Thalidomide mitigates Crohn's disease colitis by modulating gut microbiota, metabolites, and regulatory T cell immunity

Chao-Tao Tang; Yonghui Wu; Qing Tao; Chun-Yan Zeng; You-Xiang Chen

doi:10.1016/j.jpha.2024.101121

Volume 15 Issue 4

May 2025

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Chao-Tao Tang, Yonghui Wu, Qing Tao, Chun-Yan Zeng, You-Xiang Chen. Thalidomide mitigates Crohn's disease colitis by modulating gut microbiota, metabolites, and regulatory T cell immunity[J]. Journal of Pharmaceutical Analysis, 2025, 15(4): 101121. doi: 10.1016/j.jpha.2024.101121

Citation:

Chao-Tao Tang, Yonghui Wu, Qing Tao, Chun-Yan Zeng, You-Xiang Chen. Thalidomide mitigates Crohn's disease colitis by modulating gut microbiota, metabolites, and regulatory T cell immunity[J]. Journal of Pharmaceutical Analysis, 2025, 15(4): 101121. doi: 10.1016/j.jpha.2024.101121

Citation:

Chao-Tao Tang, Yonghui Wu, Qing Tao, Chun-Yan Zeng, You-Xiang Chen. Thalidomide mitigates Crohn's disease colitis by modulating gut microbiota, metabolites, and regulatory T cell immunity[J]. Journal of Pharmaceutical Analysis, 2025, 15(4): 101121. doi: 10.1016/j.jpha.2024.101121

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Thalidomide mitigates Crohn's disease colitis by modulating gut microbiota, metabolites, and regulatory T cell immunity

doi: 10.1016/j.jpha.2024.101121

a. Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China;
b. Postdoctoral Innovation Practice Base, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China;
c. Department of Gastroenterology, Jiangxi Province Hospital of Integrated Chinese and Western Medicine, Nanchang, 330003, China

Funds:

This study was supported by grants from the National Natural Science Foundation of China (Grant Nos.: 82360112), the project supported by Jiangxi Provincial Natural Science Foundation, China (Grant No.: 20232BAB216021), China Postdoctoral Science Foundation (Grant No.: 2023M741522), the Key Laboratory Project of Digestive Diseases in Jiangxi Province, China (Program No.: 2024SSY06101), and Jiangxi Clinical Research Center for Gastroenterology, China (Program No.: 20223BCG74011).

Received Date: Jun. 26, 2024
Accepted Date: Oct. 15, 2024
Rev Recd Date: Sep. 30, 2024
Publish Date: Oct. 18, 2024

Abstract

Abstract

Thalidomide (THA) is renowned for its potent anti-inflammatory properties. This study aimed to elucidate its underlying mechanisms in the context of Crohn's disease (CD) development. Mouse colitis models were established by dextran sulfate sodium (DSS) treatment. Fecal microbiota and metabolites were analyzed by metagenomic sequencing and mass spectrometry, respectively. Antibiotic-treated mice served as models for microbiota depletion and transplantation. The expression of forkhead box P3⁺ (FOXP3⁺) regulatory T cells (Tregs) was measured by flow cytometry and immunohistochemical assay in colitis model and patient cohort. THA inhibited colitis in DSS-treated mice by altering the gut microbiota profile, with an increased abundance of probiotics Bacteroides fragilis, while pathogenic bacteria were depleted. In addition, THA increased beneficial metabolites bile acids and significantly restored gut barrier function. Transcriptomic profiling revealed that THA inhibited interleukin-17 (IL-17), IL-1β and cell cycle signaling. Fecal microbiota transplantation from THA-treated mice to microbiota-depleted mice partly recapitulated the effects of THA. Specifically, increased level of gut commensal B. fragilis was observed, correlated with elevated levels of the microbial metabolite 3alpha-hydroxy-7-oxo-5beta-cholanic acid (7-ketolithocholic acid, 7-KA) following THA treatment. This microbial metabolite may stable FOXP3 expression by targeting the receptor FMR1 autosomal homolog 1 (FXR1) to inhibit autophagy. An interaction between FOXP3 and FXR1 was identified, with binding regions localized to the FOXP3 domain (aa238-335) and the FXR1 domain (aa82-222), respectively. Conclusively, THA modulates the gut microbiota and metabolite profiles towards a more beneficial composition, enhances gut barrier function, promotes the differentiation of FOXP3⁺ Tregs and curbs pro-inflammatory pathways.
- Thalidomide,
- Crohn's disease,
- FOXP3+ tregs,
- Bacteroides fragilis,
- 7-Ketolithocholic acid

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References(46)

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