AhR ligands in necrotizing enterocolitis: a provisional evidence map of ligand-specific biology and translational...

Necrotizing enterocolitis (NEC) remains a major cause of gastrointestinal morbidity and mortality in preterm infants, with no targeted mechanism-based therapy. Aryl hydrocarbon receptor (AhR) signaling is an emerging host-microbe interface because it integrates dietary, microbial, milk-derived, and host-derived ligands that regulate intestinal inflammation, epithelial homeostasis, and barrier integrity. Direct NEC-specific evidence for individual AhR ligands, however, remains sparse and uneven. This focused review maps direct NEC intervention evidence, independent replication, human NEC association or ex vivo evidence, AhR dependency, compartment specificity, mechanistic resolution, and translational considerations. Indole-3-carbinol (I3C), the synthetic agonist A18, and 3-indoleacrylic acid (IA) have direct intervention evidence in experimental NEC models. Two independent NEC studies support I3C, although the implicated cellular compartment differs between models. A18 provides direct protection in an experimental NEC model, activates AhR, and exhibits anti-inflammatory effects in human intestinal explants. However, it has not been independently replicated. IA is currently the most comprehensively characterized microbiota-derived ligand in NEC models. However, its mechanistic evidence predominantly comes from one recent study and awaits independent replication. Indole-3-lactic acid, indole-3-acetic acid, and indole-3-sulfate remain physiologically relevant candidates, supported by immature intestinal, human milk, or neonatal metabolic studies. Overall, current evidence supports a ligand-specific view of AhR biology in NEC while highlighting major gaps in replication, human validation, and translational studies.