Abstract
Gastric cancer (GC) remains one of the most commonly diagnosed cancers and a leading cause of cancer mortality globally. Clinical outcomes are heavily influenced by histological subtype, classified by the Lauren classification system as either intestinal or diffuse, and host factors such as biological sex. While the role of Helicobacter pylori as a key driver of carcinogenesis is well-documented, the role of the broader gastric microbiome and how biological sex modifies these interactions remains a critical knowledge gap. Here we investigate how gastric microbiome diversity, taxonomic composition, and predicted functional potential differ between the intestinal and diffuse subtypes, and whether biological sex modifies these patterns. Using a 16S rRNA gene sequencing dataset from a cohort of 45 GC patients (15 intestinal, 30 diffuse), we performed differential abundance and metabolic functional prediction analyses. We found that overall community composition, but not alpha diversity, differed significantly between subtypes. Moreover, within the diffuse subtype, female tumours exhibited significantly higher alpha diversity and a distinct microbial community compared to males. Taxonomic profiling revealed an enrichment of genera, including both Helicobacter and Lactobacillus in diffuse cases, with the males showing a significantly higher relative abundance of Helicobacter (p < 0.001). Predicted functional analysis further revealed increased metabolic enrichment in the diffuse subtype of male patients, including pathways related to lipid biosynthesis and overall virulence in H. pylori. These findings demonstrate that the gastric microbiome reflects histological heterogeneity and highlights the importance of biological sex in shaping gastric tumour-associated microbial patterns.