Tuo JW, Wu X, Shen ZH, Wang XY. Trans-3-indoleacrylic acid ameliorates dextran sulfate sodium-induced colitis by modulating macrophage M1 polarization through the aryl hydrocarbon receptor pathway. World J Gastroenterol 2026; 32(46): 123696 [DOI: 10.3748/wjg.123696]
Corresponding Author of This Article
Xiao-Yan Wang, PhD, Chief Physician, Professor, Department of Gastroenterology, The Third Xiangya Hospital of Central South University, No. 138 Tongzipo Road, Yuelu District, Changsha 410013, Hunan Province, China. wangxiaoyan@csu.edu.cn
Research Domain of This Article
Gastroenterology & Hepatology
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research-article
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World J Gastroenterol. Dec 14, 2026; 32(46): 123696 Published online Dec 14, 2026. doi: 10.3748/wjg.123696
Trans-3-indoleacrylic acid ameliorates dextran sulfate sodium-induced colitis by modulating macrophage M1 polarization through the aryl hydrocarbon receptor pathway
Jin-Wei Tuo, Xing Wu, Zhao-Hua Shen, Xiao-Yan Wang
Jin-Wei Tuo, Xing Wu, Zhao-Hua Shen, Xiao-Yan Wang, Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
Xiao-Yan Wang, Xiangya School of Public Health, Central South University, Changsha 410013, Hunan Province, China
Co-corresponding authors: Zhao-Hua Shen and Xiao-Yan Wang.
Author contributions: Wang XY and Shen ZH designed and coordinated the study; Tuo JW and Wu X conducted the experiments, examined and interpreted the data; Tuo JW drafted the paper; Wang XY and Shen ZH revised the manuscript; and all authors approved the final version of the manuscript.
AI contribution statement: Portions of this manuscript were edited using AI tools solely for language refinement. The authors carefully reviewed and verified all AI-assisted outputs and take full responsibility for the scientific content of the manuscript.
Supported by the Natural Science Foundation of Hunan Province, No. 2023JJ40902; Bai Qiuen-Qi Yin Future Multi-Disciplinary Research Capability Construction Project, No. BCF-QYWL-XH-2024-5; and Beijing Science and Technology Innovation Medical Development Fund Project, No. KC2023-ZZ-0011-01.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Ethics Committee for Animal Experiments of Central South University, Changsha, China (IACUC protocol number: CSU-2022-0442).
Conflict-of-interest statement: All authors declare having no conflicts of interest related to this manuscript.
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: Technical appendix, statistical code, and dataset are available from the corresponding author at wangxiaoyan@csu.edu.cn upon reasonable request.
Corresponding author: Xiao-Yan Wang, PhD, Chief Physician, Professor, Department of Gastroenterology, The Third Xiangya Hospital of Central South University, No. 138 Tongzipo Road, Yuelu District, Changsha 410013, Hunan Province, China. wangxiaoyan@csu.edu.cn
Received: May 28, 2026 Revised: July 26, 2026 Accepted: September 17, 2026 Published online: December 14, 2026 Processing time: 146 Days and 2.1 Hours
Abstract
BACKGROUND
Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease with a steadily increasing global incidence. Controlling mucosal inflammation represents a crucial therapeutic goal; however, safe and effective long-term treatments remain limited. Increasing evidence suggests that microbiota-derived tryptophan metabolites regulate intestinal immune homeostasis and participate in the pathogenesis of UC.
AIM
To investigate whether trans-3-indoleacrylic acid (IDA) alleviates dextran sulfate sodium (DSS)-induced colitis by regulating macrophage polarization.
METHODS
Male C57BL/6 mice with DSS-induced colitis and lipopolysaccharide/interferon-γ-stimulated THP-1-derived macrophages and bone marrow-derived macrophages were treated with IDA. Aryl hydrocarbon receptor (AHR) signaling involvement was evaluated using CH-223191-mediated pharmacological inhibition in vivo and siRNA-mediated AHR knockdown in vitro. Colonic inflammation, intestinal barrier integrity, and macrophage phenotypes were assessed by histological analysis, enzyme-linked immunosorbent assay, quantitative real-time PCR, Western blotting, and flow cytometry. Gut microbiota composition was characterized by 16S rRNA gene sequencing, and short-chain fatty acids (SCFAs) were quantified by targeted metabolomic analysis.
RESULTS
IDA treatment markedly alleviated colitis severity, preserved intestinal barrier integrity, and reduced pro-inflammatory mediators, including inducible nitric oxide synthase, interleukin-1β, and interleukin-6. Importantly, IDA suppressed M1 macrophage polarization without promoting M2 macrophage polarization. Mechanistically, IDA activated AHR signaling, as evidenced by increased expression of downstream targets, including CYP1A1 and CYP1B1, while AHR inhibition or knockdown attenuated the inhibitory effects of IDA on M1 macrophage polarization. Furthermore, IDA treatment was associated with alterations in gut microbiota composition, characterized by reduced abundance of potential pathobionts, such as Escherichia-Shigella, and increased abundance of beneficial commensals, including Akkermansia and Lactobacillus. Targeted metabolomic analysis revealed that IDA treatment was accompanied by increased intestinal levels of SCFAs, particularly acetic acid and butyric acid.
CONCLUSION
IDA alleviates DSS-induced colitis by suppressing M1 macrophage polarization through the AHR-CYP1A1 signaling pathway and is associated with alterations in gut microbiota composition and SCFA profiles.
Core Tip: Microbiota-derived tryptophan metabolites contribute to intestinal immune homeostasis, but the immunoregulatory role of trans-3-indoleacrylic acid (IDA) in ulcerative colitis (UC) remains unclear. This study demonstrates that IDA alleviates dextran sulfate sodium-induced colitis by suppressing pro-inflammatory M1 macrophage polarization through activation of the aryl hydrocarbon receptor (AHR)-CYP1A1 pathway. IDA treatment is also associated with alterations in gut microbiota composition and short-chain fatty acid profiles. These findings identify the IDA-AHR-macrophage axis as a potential therapeutic target for UC.
