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

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.