Neuro-immune Crosstalk in the Enteric Nervous System from Early Postnatal Development to Adulthood

Correct development and maturation of the enteric nervous system (ENS) is critical for survival. Early in life, the ENS requires significant refinement in order to adapt to the evolving needs of the tissue, changing from milk to solid food at the time of weaning. Here, we demonstrate that resident macrophages of the muscularis externa, MMϕ, refine the ENS early in life by pruning synapses and phagocytosing abundant enteric neurons. After weaning, MMϕ continue to closely interact with the ENS, acquire a microglia-like phenotype and are crucial for the survival of enteric neurons. Of note, this microglia-like phenotype is instructed by TGFβ produced by the ENS, introducing a novel reciprocal cell-cell communication responsible for the maintenance of the neuron-associated MMФ niche in the gut. These findings elucidate a novel role of intestinal macrophages in ENS refinement early in life, and open new opportunities to treat intestinal neurodegenerative disorders by manipulating the ENS-macrophage niche. ### Competing Interest Statement The authors have declared no competing interest.