Dysregulation of gut homeostasis is associated with irritable bowel syndrome (IBS), a chronic functional gastrointestinal disorder affecting approximately 11.2% of the global population. The poorly understood pathogenesis of IBS has impeded its treatment. Here, we report that the E3 ubiquitin ligase tripartite motif-containing 27 (TRIM27) is weakly expressed in IBS but highly expressed in inflammatory bowel disease (IBD), a frequent chronic organic gastrointestinal disorder. Accordingly, knockout of Trim27 in mice causes spontaneously occurring IBS-like symptoms, including increased visceral hyperalgesia and abnormal stool features, as observed in IBS patients. Mechanistically, TRIM27 stabilizes β-catenin and thus activates Wnt/β-catenin signaling to promote intestinal stem cell (ISC) self-renewal. Consistent with these findings, Trim27 deficiency disrupts organoid formation, which is rescued by reintroducing TRIM27 or β-catenin. Furthermore, Wnt/β-catenin signaling activator treatment ameliorates IBS symptoms by promoting ISC self-renewal. Taken together, these data indicate that TRIM27 is critical for maintaining gut homeostasis, suggesting that targeting the TRIM27/Wnt/β-catenin axis could be a potential treatment strategy for IBS. Our study also indicates that TRIM27 might serve as a potential biomarker for differentiating IBS from IBD.
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The 16S rRNA gene sequences are available in the NCBI Sequence Read Archive (SRA) database under accession number SRP355336. Publicly available microarray data (E-MTAB-5811, GSE1710) were downloaded from the EMBL-EBI ArrayExpress database and NCBI Gene Expression Omnibus. Any additional information required to reanalyze the data reported in this paper is available from the corresponding author upon request.
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We thank Junfeng Hao (Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing) for helping with the histological analysis and Zhihua Liu and Hongying Wang (National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College) for helping with the endoscopy experiment. This work was supported by the National Key Research and Development Project of China (2021YFA1300200 to CHL and LZ, 2022YFC2302900 to CHL and JW), the National Natural Science Foundation of China (81825014 to CHL, 31830003 to CHL, 82022041 to JW and 81871616 to JW), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB29020000 to CHL), Youth Innovation Promotion Association CAS (2018118 to JW) and the State Key Laboratory of Proteomics (SKLP-K202001 to LZ and SKLPO202003 to JW).
The authors declare no competing interests.
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Wang, J., Zhao, D., Lei, Z. et al. TRIM27 maintains gut homeostasis by promoting intestinal stem cell self-renewal. Cell Mol Immunol 20, 158–174 (2023). https://doi.org/10.1038/s41423-022-00963-1
- Wnt/β-catenin signaling
- ISC self-renewal