Eradication of Helicobacter pylori has been found to be effective for gastric cancer prevention, but uncertainties remain about the possible adverse consequences such as the potential microbial dysbiosis. In our study, we investigated the association between gut microbiota and H. pylori-related gastric lesions in 47 subjects by deep sequencing of microbial 16S ribosomal RNA (rRNA) gene in fecal samples. The dominant phyla in fecal samples were Bacteroidetes, Firmicutes, and Proteobacteria with average relative abundances of 54.77, 31.37 and 12.91%, respectively. Microbial diversity analysis showed that observed species and Shannon index were increased in subjects with past or current H. pylori infection compared with negative subjects. As for the differential bacteria, the average relative abundance of Bacteroidetes was found to significantly decrease from H. pylori negative (66.16%) to past infection group (33.01%, p = 0.007), as well as from normal (76.49%) to gastritis (56.04%) and metaplasia subjects (46.83%, p = 0.027). For Firmicutes and Proteobacteria, the average relative abundances showed elevated trends in the past H. pylori infection group (47.11, 20.53%) compared to negative group (23.44, 9.05%, p = 0.068 and 0.246, respectively), and similar increased trends were also found from normal (18.23, 5.05%) to gastritis (35.31, 7.23%, p = 0.016 and 0.294, respectively) or metaplasia subjects (32.33, 20.07%, both p < 0.05). These findings suggest that the alterations of fecal microbiota, especially the dominant phyla of Bacteroidetes, Firmicutes and Proteobacteria, may be involved in the process of H. pylori-related gastric lesion progression and provide hints for future evaluation of microbial changes after H. pylori eradication.

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

Department of Internal Medicine 1st Faculty of Medicine Charles University Military University Hospital Prague Czechia

German Center for Infection Research Partner Site Munich Munich Germany

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

Institute of Pathology Klinikum Bayreuth Bayreuth Germany

International Digestive Cancer Alliance Munich 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

Zobrazit více v PubMed

Aviles-Jimenez F., Vazquez-Jimenez F., Medrano-Guzman R., Mantilla A., Torres J. (2014). Stomach microbiota composition varies between patients with non-atrophic gastritis and patients with intestinal type of gastric cancer. Sci. Rep. 4:4202. 10.1038/srep04202 PubMed DOI PMC

Bajaj J. S., Idilman R., Mabudian L., Hood M., Fagan A., Turan D., et al. . (2018). Diet affects gut microbiota and modulates hospitalization risk differentially in an international cirrhosis cohort. Hepatology. [Epub ahead of print]. 10.1002/hep.29791 PubMed DOI

Baker G. C., Smith J. J., Cowan D. A. (2003). Review and re-analysis of domain-specific 16S primers. J. Microbiol. Methods 55, 541–555. 10.1016/j.mimet.2003.08.009 PubMed DOI

Bik E. M., Eckburg P. B., Gill S. R., Nelson K. E., Purdom E. A., Francois F., et al. . (2006). Molecular analysis of the bacterial microbiota in the human stomacH. Proc. Natl. Acad. Sci. U.S.A. 103, 732–737. 10.1073/pnas.0506655103 PubMed DOI PMC

Bokulich N. A., Subramanian S., Faith J. J., Gevers D., Gordon J. I., Knight R., et al. . (2013). Quality-filtering vastly improves diversity estimates from Illumina amplicon sequencing. Nat. Methods 10, 57–59. 10.1038/nmeth.2276 PubMed DOI PMC

Bühling A., Radun D., Müller W. A., Malfertheiner P. (2001). Influence of anti-Helicobacter triple-therapy with metronidazole, omeprazole and clarithromycin on intestinal microflora. Aliment. Pharmacol. Ther. 15, 1445–1452. 10.1046/j.1365-2036.2001.01033.x PubMed DOI

Coker O. O., Dai Z., Nie Y., Zhao G., Cao L., Nakatsu G., et al. . (2018). Mucosal microbiome dysbiosis in gastric carcinogenesis. Gut 67, 1024–1032. 10.1136/gutjnl-2017-314281 PubMed DOI PMC

Correa P. (1992). Human gastric carcinogenesis: a multistep and multifactorial process–First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res. 52, 6735–6740. PubMed

Couzin-Frankel J. (2010). Bacteria and asthma: untangling the links. Science 330, 1168–1169. 10.1126/science.330.6008.1168 PubMed DOI

Dixon M. F., Genta R. M., Yardley J. H., Correa P. (1996). Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am. J. Surg. Pathol. 20, 1161–1181. 10.1097/00000478-199610000-00001 PubMed DOI

Edgar R. C. (2013). UPARSE: highly accurate OTU sequences from microbial amplicon reads. Nat. Methods 10, 996–998. 10.1038/nmeth.2604 PubMed DOI

Edgar R. C., Haas B. J., Clemente J. C., Quince C., Knight R. (2011). UCHIME improves sensitivity and speed of chimera detection. Bioinformatics 27, 2194–2200. 10.1093/bioinformatics/btr381 PubMed DOI PMC

Eun C. S., Kim B. K., Han D. S., Kim S. Y., Kim K. M., Choi B. Y., et al. . (2014). Differences in gastric mucosal microbiota profiling in patients with chronic gastritis, intestinal metaplasia, and gastric cancer using pyrosequencing methods. Helicobacter 19, 407–416. 10.1111/hel.12145 PubMed DOI

Ferreira R. M., Pereira-Marques J., Pinto-Ribeiro I., Costa J. L., Carneiro F., Machado J. C., et al. . (2018). Gastric microbial community profiling reveals a dysbiotic cancer-associated microbiota. Gut 67, 226–236. 10.1136/gutjnl-2017-314205 PubMed DOI PMC

Flemer B., Lynch D. B., Brown J. M., Jeffery I. B., Ryan F. J., Claesson M. J., et al. . (2017). Tumour-associated and non-tumour-associated microbiota in colorectal cancer. Gut 66, 633–643. 10.1136/gutjnl-2015-309595 PubMed DOI PMC

Francino M. P. (2015). Antibiotics and the human gut microbiome: dysbioses and accumulation of resistances. Front. Microbiol. 6:1543. 10.3389/fmicb.2015.01543 PubMed DOI PMC

Garrett W. S. (2015). Cancer and the microbiota. Science 348, 80–86. 10.1126/science.aaa4972 PubMed DOI PMC

Gopalakrishnan V., Spencer C. N., Nezi L., Reuben A., Andrews M. C., Karpinets T. V., et al. . (2018). Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97–103. 10.1126/science.aan4236 PubMed DOI PMC

Heimesaat M. M., Fischer A., Plickert R., Wiedemann T., Loddenkemper C., Gobel U. B., et al. . (2014). Helicobacter pylori induced gastric immunopathology is associated with distinct microbiota changes in the large intestines of long-term infected Mongolian gerbils. PLoS ONE 9:e100362. 10.1371/journal.pone.0100362 PubMed DOI PMC

Huws S. A., Edwards J. E., Kim E. J., Scollan N. D. (2007). Specificity and sensitivity of eubacterial primers utilized for molecular profiling of bacteria within complex microbial ecosystems. J. Microbiol. Methods 70, 565–569. 10.1016/j.mimet.2007.06.013 PubMed DOI

Jo H. J., Kim J., Kim N., Park J. H., Nam R. H., Seok Y. J., et al. . (2016). Analysis of gastric microbiota by pyrosequencing: minor role of bacteria other than Helicobacter pylori in the gastric carcinogenesis. Helicobacter 21, 364–374. 10.1111/hel.12293 PubMed DOI

Lertpiriyapong K., Whary M. T., Muthupalani S., Lofgren J. L., Gamazon E. R., Feng Y., et al. . (2014). 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 63, 54–63. 10.1136/gutjnl-2013-305178 PubMed DOI PMC

Ley R. E., Turnbaugh P. J., Klein S., Gordon J. I. (2006). Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023. 10.1038/4441022a PubMed DOI

Li T. H., Qin Y. W., Sham P. C., Lau K. S., Chu K. M., Leung W. K. (2017). Alterations in gastric microbiota after H. pylori eradication and in different histological stages of gastric carcinogenesis. Sci. Rep. 7:44935. 10.1038/srep44935 PubMed DOI PMC

Lofgren J. L., Whary M. T., Ge Z., Muthupalani S., Taylor N. S., Mobley M., et al. . (2011). Lack of commensal flora in Helicobacter pylori-infected INS-GAS mice reduces gastritis and delays intraepithelial neoplasia. Gastroenterology 140, 210–220. 10.1053/j.gastro.2010.09.048 PubMed DOI PMC

Magoc T., Salzberg S. L. (2011). FLASH: fast length adjustment of short reads to improve genome assemblies. Bioinformatics 27, 2957–2963. 10.1093/bioinformatics/btr507 PubMed DOI PMC

Maldonado-Contreras A., Goldfarb K. C., Godoy-Vitorino F., Karaoz U., Contreras M., Blaser M. J., et al. . (2011). Structure of the human gastric bacterial community in relation to Helicobacter pylori status. ISME J. 5, 574–579. 10.1038/ismej.2010.149 PubMed DOI PMC

Mortha A., Chudnovskiy A., Hashimoto D., Bogunovic M., Spencer S. P., Belkaid Y., et al. . (2014). Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 343:1249288. 10.1126/science.1249288 PubMed DOI PMC

Myllyluoma E., Ahlroos T., Veijola L., Rautelin H., Tynkkynen S., Korpela R. (2007). Effects of anti-Helicobacter pylori treatment and probiotic supplementation on intestinal microbiota. Int. J. Antimicrob. Agents 29, 66–72. 10.1016/j.ijantimicag.2006.08.034 PubMed DOI

Pan K. F., Zhang L., Gerhard M., Ma J. L., Liu W. D., Ulm K., et al. . (2016). A large randomised controlled intervention trial to prevent gastric cancer by eradication of Helicobacter pylori in Linqu County, China: baseline results and factors affecting the eradication. Gut 65, 9–18. 10.1136/gutjnl-2015-309197 PubMed DOI

Parks D. H., Tyson G. W., Hugenholtz P., Beiko R. G. (2014). STAMP: statistical analysis of taxonomic and functional profiles. Bioinformatics 30, 3123–3124. 10.1093/bioinformatics/btu494 PubMed DOI PMC

Quast C., Pruesse E., Yilmaz P., Gerken J., Schweer T., Yarza P., et al. . (2013). The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res. 41, D590–D596. 10.1093/nar/gks1219 PubMed DOI PMC

Rakoff-Nahoum S., Medzhitov R. (2009). Toll-like receptors and cancer. Nat. Rev. Cancer 9, 57–63. 10.1038/nrc2541 PubMed DOI

Rooks M. G., Garrett W. S. (2016). Gut microbiota, metabolites and host immunity. Nat. Rev. Immunol. 16, 341–352. 10.1038/nri.2016.42 PubMed DOI PMC

Schulz C., Schütte K., Koch N., Vilchez-Vargas R., Wos-Oxley M. L., Oxley A. P. A., et al. . (2018). The active bacterial assemblages of the upper GI tract in individuals with and without Helicobacter infection. Gut 67, 216–225. 10.1136/gutjnl-2016-312904 PubMed DOI

Sekirov I., Russell S. L., Antunes L. C., Finlay B. B. (2010). Gut microbiota in health and disease. Physiol. Rev. 90, 859–904. 10.1152/physrev.00045.2009 PubMed DOI

Tang R., Wei Y., Li Y., Chen W., Chen H., Wang Q., et al. . (2018). Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy. Gut 67, 534–541. 10.1136/gutjnl-2016-313332 PubMed DOI

Torre L. A., Bray F., Siegel R. L., Ferlay J., Lortet-Tieulent J., Jemal A. (2015). Global cancer statistics, (2012). CA Cancer J. Clin. 65, 87–108. 10.3322/caac.21262 PubMed DOI

Tözün N., Vardareli E. (2016). Gut microbiome and gastrointestinal cancer: les liaisons dangereuses. J. Clin. Gastroenterol. 50(Suppl. 2), S191–S196. 10.1097/MCG.0000000000000714 PubMed DOI

Wang L., Zhou J., Xin Y., Geng C., Tian Z., Yu X., et al. . (2016). Bacterial overgrowth and diversification of microbiota in gastric cancer. Eur. J. Gastroenterol. Hepatol. 28, 261–266. 10.1097/MEG.0000000000000542 PubMed DOI PMC

Wong B. C., Lam S. K., Wong W. M., Chen J. S., Zheng T. T., Feng R. E., et al. . (2004). Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA 291, 187–194. 10.1001/jama.291.2.187 PubMed DOI

Yap T. W., Gan H. M., Lee Y. P., Leow A. H., Azmi A. N., Francois F., et al. . (2016). Helicobacter pylori eradication causes perturbation of the human gut microbiome in young adults. PLoS ONE 11:e0151893. 10.1371/journal.pone.0151893 PubMed DOI PMC

You W. C., Brown L. M., Zhang L., Li J. Y., Jin M. L., Chang Y. S., et al. . (2006). Randomized double-blind factorial trial of three treatments to reduce the prevalence of precancerous gastric lesions. J. Natl. Cancer Inst. 98, 974–983. 10.1093/jnci/djj264 PubMed DOI