TUDCA-3S is Associated with Acute Pancreatitis Severity and Pro-Inflammatory Macrophage Activation Involving S100A8/IL-17 Signaling

Abstract

Objective Early identification of patients at risk of severe acute pancreatitis (SAP) remains challenging, and the contribution of sulfated bile-acid metabolites to AP-associated inflammatory responses remains incompletely understood. This study investigated the association between serum TUDCA-3S and AP severity and explored its effects on inflammatory macrophage activation in vitro. Methods The study cohort comprised 100 patients with acute pancreatitis (AP) and 50 healthy controls. Serum TUDCA-3S levels were quantified using targeted metabolomics, and associations with disease severity and receiver operating characteristic (ROC) performance were evaluated. An LPS-stimulated RAW264.7 inflammatory macrophage model was used to examine cellular responses associated with TUDCA-3S exposure. Flow cytometry, RT-qPCR, Western blotting, transcriptomics, untargeted metabolomics, lipidomics, and S100A8 knockdown were used for further characterization. Results Serum TUDCA-3S levels differed significantly among the study groups, with the highest median level observed in patients with SAP. TUDCA-3S distinguished AP patients from healthy controls with an AUC of 0.873. However, its performance for severity discrimination was substantially lower, with an AUC of 0.534 for MAP versus MSAP and 0.714 for MAP/MSAP versus SAP. In LPS-stimulated RAW264.7 macrophages, TUDCA-3S exposure was associated with enhanced M1-related inflammatory features and increased S100A8 and IL-17A expression. S100A8 knockdown attenuated M1-associated markers and IL-17A expression. Transcriptomic, untargeted metabolomic, and lipidomic analyses further identified inflammatory and lipid-metabolic changes associated with TUDCA-3S exposure. Conclusion Serum TUDCA-3S is associated with AP and disease severity, although its discriminatory performance across AP severity categories is limited to moderate. The in vitro findings support an association between TUDCA-3S exposure and pro-inflammatory macrophage features involving S100A8-associated IL-17A signaling and metabolic remodeling. These findings are exploratory and require independent clinical and experimental validation.