Copyright
©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
Alkaline sphingomyelinase deficiency impairs intestinal mucosal barrier integrity and reduces antioxidant capacity in dextran sulfate sodium-induced colitis
Ye Tian, Xin Li, Xu Wang, Si-Ting Pei, Hong-Xin Pan, Yu-Qi Cheng, Yi-Chen Li, Wen-Ting Cao, Jin-Dong Ding Petersen, Ping Zhang
Ye Tian, Si-Ting Pei, Hong-Xin Pan, Wen-Ting Cao, Jin-Dong Ding Petersen, Ping Zhang, International School of Public Health and One Health, Hainan Medical University, Haikou 571199, Hainan Province, China
Xin Li, Yu-Qi Cheng, Yi-Chen Li, Medical Laboratory Science and Technology College, Harbin Medical University - Daqing Campus, Daqing 163000, Heilongjiang Province, China
Xu Wang, Department of Laboratory Diagnosis, Qiqihar Tuberculosis Control Center, Qiqihar 161000, Heilongjiang Province, China
Jin-Dong Ding Petersen, Department of Public Health, University of Copenhagen, Copenhagen 1353, Denmark
Jin-Dong Ding Petersen, Department of Public Health, University of Southern Denmark, Odense 5000, Denmark
Co-first authors: Ye Tian and Xin Li.
Author contributions: Petersen JDD and Zhang P initiated the study; Tian Y, Li X, and Wang X contributed equally to this study; Li X and Wang X conducted the experiments; Tian Y wrote the manuscript; Pei ST, Pan HX, Cheng YQ, and Li YC conducted the preliminary data analysis; Zhang P contributed to the preliminary data analysis supervision; Cao WT reviewed and reanalyzed the data and confirmed the authenticity of the data. All of the authors discussed the results, commented on the manuscript, and approved the publication submission.
Supported by the Natural Science Foundation of Hainan Province, No. 823MS046; and the Talent Program of Hainan Medical University, No. XRC2022007.
Institutional animal care and use committee statement: This study was conducted in strict accordance with ethical guidelines for animal research. All experimental animals were housed in a controlled environment. Isoflurane was used for anesthesia prior to operations to minimize pain and discomfort. The experimental protocols involving animals were carefully designed to reduce suffering and were reviewed and approved by the Ethics Committee of Hainan Medical University (Approval No. HYLL-2022-128).
Conflict-of-interest statement: The authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available. The data for this study are available upon request to the corresponding author pending approval from Hainan Medical University.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
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 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:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Ping Zhang, MD, PhD, Professor, International School of Public Health and One Health, Hainan Medical University, No. 3 Xueyuan Road, Haikou 571199, Hainan Province, China. pingzhang@hainmc.edu.cn
Received: October 12, 2023
Peer-review started: October 12, 2023
First decision: December 8, 2023
Revised: December 26, 2023
Accepted: January 29, 2024
Article in press: January 29, 2024
Published online: March 14, 2024
BACKGROUND
Ulcerative colitis is a chronic inflammatory disease of the colon with an unknown etiology. Alkaline sphingomyelinase (alk-SMase) is specifically expressed by intestinal epithelial cells, and has been reported to play an anti-inflammatory role. However, the underlying mechanism is still unclear.
AIM
To explore the mechanism of alk-SMase anti-inflammatory effects on intestinal barrier function and oxidative stress in dextran sulfate sodium (DSS)-induced colitis.
METHODS
Mice were administered 3% DSS drinking water, and disease activity index was determined to evaluate the status of colitis. Intestinal permeability was evaluated by gavage administration of fluorescein isothiocyanate dextran, and bacterial translocation was evaluated by measuring serum lipopolysaccharide. Intestinal epithelial cell ultrastructure was observed by electron microscopy. Western blotting and quantitative real-time reverse transcription-polymerase chain reaction were used to detect the expression of intestinal barrier proteins and mRNA, respectively. Serum oxidant and antioxidant marker levels were analyzed using commercial kits to assess oxidative stress levels.
RESULTS
Compared to wild-type (WT) mice, inflammation and intestinal permeability in alk-SMase knockout (KO) mice were more severe beginning 4 d after DSS induction. The mRNA and protein levels of intestinal barrier proteins, including zonula occludens-1, occludin, claudin-3, claudin-5, claudin-8, mucin 2, and secretory immunoglobulin A, were significantly reduced on 4 d after DSS treatment. Ultrastructural observations revealed progressive damage to the tight junctions of intestinal epithelial cells. Furthermore, by day 4, mitochondria appeared swollen and degenerated. Additionally, compared to WT mice, serum malondialdehyde levels in KO mice were higher, and the antioxidant capacity was significantly lower. The expression of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in the colonic mucosal tissue of KO mice was significantly decreased after DSS treatment. mRNA levels of Nrf2-regulated downstream antioxidant enzymes were also decreased. Finally, colitis in KO mice could be effectively relieved by the injection of tertiary butylhydroquinone, which is an Nrf2 activator.
CONCLUSION
Alk-SMase regulates the stability of the intestinal mucosal barrier and enhances antioxidant activity through the Nrf2 signaling pathway.
Core Tip: The protective effect of alkaline sphingomyelinase (alk-SMase) against intestinal inflammation has been demonstrated, but the underlying molecular mechanism remains unclear. In the present study, we found that alk-SMase deficiency exacerbated damage to the intestinal mucosal barrier in dextran sulfate sodium-induced colitis. Additionally, alk-SMase was shown to enhance antioxidant activity, thereby reducing susceptibility to proinflammatory factors in colitis. Furthermore, our findings revealed that alk-SMase may maintain intestinal barrier stability and increase antioxidant capacity through the nuclear factor erythroid 2-related factor 2 signaling pathway.
