Exploratory Serum Metabolomics Identifies Metabolic Subgroups Across the Gastric Dysplasia-Early Cancer Spectrum.

Abstract

Background: Gastric carcinogenesis involves progressive molecular and metabolic alterations, yet non-invasive biomarkers for early detection and risk stratification remain limited. This study aimed to characterize systemic metabolomic changes across the gastric carcinogenesis spectrum and to investigate potential associations between serum metabolites and gastric microbiome-related pathways.

Methods: In this exploratory study, untargeted serum metabolomics was performed on samples from patients with gastric dysplasia or early gastric cancer (n = 40) and healthy controls (n = 14). Differential metabolite analysis, principal component analysis, and k-means clustering were used to identify metabolic alterations and potential metabolic subgroups. Microbial pathway associations were examined using metabolite origin inference based on gastric-resident taxa reported in prior studies.

Results: Eighteen metabolites were significantly altered in gastric carcinogenesis compared with healthy controls. Six metabolites displayed distinct profiles that suggest two metabolic subgroups, including one subgroup showing a metabolic pattern closer to that of healthy controls, independent of histologic severity. Microbial pathway inference suggested contributions from Pseudomonadota, Actinomycetota, and Bacillota, with ornithine-related metabolites emerging as a key metabolic link previously implicated in dysplasia-to-carcinoma progression. These findings highlight inter-patient heterogeneity and potential metabolic-microbial interactions underlying gastric carcinogenesis.

Conclusion: These findings suggest that serum metabolomic profiling may capture metabolic heterogeneity across the gastric dysplasia-early gastric cancer spectrum and generate hypotheses regarding microbiome-related metabolic alterations. While exploratory in nature, this study provides preliminary evidence supporting the potential of serum metabolites as non-invasive indicators of early gastric carcinogenesis, warranting validation in larger and longitudinal cohorts.