Thymosin β4 released by mast cells under stress conditions impairs intestinal epithelial barrier via IL22RA1/JAK1/STAT3 signaling in irritable bowel syndrome

doi:10.3748/wjg.v31.i42.111706

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Nov 14, 2025 (publication date) through Nov 16, 2025

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World Journal of Gastroenterology

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1007-9327

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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World J Gastroenterol. Nov 14, 2025; 31(42): 111706
Published online Nov 14, 2025. doi: 10.3748/wjg.v31.i42.111706

Thymosin β4 released by mast cells under stress conditions impairs intestinal epithelial barrier via IL22RA1/JAK1/STAT3 signaling in irritable bowel syndrome

Yue-Shan Sun, Xiao-Qin Bai, Kai-Di Sun, Jiao Li, Lei Liu, Yuan-Yuan Chen, Zhao-Yu Zeng, Qiong Wang, Yuan-Biao Guo

Yue-Shan Sun, Xiao-Qin Bai, Lei Liu, Zhao-Yu Zeng, Yuan-Biao Guo, Medical Research Center, The Third People's Hospital of Chengdu, Chengdu 610031, Sichuan Province, China

Kai-Di Sun, Jiao Li, Qiong Wang, Department of Digestive, The Third People's Hospital of Chengdu, Chengdu 610031, Sichuan Province, China

Yuan-Yuan Chen, Department of Pathology, The Third People's Hospital of Chengdu, Chengdu 610031, Sichuan Province, China

Co-first authors: Yue-Shan Sun and Xiao-Qin Bai.

Co-corresponding authors: Qiong Wang and Yuan-Biao Guo.

Author contributions: Sun YS and Bai XQ performed the experiments and wrote the manuscript. Both they have made crucial and indispensable contributions towards the completion of the project and thus qualified as the co-first authors of the paper. Sun KD and Li J collected clinical specimens and analyzed data. Liu L, Chen YY and Zeng ZY provided additional expertise. Guo YB and Wang Q played important and indispensable roles in the experimental design, data interpretation and manuscript preparation as the co-corresponding authors. All authors contributed to the refinement of the study protocol and approved the final version of the manuscript.

Supported by the National Natural Science Foundation of China, No. 81270465; the Sichuan Science and Technology Program, No. 2024NSFSC0631, No. 2023JDRC0088, and No. MZGC20240097; the Basic Research Cultivation Support Program of Fundamental Research Funds for the Central Universities, No. 2682023ZTPY071; the Baiqiuen Public Welfare Foundation Program, No. BCF-LX-XH-20221014-12; the Third People’s Hospital of Chengdu Clinical Research Program, No. CSY-YN-01-2023-012; the Yibin Science and Technology Program, No. 2021ZYY009; and the Chengdu Medical Research Project Foundation, No. 2022284.

Institutional review board statement: This research on human subjects was approved by the Ethics Committee of the Third People’s Hospital of Chengdu (2024-S-212), and all patients signed a written informed consent form and completed a standardized questionnaire that contained items about IBS-symptomatic assessment.

Institutional animal care and use committee statement: The animal research was approved by the Ethics Committee of Southwest Jiaotong University Approval (Agreement No. SWJTU-2013-026).

Conflict-of-interest statement: The authors have declared 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: All data supporting the findings of this study are available from the corresponding authors upon reasonable request.

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: Yuan-Biao Guo, PhD, Medical Research Center, The Third People's Hospital of Chengdu, No. 82 Qinglong Street, Qingyang District, Chengdu 610031, Sichuan Province, China. guoyuanbiao@swjtu.edu.cn

Received: July 8, 2025
Revised: September 4, 2025
Accepted: October 13, 2025
Published online: November 14, 2025
Processing time: 128 Days and 21.6 Hours

Abstract

BACKGROUND

Mast cells (MCs) under stress conditions contribute to the development of irritable bowel syndrome (IBS), yet their precise mechanisms in IBS remain unclear.

AIM

To investigate the role of MC-derived thymosin β4 (Tβ4) in stress-induced intestinal barrier dysfunction.

METHODS

The colonic mucus Tβ4 levels in IBS patients were determined and their effects on the epithelial barrier were assessed in vitro and in vivo. Specifically, rats genetically deficient in Tβ4 (Tβ4^-/-) or mice deficient in MCs (Kit^w-sh/w-sh) were used to observe the effects of reintroducing Tβ4 or wild-type peritoneal MCs (wt-PMCs) into these animals. Additionally, the regulatory mechanism underlying Tβ4 secretion in MCs was investigated.

RESULTS

We demonstrated that high levels of Tβ4 in IBS mucus and intestinal MCs mediate stress-associated disruptive changes to the epithelial barrier. Moreover, Tβ4 treatment of wild-type or MC-deficient Kit^w-sh/w-sh mice caused a reduction in tight junction proteins and the interleukin 22 receptor A1 (IL22RA1)/Reg3γ cascade, but an increase in myosin light chain kinase. Furthermore, Tβ4^-/- rats were resistant to stress, though reintroduction of Tβ4 or wt-PMCs restored stress or corticotropin-releasing hormone (CRH)-induced barrier disturbance. Consistently, Tβ4 release from MCs was dependent on the CRH receptor 1, but not degranulation. The effect of Tβ4 was accompanied by IL22RA1/Janus kinase 1 (JAK1)/signal transducer and activation of transcription 3 (STAT3) pathway inhibition, suggesting a mechanism for physical and immune barrier suppression.

CONCLUSION

Collectively, these results suggest that Tβ4, which is abundant in IBS mucus and the secretome of MCs, plays a crucial role in the pathogenesis of IBS via IL22RA1/JAK1/STAT3 signaling, with potential implications for diagnostic and therapeutic targeting.

Keywords: Thymosin β4; Intestinal barrier; Mast cell; Janus kinase 1/signal transducer and activation of transcription 3; Irritable bowel syndrome

Core Tip: Thymosin β4 (Tβ4) is identified as a prevalent component in the intestinal mucus of irritable bowel syndrome patients that is capable of independently causing intestinal barrier disruption, even without the involvement of mast cells, when triggered by either corticotropin-releasing hormone (CRH) or stress. In addition, mast cells are the source of the Tβ4 required for intestinal barrier damage, and its release is contingent on CRH/CRH receptor 1 but not on degranulation. Mechanistically, the impact of Tβ4 on both the physical and immune barriers is mediated through the inhibition of Janus kinase 1/signal transducer and activation of transcription 3 signaling. These findings position Tβ4 as a promising diagnostic biomarker and therapeutic target for irritable bowel syndrome.