A dysbiotic polymicrobial signature characterized by oral pathogens links the oral-gastric axis to gastric carcinogenesis in a high-risk Chilean cohort

Objectives:Gastric cancer (GC) remains a formidable global health challenge, particularly in high-risk regions like Chile. The traditional etiological model centered on Helicobacter pylori is insufficient to explain the full spectrum of disease. This study aimed to identify a robust, polymicrobial signature in GC tissue and test the hypothesis that the Oral-Gastric Axis drives the carcinogenic process via chronic colonization by translocated oral pathogens. Methods: We employed high-throughput 16S rRNA amplicon sequencing to profile the gastric microbiome in tissue samples from a Chilean cohort (15 GC patients [CAN], 15 healthy controls [NOC]). Microbial composition, alpha diversity (richness, evenness), and differential abundance were assessed using non-parametric tests (Mann-Whitney U) and statistically validated through supervised machine learning approaches, including Random Forest and penalized regression models (Lasso/Ridge), to ensure robust biomarker selection. ResultsThe GC microbiome showed a profound dysbiotic shift, characterized by a significant increase in species richness (Observed ASVs, ACE, Chao1; p<0.001) but marked ecological unevenness. A core four-genus signature consistently differentiated CAN from NOC tissue: Fusobacterium (MWU p=0.024), Lactobacillus (MWU p=0.038), Neisseria (MWU p=0.005), and Prevotella (MWU p=0.023). The oral pathogens Neisseria (Random Forest Rank 1) and Fusobacterium (enriched in CAN) were identified as the top predictive features. Mechanistic insights suggest Fusobacterium contributes to immune evasion by promoting the recruitment of PD-L1-expressing tumor-associated neutrophils, linking this signature directly to immunotherapy targets. Conclusions: Gastric cancer is associated with a distinct, pathologically unstable polymicrobial signature dominated by known oral pathogens. This robust signature provides compelling quantitative evidence supporting the Oral-Gastric Axis Hypothesis. The identified microbial community offers promising candidates for novel non-invasive diagnostic biomarkers and suggests new therapeutic strategies, such as targeted depletion of pro-tumorigenic oral microbes to sensitize tumors to immune checkpoint blockade therapy in gastric cancer.