Gut-microbiota-derived 3-indoleacrylic acid alleviates neonatal necrotizing enterocolitis by inhibiting epithelial necroptosis

  • Cell Rep Med. 2026 Apr 21;7(4):102721. doi: 10.1016/j.xcrm.2026.102721.
Xiaoliang Dong  1 ,  Mengwen Wang  1 ,  Bingxin Wang  1 ,  Hongli Li  2 ,  Zeyun Cao  2 ,  Binbin Li  3 ,  Xun Zou  2 ,  Xuan Kong  2 ,  Huanxin Yang  2 ,  Yufeng Zhou  4 ,  Le Zhang  5 ,  Li-Long Pan  6 ,  Jia Sun  7
Affiliations
  • 1. Department of Neonatology, Affiliated Children's Hospital of Jiangnan University (Wuxi Children's Hospital), Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China; MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Jiangnan University, Wuxi, Jiangsu 214122, China.
  • 2. Department of Neonatology, Affiliated Children's Hospital of Jiangnan University (Wuxi Children's Hospital), Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China.
  • 3. School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China; School of Food Science and Technology, Jiangnan University, Wuxi 214122, China.
  • 4. Institute of Pediatrics, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
  • 5. Department of Neonatology, Affiliated Children's Hospital of Jiangnan University (Wuxi Children's Hospital), Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China; Clinical Research Center, Affiliated Children's Hospital of Jiangnan University, Wuxi Children's Hospital, Jiangsu Provincial Industrial Technology Engineering Center for Pediatric Metabolic Disease Prevention and Control, Wuxi Key Laboratory of Genetic and Metabolic Diseases in Children, Wuxi 214023, Jiangsu, China. Electronic address: [email protected].
  • 6. Department of Neonatology, Affiliated Children's Hospital of Jiangnan University (Wuxi Children's Hospital), Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China; MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Jiangnan University, Wuxi, Jiangsu 214122, China. Electronic address: [email protected].
  • 7. School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China; School of Food Science and Technology, Jiangnan University, Wuxi 214122, China. Electronic address: [email protected].
PMID: 41923629 DOI: 10.1016/j.xcrm.2026.102721
Abstract

Neonatal necrotizing enterocolitis (NEC) is a severe inflammatory disease primarily affecting premature infants, characterized by high mortality and morbidity, with limited therapeutic options available. While emerging evidence links microbiota to NEC pathogenesis, the role of commensal metabolites in NEC and safe metabolite-based therapies remain unexplored. Metabolomic profiling reveals a significant reduction in 3-indoleacrylic acid (IA), a tryptophan-derived metabolite, in NEC infants and animal models. IA supplementation alleviates intestinal inflammation and tissue damage. Single-cell RNA Sequencing analysis reveals the activation of STAT1 signaling as a Necroptosis driver in intestinal epithelial cells, which is suppressed by IA. Protection is abolished by Aryl Hydrocarbon Receptor (AhR) inhibitor CH-223191 or in intestinal epithelium-specific AhR knockout mice. Oral administration of Bifidobacterium longum subsp. infantis containing the IA-producing fldI gene prevents NEC in mice. Our study uncovers IA as a microbiota-derived therapeutic inhibiting STAT1-driven Necroptosis via the AhR-SOCS5 axis, offering a targeted strategy for NEC management.

Keywords
3-indoleacrylic acid; aryl hydrocarbon receptor; necroptosis; necrotizing enterocolitis.
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