Gastric Microbiome Diversities in Gastric Cancer Patients from Europe and Asia Mimic the Human Population Structure and Are Partly Driven by Microbiome Quantitative Trait Loci

Abstract

The human gastrointestinal tract harbors approximately 100 trillion microorganisms with different microbial compositions across geographic locations. In this work, we used RNASeq data from stomach samples of non-disease (164 individuals from European ancestry) and gastric cancer patients (137 from Europe and Asia) from public databases. Although these data were intended to characterize the human expression profiles, they allowed for a reliable inference of the microbiome composition, as confirmed from measures such as the genus coverage, richness and evenness. The microbiome diversity (weighted UniFrac distances) in gastric cancer mimics host diversity across the world, with European gastric microbiome profiles clustering together, distinct from Asian ones. Despite the confirmed loss of microbiome diversity from a healthy status to a cancer status, the structured profile was still recognized in the disease condition. In concordance with the parallel host-bacteria population structure, we found 16 human loci (non-synonymous variants) in the European-descendent cohorts that were significantly associated with specific genera abundance. These microbiome quantitative trait loci display heterogeneity between population groups, being mainly linked to the immune system or cellular features that may play a role in enabling microbe colonization and inflammation.

Keywords: European and Asian diversity; biomarkers; gastric cancer; gastric microbiome; miQTL; microbiome quantitative trait loci.

Figure 1

Microbiota composition in gastric cancer and non-cancerous samples. (A) Heatmap of statistically significant differentiated genera and phyla abundance when comparing the control Genotype-Tissue Expression (GTEx) non-cancer gastric microbiome with the European ancestry (Europe and USA) The Cancer Genome Atlas (TCGA) cancer samples. (B) Log2 fold change of the statistically significant differentiated genera and phyla between the non-cancer (negative axis) and cancer (positive axis) cohorts.

Figure 2

Alpha diversity and phylogenetic analysis of the gastric microbiome. (A) Good’s coverage, Chao1, Shannon and evenness in the inferred microbiome patterns. (B) Phylogenetic tree and respective abundance of genera found in the gastric microbiome (only genera that passed a mean threshold of 1% in at least one population are displayed in the graph). Samples are from non-cancer individuals from the GTEx dataset (United States n = 164, in brink pink) and cancer patients from the TCGA 2012 batch (United States n = 14 in gold; Ukraine n = 24 in limeade, Poland n = 11 in Caribbean green; Russia n = 34 in cerulean; South Korea n = 28 in purple and Vietnam n = 26 in pink).

Figure 3

Gastric cancer microbiome profiling in function of the host geographical origin. (A) non-metric multidimensional scale (nMDS) plot for the weighted UniFrac distances and PERMANOVA analysis (stress = 0.17; r2 = 0.05; p~0.054) between the geographic groups in the cancer cohort (same colors as in Figure 1). (B) Neighbor-joining tree of the mean weighted UniFrac distances between the geographic groups in the cancer cohort. (C) Neighbor-joining tree of the mean weighted UniFrac distances between the geographic groups in the cancer and non-cancer cohorts.

Figure 4

Example of an identified microbiome quantitative trait locus. (A) Worldwide genotype frequencies of rs2219078 SNP located in the SULT1C3 gene for 1000 Genomes project populations. (B) Acinetobacter relative abundances of the rs2219078 genotypes in the TCGA European cohort. (C) The TCGA East Asian cohort. (D) The GTEx European-descendent cohort.