Neonatal Enteric Infection Disrupts the Microbiota-Gut-Brain Axis Through Pattern Recognition Receptors and Altered Neuroimmune Signaling

Early-life enteric infection can have long-lasting effects on the microbiota-gut-brain (MGB) axis. Using a neonatal Enteropathogenic <i>Escherichia coli</i> (EPEC) model, we show that intestinal epithelial cell (IEC) NOD1 signaling coordinates mucosal immunity, barrier repair, and neuroimmune outcomes throughout early development and into adulthood. Neonates infected at postnatal day (P) 7 exhibited ileal inflammation, as demonstrated by increased expression of inflammatory cytokines (<i>Il1β</i>, <i>Il6</i>, <i>Il12</i>, <i>Il22</i>), chemokines/chemokine receptors (<i>Ccl2</i>, <i>Cxcl1</i>, <i>Ccr2</i>), and barrier-repair genes (<i>Muc2</i>, <i>Slc26a3</i>), with increased monocyte/macrophage infiltration and reduced epithelial proliferation in WT mice that was blunted in Nod1^ΔIEC mice. Neonatal infection of WT mice induced persistent defects into adulthood (P56), including increased intestinal permeability, sustained inflammatory/repair signatures, hippocampal inflammation, altered neurogenesis, and impaired recognition memory, which were largely absent in Nod1^ΔIEC mice, establishing a crucial role for IEC NOD1 as a determinant of long-term MGB remodeling. Microbially derived ligands of NOD2, muropeptides, isolated from probiotic <i>Lactobacillus</i> species attenuated EPEC-induced mucosal inflammation and chemokine induction without altering bacterial burden, demonstrating NOD2 host-directed immunomodulation. Together, these findings identify an important role for NOD-dependent signaling axis in the gastrointestinal tract that links early-life infection to enduring gut-brain dysfunction and reveals probiotic-derived muropeptides as candidate microbial therapeutics.