Objective Gastric cancer (GC) is a leading cause of cancer-related mortality. Although microbes besides Helicobacter pylori may also contribute to gastric carcinogenesis, wild-type germ-free (GF) mouse models investigating the role of human gastric microbiota in the process are not yet available. We aimed to evaluate the histopathological features of GF mouse stomachs transplanted with gastric microbiota from patients with different gastric disease states and their relationships with the microbiota.
Design Microbiota profiles in corpus and antrum tissues and gastric fluid from 12 patients with gastric dysplasia or GC were analysed. Thereafter, biopsied corpus and antrum tissues and gastric fluid from patients (n=15 and n=12, respectively) with chronic superficial gastritis, intestinal metaplasia or GC were inoculated into 42 GF C57BL/6 mice. The gastric microbiota was analysed by amplicon sequencing. Histopathological features of mouse stomachs were analysed immunohistochemically at 1 month after inoculation. An independent set of an additional 15 GF mice was also analysed at 1 year.
Results The microbial community structures of patients with dysplasia or GC in the corpus and antrum were similar. The gastric microbiota from patients with intestinal metaplasia or GC selectively colonised the mouse stomachs and induced premalignant lesions: loss of parietal cells and increases in inflammation foci, in F4/80 and Ki-67 expression, and in CD44v9/GSII lectin expression. Marked dysplastic changes were noted at 1 year post inoculation.
Conclusion Major histopathological features of premalignant changes are reproducible in GF mice transplanted with gastric microbiota from patients with intestinal metaplasia or GC. Our results suggest that GF mice are useful for analysing the causality of associations reported in human gastric microbiome studies.
- gastric cancer
- intestinal microbiology
Data availability statement
Data are available in a public, open access repository.
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S-KK, JCP and KHK are joint first authors.
JFK, KTN and YCL are joint senior authors.
S-KK, JCP and KHK contributed equally.
Correction notice This article has been corrected since it published Online First. The author, So Dam Lee, has been added.
Contributors YCL, KTN and JFK conceived, designed and directed the study. YCL, JCP, SDL and BRH collected the human samples and arranged the clinical data. KHK, YC, BL, J-JL, HJ, YO, S-HK and KTN performed the GF mouse experiments and observed the GF mouse phenotypes. S-KK, J-KY, YC and JFK obtained and analysed the microbiota data. S-KK, JCP and KHK interpreted the results and drafted the manuscript. JFK, YCL and KTN reviewed and edited the manuscript. All authors discussed the results and commented on the manuscript.
Funding This study was supported in part by grants from the National Research Foundation of Korea (grant nos. NRF-2017R1A2B201288714 and NRF-2017M3A9F304772821) and the Korea Health Technology R&D Project (HI17C1516010018) through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea to YCL; the Korea Mouse Phenotyping Project (NRF-2016M3A9D5A01952416) and National Research Foundation of Korea (NRF-2017M3A9F3041234) to KTN; the National Research Foundation of Korea (NRF-2014M3C9A3068822 and NRF-2017M3A9F3047857) to JFK; the National Research Foundation of Korea (NRF- 2020R1C1C1004778) to S-KK; and a Faculty Research Grant of Yonsei University College of Medicine (6-2016-0059) to JCP. Publication was supported in part by the Brain Korea 21 program; JKY and YC are fellowship awardees of this program.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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