both p<0.001) after successful eradication and showed no difference to those of negative subjects (p=0.493 for richness and p=0.420 for Shannon index). Differential taxa analysis identified 18 significantly altered gastric genera after eradication. The combination of these genera into a Microbial Dysbiosis Index revealed that the dysbiotic microbiota in H. pylori positive mucosa was associated with advanced gastric lesions (chronic atrophic gastritis and intestinal metaplasia/dysplasia) and could be reversed by eradication. Strong coexcluding interactions between Helicobacter and Fusobacterium, Neisseria, Prevotella, Veillonella, Rothia were found only in advanced gastric lesion patients, and were absent in normal/superficial gastritis group. Changes in faecal microbiota included increased Bifidobacterium after successful H. pylori eradication and more upregulated drug-resistant functional orthologs after failed treatment. CONCLUSION: H. pylori infection contributes significantly to gastric microbial dysbiosis that may be involved in carcinogenesis. Successful H. pylori eradication potentially restores gastric microbiota to a similar status as found in uninfected individuals, and shows beneficial effects on gut microbiota.

2 Medizinische Klinik Klinikum Rechts der Isar Technische Universität München Munich Germany

Department of Medicine 1st Faculty of Medicine Military University Hospital Charles University Prague Czech Republic

German Center for Infection Research Partner Site Munich Munich Germany

Institute of Medical Informatics Statistics and Epidemiology Technische Universität München Munich Germany

Institute of Medical Microbiology Immunology and Hygiene Technische Universität München Munich Germany

Institute of Pathology Klinikum Bayreuth Bayreuth Germany

Key Laboratory of Carcinogenesis and Translational Research Department of Cancer Epidemiology Peking University Cancer Hospital and Institute Beijing China

Linqu Public Health Bureau Linqu Shandong China

PYLOTUM Key joint laboratory for upper GI cancer Technische Universität München Peking University Cancer Hospital and Institute Munich Beijing Germany China

Zobrazit více v PubMed

Schistosomes, liver flukes and Helicobacter pylori. IARC Working group on the evaluation of carcinogenic risks to humans. Lyon, 7-14 June 1994. IARC Monogr Eval Carcinog Risks Hum 1994;61:1–241. PubMed PMC

Ma J-L, Zhang L, Brown LM, et al. . Fifteen-year effects of Helicobacter pylori, garlic, and vitamin treatments on gastric cancer incidence and mortality. J Natl Cancer Inst 2012;104:488–92. 10.1093/jnci/djs003 PubMed DOI PMC

Li W-Q, Ma J-L, Zhang L, et al. . Effects of Helicobacter pylori treatment on gastric cancer incidence and mortality in subgroups. J Natl Cancer Inst 2014;106:dju116 10.1093/jnci/dju116 PubMed DOI PMC

Wong BCY, Zhang L, Ma J-ling, et al. . Effects of selective COX-2 inhibitor and Helicobacter pylori eradication on precancerous gastric lesions. Gut 2012;61:812–8. 10.1136/gutjnl-2011-300154 PubMed DOI

International Agency for Research on Cancer Helicobacter pylori eradication as a strategy for preventing gastric cancer. IARC working group reports Volume 8. Available: http://www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.php

Coker OO, Dai Z, Nie Y, et al. . Mucosal microbiome dysbiosis in gastric carcinogenesis. Gut 2018;67:1024–32. 10.1136/gutjnl-2017-314281 PubMed DOI PMC

Ferreira RM, Pereira-Marques J, Pinto-Ribeiro I, et al. . Gastric microbial community profiling reveals a dysbiotic cancer-associated microbiota. Gut 2018;67:226–36. 10.1136/gutjnl-2017-314205 PubMed DOI PMC

Gotoda T, Takano C, Kusano C, et al. . Gut microbiome can be restored without adverse events after Helicobacter pylori eradication therapy in teenagers. Helicobacter 2018;23:e12541 10.1111/hel.12541 PubMed DOI

Hsu P-I, Pan C-Y, Kao JY, et al. . Helicobacter pylori eradication with bismuth quadruple therapy leads to dysbiosis of gut microbiota with an increased relative abundance of Proteobacteria and decreased relative abundances of Bacteroidetes and Actinobacteria. Helicobacter 2018;23:e12498 10.1111/hel.12498 PubMed DOI

Yap TW-C, Gan H-M, Lee Y-P, et al. . Helicobacter pylori eradication causes perturbation of the human gut microbiome in young adults. PLoS One 2016;11:e0151893 10.1371/journal.pone.0151893 PubMed DOI PMC

Jakobsson HE, Jernberg C, Andersson AF, et al. . Short-term antibiotic treatment has differing long-term impacts on the human throat and gut microbiome. PLoS One 2010;5:e9836 10.1371/journal.pone.0009836 PubMed DOI PMC

You WC, Blot WJ, Chang YS, et al. . Diet and high risk of stomach cancer in Shandong, China. Cancer Res 1988;48:3518–23. PubMed

You WC, Blot WJ, Li JY, et al. . Precancerous gastric lesions in a population at high risk of stomach cancer. Cancer Res 1993;53:1317–21. PubMed

Dixon MF, Genta RM, Yardley JH, et al. . Classification and grading of gastritis. The updated Sydney system. International workshop on the histopathology of gastritis, Houston 1994. Am J Surg Pathol 1996;20:1161–81. 10.1097/00000478-199610000-00001 PubMed DOI

Lagkouvardos I, Joseph D, Kapfhammer M, et al. . IMNGS: a comprehensive open resource of processed 16S rRNA microbial profiles for ecology and diversity studies. Sci Rep 2016;6:33721 10.1038/srep33721 PubMed DOI PMC

Edgar RC. UPARSE: highly accurate otu sequences from microbial amplicon reads. Nat Methods 2013;10:996–8. 10.1038/nmeth.2604 PubMed DOI

Edgar RC. Search and clustering orders of magnitude faster than blast. Bioinformatics 2010;26:2460–1. 10.1093/bioinformatics/btq461 PubMed DOI

Wang Q, Garrity GM, Tiedje JM, et al. . Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy. Appl Environ Microbiol 2007;73:5261–7. 10.1128/AEM.00062-07 PubMed DOI PMC

Lagkouvardos I, Fischer S, Kumar N, et al. . Rhea: a transparent and modular R pipeline for microbial profiling based on 16S rRNA gene amplicons. PeerJ 2017;5:e2836 10.7717/peerj.2836 PubMed DOI PMC

Benjamini Y, Yekutieli D. The control of the false discovery rate in multiple testing under dependency. Annals of Statistics 2001;29:1165–88.

Sokal RR, Rohlf JF. Biometry: the principles and practice of statistics in biological research. New York: Freeman, 1995.

Aßhauer KP, Wemheuer B, Daniel R, et al. . Tax4Fun: predicting functional profiles from metagenomic 16S rRNA data: fig. 1. Bioinformatics 2015;31:2882–4. 10.1093/bioinformatics/btv287 PubMed DOI PMC

Quast C, Pruesse E, Yilmaz P, et al. . The Silva ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res 2013;41:D590–6. 10.1093/nar/gks1219 PubMed DOI PMC

Kanehisa M, Goto S, Sato Y, et al. . Data, information, knowledge and principle: back to metabolism in KEGG. Nucleic Acids Res 2014;42:D199–205. 10.1093/nar/gkt1076 PubMed DOI PMC

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 2018;67:216–25. 10.1136/gutjnl-2016-312904 PubMed DOI

Bik EM, Eckburg PB, Gill SR, et al. . Molecular analysis of the bacterial microbiota in the human stomach. Proc Natl Acad Sci U S A 2006;103:732–7. 10.1073/pnas.0506655103 PubMed DOI PMC

Parsons BN, Ijaz UZ, D'Amore R, et al. . Comparison of the human gastric microbiota in hypochlorhydric states arising as a result of Helicobacter pylori-induced atrophic gastritis, autoimmune atrophic gastritis and proton pump inhibitor use. PLoS Pathog 2017;13:e1006653 10.1371/journal.ppat.1006653 PubMed DOI PMC

Klymiuk I, Bilgilier C, Stadlmann A, et al. . The Human Gastric Microbiome Is Predicated upon Infection with Helicobacter pylori. Front Microbiol 2017;8:2508 10.3389/fmicb.2017.02508 PubMed DOI PMC

Li TH, Qin Y, Sham PC, et al. . Alterations in gastric microbiota after H. pylori eradication and in different histological stages of gastric carcinogenesis. Sci Rep 2017;7:44935 10.1038/srep44935 PubMed DOI PMC

Waldum HL, Kleveland PM, Sørdal Øystein F. Helicobacter pylori and gastric acid: an intimate and reciprocal relationship. Therap Adv Gastroenterol 2016;9:836–44. 10.1177/1756283X16663395 PubMed DOI PMC

Wong JMW, de Souza R, Kendall CWC, et al. . Colonic health: fermentation and short chain fatty acids. J Clin Gastroenterol 2006;40:235–43. 10.1097/00004836-200603000-00015 PubMed DOI

Espinoza JL, Matsumoto A, Tanaka H, et al. . Gastric microbiota: an emerging player in Helicobacter pylori-induced gastric malignancies. Cancer Lett 2018;414:147–52. 10.1016/j.canlet.2017.11.009 PubMed DOI

Liou J-M, Chen C-C, Chang C-M, et al. . Long-Term changes of gut microbiota, antibiotic resistance, and metabolic parameters after Helicobacter pylori eradication: a multicentre, open-label, randomised trial. Lancet Infect Dis 2019;19:1109–20. 10.1016/S1473-3099(19)30272-5 PubMed DOI

Ley RE, Turnbaugh PJ, Klein S, et al. . Microbial ecology: human gut microbes associated with obesity. Nature 2006;444:1022–3. 10.1038/4441022a PubMed DOI

Hidalgo-Cantabrana C, Delgado S, Ruiz L, et al. . Bifidobacteria and their health-promoting effects. Microbiol Spectr 2017;5 10.1128/microbiolspec.BAD-0010-2016 PubMed DOI PMC

Advances in the Aetiology & Endoscopic Detection and Management of Early Gastric Cancer

Microbiota alteration at different stages in gastric lesion progression: a population-based study in Linqu, China