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. 2018 Feb;67(2):226-236.
doi: 10.1136/gutjnl-2017-314205. Epub 2017 Nov 4.

Gastric microbial community profiling reveals a dysbiotic cancer-associated microbiota

Rui M Ferreira  1   2 , Joana Pereira-Marques  1   2   3 , Ines Pinto-Ribeiro  1   2   4 , Jose L Costa  1   2   4 , Fatima Carneiro  1   2   4   5 , Jose C Machado  1   2   4 , Ceu Figueiredo  1   2   4
Affiliations

Gastric microbial community profiling reveals a dysbiotic cancer-associated microbiota

Rui M Ferreira et al. Gut. 2018 Feb.

Abstract

Objective: Gastric carcinoma development is triggered by Helicobacter pylori. Chronic H. pylori infection leads to reduced acid secretion, which may allow the growth of a different gastric bacterial community. This change in the microbiome may increase aggression to the gastric mucosa and contribute to malignancy. Our aim was to evaluate the composition of the gastric microbiota in chronic gastritis and in gastric carcinoma.

Design: The gastric microbiota was retrospectively investigated in 54 patients with gastric carcinoma and 81 patients with chronic gastritis by 16S rRNA gene profiling, using next-generation sequencing. Differences in microbial composition of the two patient groups were assessed using linear discriminant analysis effect size. Associations between the most relevant taxa and clinical diagnosis were validated by real-time quantitative PCR. Predictive functional profiling of microbial communities was obtained with PICRUSt.

Results: The gastric carcinoma microbiota was characterised by reduced microbial diversity, by decreased abundance of Helicobacter and by the enrichment of other bacterial genera, mostly represented by intestinal commensals. The combination of these taxa into a microbial dysbiosis index revealed that dysbiosis has excellent capacity to discriminate between gastritis and gastric carcinoma. Analysis of the functional features of the microbiota was compatible with the presence of a nitrosating microbial community in carcinoma. The major observations were confirmed in validation cohorts from different geographic origins.

Conclusions: Detailed analysis of the gastric microbiota revealed for the first time that patients with gastric carcinoma exhibit a dysbiotic microbial community with genotoxic potential, which is distinct from that of patients with chronic gastritis.

Keywords: Helicobacter pylori; bacterial infection; gastric carcinoma; gastritis.

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Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
The gastric microbiota profile differs in chronic gastritis and gastric carcinoma. (A) Shannon index of diversity in patients with chronic gastritis and gastric carcinoma. (B) Good’s estimator of coverage, measuring the proportion of total bacterial species represented in samples of each group of patients. Principal coordinate analysis (PCoA) plots of (C) unweighted and (D) weighted UniFrac distances in which samples were coloured by clinical outcome. The percentage of diversity captured by each coordinate is shown. ANOSIM, analysis of similarity.
Figure 2
Figure 2
The influence of Helicobacter pylori in the microbiota composition of chronic gastritis and gastric carcinoma. (A) Relative abundance of phyla in all subjects and in each group of patients. (B) Spearman’s rank correlation between relative abundance of Helicobacter spp. and non-Helicobacter Proteobacteria in all patients. Principal coordinate analysis (PCoA) plots of the weighted UniFrac distance matrix coloured by (C) increasing relative abundance of Helicobacter and of (D) non-Helicobacter Proteobacteria.
Figure 3
Figure 3
Microbial taxa associated with gastric carcinoma. (A) Cladogram representation of the gastric microbiota taxa associated with chronic gastritis and gastric carcinoma. (B) Association of specific microbiota taxa with the group of chronic gastritis and gastric carcinoma by linear discriminant analysis (LDA) effect size (LEfSe). Green indicates taxa enriched in chronic gastritis group and red indicates taxa enriched in gastric carcinoma group. (C) Relative abundance of the 10 genera differentially enriched in the two clinical settings across Portuguese discovery and Chinese validation cohorts. *Significance obtained by LEfSe analysis at P<0.05. (D,E) Validation of LEfSe results by quantitative PCR (qPCR) of the 10 genera differentially enriched in the discovery cohort (D) and in the Portuguese validation cohort (E). Significance was obtained by Student’s t-test.
Figure 4
Figure 4
Microbial dysbiosis is associated with gastric carcinoma. (A) Box plot showing the MDI in the discovery cohort and in the Chinese and Mexican validation cohorts. Significance was obtained by one-way analysis of variance (ANOVA) corrected with Holm-Sidak test for multiple comparisons. (B) Box plot showing the MDI of the Portuguese validation cohort. Significance was obtained by Student’s t-test. (C) Negative Pearson’s correlation between MDI and Shannon index. (D) Principal coordinate analysis (PCoA) plot of the weighted UniFrac distance coloured by increasing MDI. The percentage of diversity captured by each coordinate is shown. Mantel correlations controlled with 104 permutations were used to compare distances. (E,F) ROC curves analysis to evaluate the discriminatory potential of MDI in gastric carcinoma detection in the discovery cohort (E) and in the Portuguese validation cohort (F). AUC, area under the curve; MDI, microbial dysbiosis index; ROC, receiver operating characteristic.
Figure 5
Figure 5
The gastric carcinoma microbiota is characterised by nitrosating bacteria. Functional classification of the predicted metagenome content of the microbiota of chronic gastritis and gastric carcinoma using (A) COG and (B) KO. The normalised relative frequency of nitrate reductase and nitrite reductase in patients with chronic gastritis and gastric carcinoma is shown. Significance was considered for adjusted P<0.05. COG, Clusters of Orthologous Groups; KO, Kyoto Encyclopedia of Genes and Genome (KEGG) orthology; NADH, nicotinamide adenine dinucleotide; NO, nitric oxide; TMAO, trimethylamine N-oxide.
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