Multi-omics Analysis Reveals How Intratumoral Bacteria Shape the Immune Microenvironment in Gastric Cancer

The occurrence and progression of gastric cancer (GC) are closely associated with dysbiosis of the gastric microbiota and alteration in host microenvironments. However, the interaction between intratumoral bacteria and gastric microenvironments remains incompletely understood. In this study, we characterized the biological profiles of intratumoral bacteria, metabolome, and proteome in 20 GC tumors and paired non-tumor tissues, in combination with 6 independent datasets (comprising 477 gastric tissue biopsies and 534 normal tissues), as well as mucosal tissues from 10 individuals without GC. We found that the diversity and richness of gastric microbiota were significantly higher in tumor tissues than in non-tumor tissues. In contrast, the lowest biodiversity, at both the genus and species levels, was found in the microbiota of individuals without GC. Specifically, tumors were enriched with Bacteroides thetaiotaomicron, Lactobacillus parabrevis, Brevundimonas nasdae, and Brevundimonas vesicularis. We also identified 39 human immunity-related proteins, particularly in the tryptophan metabolic pathway, which were differentially expressed across various microenvironments (tumor and non-tumor). Furthermore, we found that several pathways involved in the human immune system and associated with the gastric microbiota, such as thiazole biosynthesis II, pyrimidine deoxyribonucleoside salvage, superpathway of pyrimidine deoxyribonucleoside salvage, and superpathway of heme biosynthesis from uroporphyrinogen-III, hold potential as biomarkers for early detection of GC. Our results provide a comprehensive framework for investigating the complex interactions between the tumor immune microenvironment and intratumoral bacterial community.