Diet, Gastric Microbiota, and Metabolites in Gastric Tumorigenesis

Abstract

Gastric cancer (GC) is one of the most common cancers worldwide particularly in Asian populations, and certain diets have been associated with increased risk of GC. Recent advances in microbial profiling technology have facilitated investigations on microbes residing on the gastric mucosa and increasing evidence has revealed the critical roles of non-Helicobacter pylori gastric microbes in gastric tumorigenesis. On the other hand, diets can affect microbial communities, causing compositional and functional shift of the microbiota. In this review, we summarize the influence of various diets including processed meat, salt-preserved food, high-fat diet, and alcohol on the development and progression of GC. We also explore microbial metabolites and host-microbe interactions in gastric tumorigenesis, alongside dietary interventions targeting the microbiota for the prevention and management against GC.

Fig. 1.

Dietary patterns and their pathogenic mechanisms in gastric cancer. Dietary patterns including salt-preserved foods, processed meat, alcohol, and high-fat diet influence gastric tumorigenesis through different mechanisms. (a) Excess dietary salts elevate urinary sodium excretion and promote H. pylori colonization and clonal expansion of mutated epithelial cells. Chronic salt exposure induces oxidative DNA damage by increasing reactive oxygen species, which synergize with H. pylori to trigger genomic instability. Excess salts also activate the COX-2-PGE₂ axis, thereby promoting cellular proliferation and disrupting gastric epithelial homeostasis. (b) Carcinogenic compounds like HCAs and PAHs are generated in processed meat during cooking, which can induce mitochondrial dysfunction and cause double-strand breaks in DNA, resulting in mutations. (c) Alcohol is metabolized to generate acetaldehyde in the stomach, a metabolite known to disrupt gastric mucosal barrier and induce mitochdonrial damage with elevated reactive oxygen species. The accumulation of toxic aldehydes also exacerbates DNA damage and leads to chronic gastritis, while chronic inflammation promotes immature myeloid cell infiltration and subsequently gastric tumorigenesis. (d) Excess dietary fats can up-regulate DGAT2 activity, thereby increasing reactive oxygen species and STAT3 signaling. This pro-inflammatory milieu further enhances IL-17A production to promote angiogenesis and the recruitment of immature myeloid cells. Figure was created with BioRender.com.

Fig. 2.

Interplays between diets and gastric microbiota in gastric cancer. Human gastric microbiota is heavily influenced by diets, whereas different diets have distinct effects on gastric tumorigenesis. High-fat diet induces gastric microbial dysbiosis with increased Lactobacillus and decreased Bifidobacterium, and promotes leptin secretion to activate pro-inflammatory pathways (e.g., COX-2/PGE₂/NF- κ B). Excess dietary salts promote H. pylori colonization and deplete short-chain fatty acids (SCFAs) (e.g., butyrate), thereby disrupting the integrity of gastric mucosal barrier integrity and inducing IL-6/STAT3-mediated inflammation. On the other hand, fruits, vegetables (e.g., sulforaphane-rich broccoli sprouts), and walnuts can up-regulate the HO-1/NRF2 antioxidant pathway, while suppressing leptin production and pro-inflammatory factors (e.g., COX-2, PGE₂, and STAT3), as well as H. pylori colonization. These features collectively facilitate the inhibition of gastric tumorigenesis. Figure was created with BioRender.com.

Fig. 3.

Summary of mechanisms and research priorities. An overview of the crosstalk and underlying mechanisms between diets and the gastric microbiota in GC. Certain diets (e.g., high-salt diet, processed meat, alcohol, and HFD) directly influence gastric tumorigenesis or induce changes in the gastric microbiota to contribute to GC development. Meanwhile, apart from H. pylori, a dysbiotic gastric microbiota with enriched pathogenic bacteria (e.g., S. anginosus) and their metabolites can also promote gastric tumorigenesis. Given their critical roles, future studies should emphasize actionable research priorities for prevention and therapy against GC. These priorities include tailored dietary interventions such as salt-restricted diets and prebiotics (e.g., resistant starch) to promote the growth of beneficial commensal bacteria, engineered probiotics to restore the gastric microbiota, and microbial biomarkers (e.g., S. anginosus) for early detection of GC. Figure was created with BioRender.com.