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已发表论文
肠道免疫网络中 IgA 的生成与脓毒症的发展及进展有关：一项多组学研究
Authors Wang YF , Gao S , Gao F, Wu ML, Yang L , Zhang JY , Wang YN , Xu HY
Received 8 July 2025
Accepted for publication 3 November 2025
Published 13 November 2025 Volume 2025:18 Pages 15887—15910
DOI https://doi.org/10.2147/JIR.S548786
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Rongxue Wu
Yi-Feng Wang,1,* Song Gao,2,* Fei Gao,1 Mei-Li Wu,3 Lan Yang,1 Jia-Yue Zhang,1 Ya-Nan Wang,4 Hong Yang Xu1
1Department of Critical Care Medicine, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu, People’s Republic of China; 2Department of Critical Care Medicine, Xishan People’s Hospital of Wuxi City, Wuxi, Jiangsu, People’s Republic of China; 3Center of Clinical Research, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu, People’s Republic of China; 4Department of Gastroenterology, Henan Provincial People’s Hospital, Zhengzhou, Henan, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Hong Yang Xu, Email xhy1912@aliyun.com Ya-Nan Wang, Email wangyananln@163.com
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.
Keywords: Sepsis, intestinal immune network for IgA production, biomarker, nomogram model, single-cell RNA sequencing, mendelian randomization
1Department of Critical Care Medicine, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu, People’s Republic of China; 2Department of Critical Care Medicine, Xishan People’s Hospital of Wuxi City, Wuxi, Jiangsu, People’s Republic of China; 3Center of Clinical Research, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu, People’s Republic of China; 4Department of Gastroenterology, Henan Provincial People’s Hospital, Zhengzhou, Henan, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Hong Yang Xu, Email xhy1912@aliyun.com Ya-Nan Wang, Email wangyananln@163.com
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.
Keywords: Sepsis, intestinal immune network for IgA production, biomarker, nomogram model, single-cell RNA sequencing, mendelian randomization