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Background Gastric cancer (GC) development is a long-term process involving multiple molecular alterations. This study aims to identify the differentiate microbes, methylation and mutation genes, and comprehensively investigate their interactions in the GC initiation and progression process.Methods We enrolled 23 superficial gastritis (SG), 40 early GC (EGC) and 42 advanced GC (AGC) subjects from an early detection project and outpatients in the county hospital of Linqu, a high-risk area of GC in China. The gastric lesion tissues and paired AGC adjacent samples were detected for a 360-methylation-gene and a 144-amplicon-mutation panel with Mutation Capsule Plus (MCP) and microbiota with 16S rRNA sequencing. Helicobacter pylori (H.pylori) specific antibodies were detected with a recomLine assay.Results The methylation and microbiota profiles showed significant differences among SG, EGC, AGC and AGC adjacent tissues ( IDDF2026-ABS-0375 Figure 1. The methylation and microbiota profiles among SG, EGC, AGC and AGC adjacent tissues. (A) methylation profile by principal component analysis; (B) microbial alpha diversity analysis; (C) community structure analysis). A GC-initiation-methylation panel with 132 differential genes between EGC and SG, and a GC-progression-methylation panel with 58 genes between AGC and EGC or AGC and adjacent samples, were established and integrated with a GC-associated-microbe panel with 97 genera/species. The differential methylation genes and microbes were enriched into similar functions including PI3K-Akt signaling pathway and MAPK signaling pathway, suggesting potential microbe-methylation interactions in GC development. Significant positive correlations of differential microbes were found with GC-initiation methylation including H.pylori, Peptostreptococcus or Actinobacillus in SG, and Veillonella parvula or Haemophilus in EGC (IDDF2026-ABS-0375 Figure 2. Correlation analyses of differential microbes and GC initiation methylation. (A) correlation analysis between microbes and GC-initiation methylation). Specific antibodies of H.pylori showed strong positive correlations with GC-initiation methylation including CagA, gGT, FliD and GroEL in SG, while HpaA, HtrA and Omp in EGC (IDDF2026-ABS-0375 Figure 2. Correlation analyses of differential microbes and GC initiation methylation. (B) correlation analysis between H.pylori antibodies and GC-initiation methylation). P53 mutations were important for GC-progression in 59.5% AGC and only 5.0% EGC samples. EGC/AGC subjects with mutant-type P53 were characterized by higher microbial diversity (IDDF2026-ABS-0375 Figure 3. Characteristics of EGCAGCS with wild or mutant type p53. (A) alpha diversity analysis), while EGC/AGCs with wild-type P53 were characterized by more significant correlations between microbes and GC-progression methylation (IDDF2026-ABS-0375 Figure 3. Characteristics of EGCAGCS with wild or mutant type p53. (B) correlation analysis between microbes and GC-progression methylation).Conclusions Our study suggested comprehensive interactions of microbiota with epigenetic and genetic alterations in GC initiation and progression.Abstract IDDF2026-ABS-0375 Figure 1Abstract IDDF2026-ABS-0375 Figure 2Abstract IDDF2026-ABS-0375 Figure 3