Analysis of gastric mucosal commensal bacteria and plasma metabolites across different stomach microhabitats using multi-omic analyses in development of gastric cancer

As an important component of microenvironment, the gastric microbiota and their metabolites are associated to tumor occurrence, progression and metastasis. However, the relationship between gastric microbiota and the development of gastric cancer is far from clear. To investigate the role of gastric mucosa microbiome and metabolites as etiological factors in gastric carcinogenesis, gastric biopsies (n=70) and blood samples (n=95) were applied to identify microbial structure and plasma metabolic changes in different stomach microhabitats using multi-omics techniques including the 16S rRNA amplicon sequencing and metabolomics. It was noted that the microbiota diversity and community composition were remarkably changed in different stomach microhabitats during gastric carcinogenesis, especially in the presence of Helicobacter pylori . High H. pylori colonization modified the overall diversity and the composition of the gastric microbiota in gastritis and tumoral microhabitats. Most importantly, the gastric carcinoma microbiota was characterized by reduced abundance of Helicobacter and by the prevalence of other bacterial genera at the developmental stage of gastric cancer, mostly represented by oral cavity and intestinal microbiota. PiCRUSt2 analysis revealed that the nitrate reductase genes were significantly enriched in tumoral microbiota, while urease-producing function was significantly enriched in microbiota of Hp -positive cases. The untargeted metabolomics analysis uncovered 81 metabolites, including 2-methoxyestradiol, 8,9-DiHETrE and leukotriene B4, were significantly different between superficial gastritis and gastric cancer patients and they were related to top 25 signal pathways. On the other hand, uric acid, N-acetylserotonin and phenylethylamine significantly discriminated H. pylori -positive and H. pylori -negative patients with chronic atrophic gastritis. Furthermore, ROC curve analysis identified a series of gastric microbiota and plasma metabolite signatures which might playimportant roles in gastric carcinogenesis and had the potential to be used as biomarkers for diagnosis, making surveillance of gastric cancer patients with a minimally invasive possibility.