Based on multistage metabolomic profiling and Mendelian randomization analyses, the current study identified plasma metabolites that predicted the risk of developing gastric cancer (GC) and determined whether key metabolite levels modified the GC primary prevention effects.

Plasma metabolites associated with GC risk were identified through a case-control study. Bi-directional two-sample Mendelian randomization analyses were performed to determine potential causal relationships utilizing the Shandong Intervention Trial (SIT), a nested case-control study of the Mass Intervention Trial in Linqu, Shandong province (MITS), China, the UK Biobank, and the FinnGen project.

A higher genetic risk score for plasma L-aspartic acid was significantly associated with an increased GC risk in the northern Chinese population (SIT: HR = 1.26 per 1 SD change, 95% CI: 1.07–1.49; MITS: HR = 1.07, 95% CI: 1.00–1.14) and an increased gastric adenocarcinoma risk in FinnGen (OR = 1.68, 95% CI: 1.16–2.45). Genetically predicted plasma L-aspartic acid levels also modified the GC primary prevention effects with the beneficial effect of Helicobacter pylori eradication notably observed among individuals within the top quartile of L-aspartic acid level (P-interaction = 0.098) and the beneficial effect of garlic supplementation only for those within the lowest quartile of L-aspartic acid level (P-interaction = 0.02).

Elevated plasma L-aspartic acid levels significantly increased the risk of developing GC and modified the effects of GC primary prevention. Further studies from other populations are warranted to validate the modification effect of plasma L-aspartic acid levels on GC prevention and to elucidate the underlying mechanisms.

This study aimed at examining the alterations in metabolomic profiles caused by treatment of H. pylori infection, and the associations between key plasma metabolites and the risk of gastric lesion progression during follow-up after treatment.

An intervention trial was performed in 183 participants, 117 of whom were H. pylori positive participants receiving treatment for H. pylori infection. H. pylori positive participants were prospectively followed for 182 to 1,289 days. Untargeted metabolomics assays were conducted on plasma samples collected at baseline, 6 months after treatment, and during continued follow-up.

We identified 59 metabolites with differential posttreatment changes between participants with successful and failed H. pylori eradication, 17 metabolites significantly distinguished participants with successful vs. failed eradication. Two metabolites [PC(18:1(11Z)/14:1(9Z)) and (2S)-6-amino-2-formamidohexanamide] showed posttreatment changes positively associated with successful H. pylori eradication, and were inversely associated with the risk of gastric lesion progression among participants with successful eradication. In contrast, 9-decenoic acid showed posttreatment changes inversely associated with successful eradication: its level was positively associated with the risk of gastric lesion progression among participants with successful eradication. Although the identified metabolites showed a temporary but significant decline after treatment, the trend generally reversed during continued follow-up, and pretreatment levels were restored.

Treatment of H. pylori infection significantly altered plasma metabolic profiles in the short term, and key metabolites were capable of distinguishing participants with successful vs. failed eradication, but might not substantially affect metabolic regulation in the long term. Several plasma metabolites were differentially associated with the risk of gastric lesion progression among participants with successful or failed eradication.