Single-cell profiling reveals phenotypic changes in chronic atrophic gastritis

Purpose To identify key cellular changes and molecular events that are involved in the atrophic mucosa, thus help understand the molecular mechanisms driving the occurrence of chronic atrophic gastritis (CAG). Methods We used single-cell RNA sequencing (scRNA-seq) to characterize changes in the epithelial state and tissue microenvironment associated with CAG. The molecular changes were mainly identified by comparing differentially expressed genes between the two mucosa states. Gene Ontology (GO) pathway enrichment analysis was used to explore the potential functional changes in each cell subtype in atrophic mucosa. Gene set score analysis was conducted to compare the functional roles of different fibroblast subtypes and functional changes in cell subtypes between the CAG and control conditions. Metabolic analysis was conducted to compare the metabolic activity of C1Q ⁺ macrophages under different conditions. NichNet analysis was used to analyze the regulatory relationships between CXCL11 ⁺ APOE ⁺ fibroblasts and C1Q ⁺ macrophages, and between CXCL11 ⁺ APOE ⁺ fibroblasts and CD8 ⁺ effector T cells. Transcription Factor (TF) analysis was used to infer the transcription status of different T cell subtypes in atrophic and normal mucosa tissues. Results We generated a single cell transcriptome atlas from 3 CAG biopsy samples and their paired adjacent normal tissues. Our analysis revealed that chief cells and parietal cells exhibited a loss of detoxification ability and that surface mucous cells displayed a reduced antimicrobial defense ability in CAG lesions. The mucous neck cells in CAG lesions upregulated genes related to cell cycle transition, which may lead to aberrant DNA replication. Additionally, the T exhaustion phenotype was infiltrated in CAG conditions. C1Q ⁺ macrophages exhibited reduced phagocytosis ability, downregulated expression of pattern recognition receptors and decreased metabolic activity. NichNet analysis revealed that a subpopulation of CXCL11 ⁺ APOE ⁺ fibroblasts regulated the inflammatory response in the pathogenesis of atrophic gastritis. Conclusions In the occurrence of CAG, there is a certain degree of immune decline in the mucosal microenvironment, including a reduced immune response of C1Q ⁺ macrophages, reduced cytotoxicity of T cell, as well as increased infiltration of exhausted T cells. Additionally, different epithelial subtypes aberrantly express genes that may be susceptible to external bacterial infection and undergo aberrant cell cycle progression.