Macrophage-enteric nervous system crosstalk in Hirschsprung disease and associated enterocolitis: a focused narrative review with clinical implications.

Hirschsprung disease (HSCR) results from incomplete distal bowel colonization by enteric neural crest-derived cells. Macrophage-enteric nervous system (ENS) interactions may influence postnatal neuromuscular function and Hirschsprung-associated enterocolitis (HAEC), but direct evidence that macrophages initiate embryonic aganglionosis is limited. This focused narrative review therefore treats postnatal dysmotility and HAEC as its primary focus and examines prenatal development chiefly to define the boundary of causal claims. In the normal muscularis, macrophage-neuron interactions contribute to ENS refinement and maintenance. A proposed bone morphogenetic protein 2 and colony-stimulating factor 1 circuit has influenced the field, although recent deletion studies question whether macrophage-derived bone morphogenetic protein 2 controls motility. In HSCR, the strongest disease-specific evidence concerns secondary neuromuscular dysfunction and HAEC. Pro-inflammatory macrophages can induce an interstitial cell of Cajal C-KIT phenotypic switch through a TNF-α, NF-κB and miR-221 pathway, while microbial, stromal and epithelial signals can further modify macrophage function. These mechanisms may help explain persistent dysmotility and enterocolitis susceptibility, but no macrophage biomarker or macrophage-directed treatment has established clinical utility. Current care remains based on prompt recognition, bowel decompression, antibiotics and correction of obstructive causes. Available evidence supports macrophages as modifiers of postnatal dysfunction, not as a proven primary cause of aganglionosis.