摘要Objective:Dietary nitrate has been increasingly recognized as a potential carcinogen associated with gastritis.In this study the mechanistic role of a high-nitrate diet(NaD)in driving gastritis was elucidated with a focus on modulation of the gastric microbiota composition and metabolomic profiles.Methods:Animals were randomly assigned to two dietary intervention groups using a C57BL/6 mouse model:a NaD containing 7.5％nitrate;or a standard normal diet(ND).Gastric microbiota composition was characterized based on full-length 16S rRNA sequencing and gastric metabolite profiles were analyzed using high-performance liquid chromatography-mass spectrometry(HPLC/MS).Finally,the roles of the microbiome and metabolites in gastritis development were validated using the human gastric epithelial cell line(GES-1),as well as conventional and germ-free mouse models.Results:NaD induced gastritis in conventional mice compared to ND-fed mice.In addition,NaD incited the infiltration of macrophages and neutrophils with elevated levels of inflammatory cytokine genes(IL-17a,Ccl20,Cxcl5,IL-6,and Ccl2).A significant shift in the composition of the gastric microbiota occurred with an increase in pathogenic bacteria(Enterococcus gallinarum,Prevotella timonensis,and Mycobacterium gordona)and a decrease in probiotics(Roseburia hominis,Clostriduim scindens,and Faecalibacterium prausnitzii).Furthermore,NaD induced alterations in the metabolic profile,marked by an elevated level of 5-hydroxyindoleacetate(5-HIAA),a key downstream metabolite of the tryptophan metabolic pathway.Notably,5-HIAA also upregulated the levels of inflammatory cytokines in the human gastric epithelial GES-1 cell line.In addition,both E.gallinarum colonization and 5-HIAA exposure significantly increased inflammatory responses in conventional and germ-free mouse models.Conclusions:NaD drives gastritis in mice by inducing gastric microbial dysbiosis and metabolomic dysregulation with elevated 5-HIAA.