A neuroimmune IL-13 axis is associated with human enteric nervous system development

Abstract

The mechanisms governing maturation of the human enteric nervous system (ENS) during early postnatal life remain poorly defined. Here, we characterize the transcriptomic, cellular, and functional landscape of the neonatal human ileum and identify a neuro-immune axis associated with ENS expansion. Using human tissue transcriptomics, flow cytometry, iPSC-derived enteric neural lineages, and single-cell interactome analyses, we show that the neonatal ileum is enriched for pro-neurogenic transcriptional programs and harbors a greater abundance of enteric neurons and glia than the adult tissue. T cells emerge as a predominant source of interleukin-13 (IL-13) in the neonatal gut, and enteric neurons express its receptor IL13RA1, enabling direct immune-to-neuron signaling. Functional experiments demonstrate that IL-13 enhances expression of key enteric neuronal markers in a concentration-dependent manner. In parallel, single-cell analyses identify enteric neurons as a major predicted source of macrophage migration inhibitory factor (MIF), with signaling directed toward T and NK cell populations, suggesting that the ENS actively shapes the immune environment it depends upon. Together, these findings support a model in which bidirectional neuro-immune communication establishes a pro-neurogenic niche during a critical window of ENS development. This work positions the neonatal immune system as an active contributor to ENS maturation and offers a new perspective on how neuro-immune crosstalk shapes intestinal development in early life.