Sodium butyrate protects against necrotizing enterocolitis through a mechanism involving YB-1-dependent regulation of intestinal epithelial apoptosis

  • Sci Rep. 2026 Apr 27;16(1):19459. doi: 10.1038/s41598-026-50396-3.
Qingqing Xiang  1  2  3  4 ,  Rong Yu  1  2  3  4 ,  Li Huang  1  2  3  4 ,  Qingqing Liu  1  2  3  4 ,  Nuo Qin  1  2  3  4 ,  Li Wang  5  6  7  8 ,  Yan Wu  9  10  11  12 ,  Hang Fu  13  14  15  16
Affiliations
  • 1. Department of Pediatrics, Chongqing Health Center for Women and Children, Chongqing, China.
  • 2. Department of Pediatrics, Women and Children's Hospital of Chongqing Medical University, No. 120 Longshan Road, Yubei District, Chongqing, 401147, China.
  • 3. NHC Key Laboratory of Birth Defects and Reproductive Health, Chongqing, China.
  • 4. Chongqing Research Center for Prevention & Control of Maternal and Child Diseases and Public Health, Chongqing, China.
  • 5. Department of Pediatrics, Chongqing Health Center for Women and Children, Chongqing, China. [email protected].
  • 6. Department of Pediatrics, Women and Children's Hospital of Chongqing Medical University, No. 120 Longshan Road, Yubei District, Chongqing, 401147, China. [email protected].
  • 7. NHC Key Laboratory of Birth Defects and Reproductive Health, Chongqing, China. [email protected].
  • 8. Chongqing Research Center for Prevention & Control of Maternal and Child Diseases and Public Health, Chongqing, China. [email protected].
  • 9. Department of Pediatrics, Chongqing Health Center for Women and Children, Chongqing, China. [email protected].
  • 10. Department of Pediatrics, Women and Children's Hospital of Chongqing Medical University, No. 120 Longshan Road, Yubei District, Chongqing, 401147, China. [email protected].
  • 11. NHC Key Laboratory of Birth Defects and Reproductive Health, Chongqing, China. [email protected].
  • 12. Chongqing Research Center for Prevention & Control of Maternal and Child Diseases and Public Health, Chongqing, China. [email protected].
  • 13. Department of Pediatrics, Chongqing Health Center for Women and Children, Chongqing, China. [email protected].
  • 14. Department of Pediatrics, Women and Children's Hospital of Chongqing Medical University, No. 120 Longshan Road, Yubei District, Chongqing, 401147, China. [email protected].
  • 15. NHC Key Laboratory of Birth Defects and Reproductive Health, Chongqing, China. [email protected].
  • 16. Chongqing Research Center for Prevention & Control of Maternal and Child Diseases and Public Health, Chongqing, China. [email protected].
PMID: 42045470 DOI: 10.1038/s41598-026-50396-3
Abstract

Due to a lack of complete mechanistic understanding, there are no specific therapeutics for necrotizing enterocolitis (NEC), a deadly gastrointestinal disease affecting premature newborns. While sodium butyrate offers intestinal protection, its efficacy is strictly dose-dependent, and the underlying mechanisms regulating intestinal epithelial cell (IEC) survival remain elusive. Here, using neonatal murine NEC models and human IECs, we demonstrate that moderate-dose butyrate (50 mg/kg) significantly attenuates mucosal injury and improves survival, whereas high-dose butyrate (250 mg/kg) exacerbates mortality by inducing complex cell death pathways including Necroptosis and Ferroptosis. Mechanistically, moderate butyrate suppresses glycolysis and intracellular lactate production, which restores expression of the translational regulator PABPC1; PABPC1 then binds to YB-1 mRNA to enhance YB-1 protein synthesis without altering transcription. Elevated YB-1 subsequently binds Bcl-2 mRNA, increasing Bcl-2 protein levels to inhibit intrinsic mitochondrial Apoptosis. Functional validation shows that YB-1 knockdown abolishes butyrate-mediated protection and exacerbates TNF-α-induced Apoptosis, while YB-1 overexpression rescues cell viability, and exogenous lactate supplementation reverses these effects by suppressing the PABPC1-YB-1 axis. These findings elucidate a novel Lactate-PABPC1-YB-1-BCL-2 signaling axis through which butyrate safeguards the intestinal epithelium, highlighting precise dosing and the modulation of epithelial translational control as promising therapeutic strategies for NEC.

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