Energy Metabolic Reprogramming Characterized by Succinate Accumulation Aggravates Necrotizing Enterocolitis.
- 1Department of Neonatology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents' Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing 400014, China.
Abstract
Necrotizing enterocolitis (NEC) is a severe inflammatory intestinal disorder of preterm infants associated with substantial morbidity and mortality. This study investigated energy metabolic alterations in NEC and the contribution of succinate to disease progression. Fecal energy metabolites were quantified by high-performance liquid chromatography-mass spectrometry in preterm infants and neonatal mice. Neonatal C57BL/6 mice were assigned to the Control, NEC, NEC+dimethyl malonate (DMM), NEC+succinate (Suc), and NEC+DMM+Suc groups. Ileal tissues were analyzed by metabolomics, transcriptomics, histopathology, immunofluorescence, flow cytometry, Western blotting, reverse transcription quantitative PCR, and succinate dehydrogenase (SDH) activity assays. Both human neonates and neonatal mice with NEC exhibited metabolic reprogramming characterized by prominent succinate accumulation. Exogenous succinate further altered intestinal metabolism, reduced survival, aggravated weight loss and intestinal injury, decreased tight junction protein expression and lamina propria CD4⁺Foxp3⁺ regulatory T-cell proportions, and enhanced hypoxia-inducible factor-1α (HIF-1α)/interleukin-1β (IL-1β) signaling. Intestinal SDH activity and succinate dehydrogenase complex flavoprotein subunit A (SDHA) expression were increased in NEC and further enhanced by exogenous succinate, accompanied by increased colocalization of SDHA with F4/80⁺ macrophages. Pharmacological inhibition of SDH with DMM partially improved survival, intestinal injury, barrier disruption, and Treg loss, while suppressing HIF-1α/IL-1β signaling. These findings identify succinate accumulation as a metabolic hallmark of NEC and support a potential succinate-SDH-HIF-1α/IL-1β axis linking metabolic dysregulation to intestinal injury and immune imbalance.
Related
- Sphingosine-1-phosphate ameliorates necrotizing enterocolitis by regulating mitochondrial redox homeostasis and gut microbiota.
- Ferroptosis-pyroptosis crosstalk in neonatal necrotizing enterocolitis: epithelial barrier failure, immune amplification, and precision targeting.
- Acid-Sensing Ion Channel 1 Deficiency Aggravates Cuprizone-Induced Demyelination, Axonal Damage and Microgliosis in Mice
- Exogenous tryptophan aggravates experimental lung fibrosis through activation of AKT-mTORC1 pathway
- Chronic Intermittent Hypoxia Aggravates the Pyroptosis of Renal Tubular Epithelial Cells Through Regulating Mitophagy‐Mediated NLRP3 Inflammasome Activation
BibTeX
@article{yan2026energy,
title = {{Energy Metabolic Reprogramming Characterized by Succinate Accumulation Aggravates Necrotizing Enterocolitis.}},
author = {Xiao-Lin Yan and Yu He and Xiao-Chen Liu and Yu-Ni Zhang and Fang-Ling Tang and Lei Bao and Yuan Shi},
journal = {International journal of molecular sciences},
year = {2026},
month = sep,
doi = {10.3390/ijms27198691},
url = {https://europepmc.org/article/MED/42883936},
note = {CC BY},
}
RIS
TY - JOUR
TI - Energy Metabolic Reprogramming Characterized by Succinate Accumulation Aggravates Necrotizing Enterocolitis.
AU - Xiao-Lin Yan
AU - Yu He
AU - Xiao-Chen Liu
AU - Yu-Ni Zhang
AU - Fang-Ling Tang
AU - Lei Bao
AU - Yuan Shi
PY - 2026
DA - 2026/09/29
JO - International journal of molecular sciences
DO - 10.3390/ijms27198691
UR - https://europepmc.org/article/MED/42883936
AB - Necrotizing enterocolitis (NEC) is a severe inflammatory intestinal disorder of preterm infants associated with substantial morbidity and mortality. This study investigated energy metabolic alterations in NEC and the contribution of succinate to disease progression. Fecal energy metabolites were quantified by high-performance liquid chromatography-mass spectrometry in preterm infants and neonatal mice. Neonatal C57BL/6 mice were assigned to the Control, NEC, NEC+dimethyl malonate (DMM), NEC+succinate (Suc), and NEC+DMM+Suc groups. Ileal tissues were analyzed by metabolomics, transcriptomics, histopathology, immunofluorescence, flow cytometry, Western blotting, reverse transcription quantitative PCR, and succinate dehydrogenase (SDH) activity assays. Both human neonates and neonatal mice with NEC exhibited metabolic reprogramming characterized by prominent succinate accumulation. Exogenous succinate further altered intestinal metabolism, reduced survival, aggravated weight loss and intestinal injury, decreased tight junction protein expression and lamina propria CD4⁺Foxp3⁺ regulatory T-cell proportions, and enhanced hypoxia-inducible factor-1α (HIF-1α)/interleukin-1β (IL-1β) signaling. Intestinal SDH activity and succinate dehydrogenase complex flavoprotein subunit A (SDHA) expression were increased in NEC and further enhanced by exogenous succinate, accompanied by increased colocalization of SDHA with F4/80⁺ macrophages. Pharmacological inhibition of SDH with DMM partially improved survival, intestinal injury, barrier disruption, and Treg loss, while suppressing HIF-1α/IL-1β signaling. These findings identify succinate accumulation as a metabolic hallmark of NEC and support a potential succinate-SDH-HIF-1α/IL-1β axis linking metabolic dysregulation to intestinal injury and immune imbalance.
SN - 1422-0067
ER -