The Intestinal Immune Network for IgA Production is Involved in the Development and Progression of Sepsis: A Multi-Omics Study.

Introduction: Intestinal barrier injury plays a significant role in the development and progression of sepsis. However, the underlying mechanisms remain unclear. Methods: The "intestinal immune network for IgA production" pathway (KEGG ID: hsa04672) is closely associated with the intestinal barrier. This study integrated bulk and single-cell RNA sequencing data, a clinical trial, an animal study and Mendelian randomization (MR) analyses to elucidate the role of hsa04672 during sepsis. Results: Enrichment analyses confirmed the relationship between hsa04672 and sepsis. Four machine learning algorithms identified HLA-DPA1 (area under the curve [AUC] = 0.995), ITGB7 (AUC = 0.967), and CXCR4 (AUC = 0.942) as hsa04672-associated diagnostic biomarkers. Gene Set Variation Analysis (GSVA) revealed suppressed activity of hsa04672 in sepsis patients. Two independent methods (GSVA scores and consensus clustering) generated hsa04672-associated sepsis subgroups. Kaplan-Meier analyses subsequently confirmed significant survival differences between these subgroups, indicating a relationship between hsa04672 and sepsis prognosis. Afterwards, univariable Cox, LASSO, and multivariable Cox regression analyses identified ANKRD55, CX3CR1, and GIMAP4 as hsa04672-associated prognostic biomarkers. Based on these prognostic biomarkers, we constructed a nomogram model, whose accuracy and robustness were demonstrated through calibration curves, decision curve analyses, and time-dependent ROC curves. In the animal study, reduced intestinal IgA production was observed in severe sepsis. Single-cell analyses revealed the activities of hsa04672 and the expression patterns of biomarkers within each immune cell type across healthy controls, sepsis survivors, and sepsis nonsurvivors. MR analyses suggested that elevated CXCR4 expression was a risk factor of sepsis (OR = 1.27, 95% CI: 1.02-1.58, P = 0.036), and decreased GIMAP4 expression was a risk factor of 28-day death in sepsis (OR = 0.76, 95% CI: 0.60-0.98, P = 0.032). Conclusion: The "intestinal immune network for IgA production" is deeply involved in the development and progression of sepsis.