The Immunosuppressive Landscape of the Gastric Mucosa under Helicobacter pylori Infection

Helicobacter pylor (H. pylori) infection triggers a complex interplay between adaptive immune responses and immune suppression. However, these combined reactions typically fail to eliminate the infection. The immune suppressive mechanisms underlying H. pylori infection at the single cell level and spatial resolution remain poorly understood. In this study, we performed single-cell RNA sequencing of the gastric mucosa from both H. pylori-infected individuals and uninfected controls. By integrating spatially resolved transcriptomics data, we identified a conserved continuum spanning from normal gastric mucosa to inflammatory regions, intestinal metaplasia, and gastric cancer. We observed spatial microenvironment heterogeneity of gastric mucosa across different pathological stages spanning beyond that previously appreciated in H. pylori infection. Through comparative analysis, We identified several pathways of T cell exhaustion and observed that the presence of exhaustion-like mucosal-associated invariant T (MAIT) cells correlates with an inflammatory environment, increased myeloid cell activity, Th17 cell expansion, and upregulation of cytokine-associated pathways. Additionally, we traced the progression of intestinal metaplasia in epithelial cells, noting the accumulation of lipid-associated enterocytes, which may interact with immune cells and contribute to the immune suppressive microenvironment. Overall, our findings offer new insights into the pathogenic mechanisms of H. pylori and suggest potential avenues for developing novel immunoprophylactic strategies.