Chen YF, Wang ZT, Zhao J, Tang JG, Zhang BY. Sphinganine inhibits macrophage polarization and protects against sepsis-induced intestinal injury. World J Gastroenterol 2025; 31(48): 112004 [DOI: 10.3748/wjg.v31.i48.112004]
Corresponding Author of This Article
Bai-Yin Zhang, PhD, Professor, Department of Trauma-Emergency and Critical Care Medicine Center, Shanghai Fifth People’s Hospital, Fudan University, No. 801 Heqing Road, Minhang District, Shanghai 200240, China. boyinercheung@hotmail.com
Research Domain of This Article
Critical Care Medicine
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Yi-Fan Chen, Jian-Guo Tang, Bai-Yin Zhang, Department of Trauma-Emergency and Critical Care Medicine Center, Shanghai Fifth People’s Hospital, Fudan University, Shanghai 200240, China
Ze-Tian Wang, Department of Anesthesiology and Pain Management, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200240, China
Jian Zhao, Department of Emergency, Shanghai Tenth People’s Hospital, Shanghai 200072, China
Co-corresponding authors: Jian-Guo Tang and Bai-Yin Zhang.
Author contributions: Zhang BY and Tang JG designed the research study; Zhao J and Wang ZT performed the research, contributed new reagents and analytic tools; Chen YF analyzed the data and wrote the manuscript; all authors have read and approved the final manuscript.
Supported by the Natural Science of Minhang District of Shanghai, No. 2023MH2085.
Institutional review board statement: This study does not involve any human experiments.
Institutional animal care and use committee statement: All animal studies were performed at the Animal Experiment Center of East China Normal University with approval from the Experimental Animal Ethical Review Committee at East China Normal University (No. R20211202).
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: Not applicable.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Bai-Yin Zhang, PhD, Professor, Department of Trauma-Emergency and Critical Care Medicine Center, Shanghai Fifth People’s Hospital, Fudan University, No. 801 Heqing Road, Minhang District, Shanghai 200240, China. boyinercheung@hotmail.com
Received: July 23, 2025 Revised: September 20, 2025 Accepted: November 10, 2025 Published online: December 28, 2025 Processing time: 157 Days and 16.6 Hours
Abstract
BACKGROUND
Sepsis-induced intestinal injury disrupts barrier function and exacerbates systemic inflammation, contributing to high mortality.
AIM
To investigate the mechanism by which sphinganine protects against sepsis-induced intestinal injury, focusing on macrophage polarization and toll like receptor 2 (TLR2)/nuclear factor kappa-B (NF-κB) signaling.
METHODS
A cecal ligation and puncture sepsis model was established in mice (n = 20/group). Treatments included sphinganine (15 mg/kg) and a TLR2 agonist [fibroblast-stimulating lipopeptide-1 (FSL-1), 10 μg/kg]. Serum markers [diamine oxidase (DAO), interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6] were measured by enzyme-linked immunosorbent assay. Intestinal injury and macrophage polarization [cluster of differentiation (CD) 86+ M1, CD206+ M2] were assessed via hematoxylin and eosin and immunofluorescence staining. Proteomic analysis, molecular docking, and Western blot were used to evaluate TLR2/NF-κB signaling. Data were analyzed by analysis of variance and t-test.
RESULTS
Sphinganine significantly reduced serum levels of DAO (P < 0.05), IL-1β, TNF-α, and IL-6 (P < 0.05), preserved intestinal crypt structure, and enhanced tight junction protein zonula occludens-1 expression. It promoted a shift from M1 (CD86+) to M2 (CD206+) macrophages. Proteomics identified TLR2 as the most differentially expressed protein, and molecular docking confirmed strong binding between sphinganine and TLR2 (-4.3 kcal/mol). Sphinganine downregulated TLR2 and phosphorylated-NF-κB p65 expression (P < 0.05), effects reversed by FSL-1. Total NF-κB p65 levels remained unchanged.
CONCLUSION
Sphinganine protects against sepsis-induced intestinal injury by inhibiting TLR2/NF-κB signaling, modulating macrophage polarization toward the M2 phenotype, and preserving intestinal barrier integrity.
Core Tip: This study reveals that sphinganine protects against sepsis-induced intestinal injury by inhibiting toll like receptor 2/nuclear factor kappa-B signaling, modulating macrophage polarization toward the M2 phenotype, and preserving intestinal barrier integrity.
