Sphingosine-1-phosphate ameliorates necrotizing enterocolitis by regulating mitochondrial redox homeostasis and gut microbiota.
8 affiliations
- 1Department of Neonatology, Children's Hospital of Soochow University, Suzhou, China. [email protected].
- 2Suzhou Medical College, Soochow University, Suzhou, China. [email protected].
- 3Department of Neonatology, Children's Hospital of Soochow University, Suzhou, China.
- 4Suzhou Medical College, Soochow University, Suzhou, China.
- 5Department of Neonatology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.
- 6Department of Neonatology, Children's Hospital of Soochow University, Suzhou, China. [email protected].
- 7Suzhou Medical College, Soochow University, Suzhou, China. [email protected].
- 8Department of Neonatology, Children's Hospital of Soochow University, Suzhou, China. [email protected].
Abstract
Sphingolipid metabolism critically links intestinal barrier integrity to inflammatory responses, and its role in necrotizing enterocolitis (NEC) pathogenesis may inform strategies for prevention and treatment. To investigate this association, metabolomic profiling of serum samples from preterm infants was performed, and the findings were validated in independent cohorts. The effects of sphingosine-1-phosphate (S1P) were evaluated in LPS-induced IEC-6 cells and experimental NEC models. Mechanistic studies were performed using pharmacological inhibitors, and microbiota-dependent effects were assessed through bacterial intervention experiments. Serum S1P levels were reduced prior to NEC diagnosis and correlated with disease severity. Opaganib reduced S1P levels and exacerbated NEC pathology, while S1P supplementation reversed these effects. Mechanistic investigations revealed that S1P exerted a protective effect against NEC by modulating mitochondrial oxidative respiration and redox balance, as well as by reshaping the gut microbiota to attenuate inflammation, apoptosis, and intestinal barrier disruption. The protective effects of S1P were partially attenuated by S1PR1 blockade. In addition, supplementation with Bacteroides thetaiotaomicron improved sphingolipid metabolic profiles in NEC intestinal tissues and upregulated S1P levels. These findings suggest that dysregulation of sphingolipid metabolism is associated with NEC and intestinal barrier dysfunction. S1P may alleviate NEC-related injury in experimental models, potentially involving S1PR1 signaling, mitochondrial redox balance, and interactions with the gut microbiota.
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BibTeX
@article{sun2026sphingosine1phosphate,
title = {{Sphingosine-1-phosphate ameliorates necrotizing enterocolitis by regulating mitochondrial redox homeostasis and gut microbiota.}},
author = {Wenqiang Sun and Yihui Li and Xue Liu and Minqian Zhou and Huawei Wang and Haifeng Geng and Wenmei Li and Zhirong Xie and Lili Li and Xinyun Jin and Xueping Zhu},
journal = {Cell death \& disease},
year = {2026},
month = jul,
doi = {10.1038/s41419-026-09144-8},
url = {https://europepmc.org/article/MED/42957664},
note = {CC BY},
}
RIS
TY - JOUR
TI - Sphingosine-1-phosphate ameliorates necrotizing enterocolitis by regulating mitochondrial redox homeostasis and gut microbiota.
AU - Wenqiang Sun
AU - Yihui Li
AU - Xue Liu
AU - Minqian Zhou
AU - Huawei Wang
AU - Haifeng Geng
AU - Wenmei Li
AU - Zhirong Xie
AU - Lili Li
AU - Xinyun Jin
AU - Xueping Zhu
PY - 2026
DA - 2026/07/31
JO - Cell death & disease
DO - 10.1038/s41419-026-09144-8
UR - https://europepmc.org/article/MED/42957664
AB - Sphingolipid metabolism critically links intestinal barrier integrity to inflammatory responses, and its role in necrotizing enterocolitis (NEC) pathogenesis may inform strategies for prevention and treatment. To investigate this association, metabolomic profiling of serum samples from preterm infants was performed, and the findings were validated in independent cohorts. The effects of sphingosine-1-phosphate (S1P) were evaluated in LPS-induced IEC-6 cells and experimental NEC models. Mechanistic studies were performed using pharmacological inhibitors, and microbiota-dependent effects were assessed through bacterial intervention experiments. Serum S1P levels were reduced prior to NEC diagnosis and correlated with disease severity. Opaganib reduced S1P levels and exacerbated NEC pathology, while S1P supplementation reversed these effects. Mechanistic investigations revealed that S1P exerted a protective effect against NEC by modulating mitochondrial oxidative respiration and redox balance, as well as by reshaping the gut microbiota to attenuate inflammation, apoptosis, and intestinal barrier disruption. The protective effects of S1P were partially attenuated by S1PR1 blockade. In addition, supplementation with Bacteroides thetaiotaomicron improved sphingolipid metabolic profiles in NEC intestinal tissues and upregulated S1P levels. These findings suggest that dysregulation of sphingolipid metabolism is associated with NEC and intestinal barrier dysfunction. S1P may alleviate NEC-related injury in experimental models, potentially involving S1PR1 signaling, mitochondrial redox balance, and interactions with the gut microbiota.
SN - 2041-4889
ER -