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Enterotoxigenic Escherichia coli (ETEC) Infection Triggers Pyroptosis Through ER Stress Response-Mediated Mitochondrial Impairment and STING Activation in Intestinal Epithelial Cells
by
and
Wenjie Yang
1,2, 
Xi Qiu
1,2,
Jianan Guo
1,2,
Yongxiang Wang
1,2,
Jie Wang
1,2,
Hongliang Chen
1,2,
Di Zhang
1,2,* and
Lei Zhang
1,2,* 1
College of Veterinary Medicine, Jilin Agricultural University, Changchun 130118, China
2
Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun 130118, China
*
Authors to whom correspondence should be addressed.
Biology 2025, 14(12), 1653; https://doi.org/10.3390/biology14121653 (registering DOI)
Submission received: 26 September 2025
/
Revised: 21 November 2025
/
Accepted: 21 November 2025
/
Published: 23 November 2025
(This article belongs to the Section Infection Biology)
Simple Summary
Infectious diarrhea disease has long been one of the leading causes of morbidity and mortality in the swine industry. Enterotoxigenic Escherichia coli (ETEC) is one of the major pathotypes of E. coli that confers the ability to cause diarrheal diseases. Prevention of E. coli infection is extremely important to maintain the growth performance and welfare of pigs. This study showed that ETEC activated the NLRP3 inflammasome and triggered pyroptosis in the intestinal epithelial cells (IECs) of mice. Activation of ER stress was found to be essential for ETEC-related pyroptosis by impairing mitochondria and activating STING signaling. Attenuation of ER stress with TUDCA ameliorated the inflammation and pyroptosis of IECs. These findings reveal that ER stress is a potential therapeutic target for ETEC-induced diarrheal disease.
Abstract
Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrhea in pigs. Virulence factors, such as colonization factors and enterotoxins, bind to specific receptors on intestinal epithelial cells (IECs), impairing the integrity of the IEC barrier by inducing cell death. Pyroptosis is a newly discovered form of programmed cell death (PCD), which is widely involved in the pathogenesis of multiple infectious gastrointestinal diseases. However, it is still unclear whether pyroptosis contributes to the ETEC-mediated damage of IECs. This study demonstrated that ETEC infection activated NLRP3 inflammasome and triggered gasdermin D (GSDMD)-executed pyroptosis of mouse IECs in vitro and in vivo. Mechanistically, ETEC infection triggered endoplasmic reticulum (ER) stress response to increase the expression of thioredoxin-interacting protein (TXNIP) by upregulation of C/EBP homologous protein (CHOP), which subsequently activated NLRP3 inflammasome. Removal of ER stress by tauroursodeoxycholic acid (TUDCA) alleviated the pyroptosis of IECs that was caused by ETEC infection. In addition, the induced ER stress impaired mitochondria and led to mitochondrial reactive oxygen species (mtROS) overproduction and cytosolic release of mitochondrial DNA (mtDNA), which activated STING, another factor that contributed to ETEC-triggered pyroptosis. Chemical inhibition of STING attenuated ETEC-induced pyroptosis of IECs. Collectively, this study demonstrated that the activation of the STING/ER stress/mitochondrial impairment/NLRP3 inflammasome axis is a critical pathway in the ETEC infection-derived pyroptosis of IECs. Hence, targeting ER stress response may serve as a promising therapeutic strategy to prevent ETEC infection caused damage to IECs.
Keywords:
ETEC; pyroptosis; ER stress; mitochondria; STING; intestinal epithelial cells (IECs)
