d Two-day-old (P2), but not 9-day-old (P9), rat pups are susceptible to systemic infection following gastrointestinal colonization by Escherichia coli K1. Age dependency reflects the capacity of colonizing K1 to translocate from gastrointestinal (GI) tract to blood. A complex GI microbiota developed by P2, showed little variation over P2 to P9, and did not prevent stable K1 colonization. Substantial developmental expression was observed over P2 to P9, including upregulation of genes encoding components of the small intestinal (␣-defensins Defa24 and Defa-rs1) and colonic (trefoil factor Tff2) mucus barrier. K1 colonization modulated expression of these peptides: developmental expression of Tff2 was dysregulated in P2 tissues and was accompanied by a decrease in mucin Muc2. Conversely, ␣-defensin genes were upregulated in P9 tissues. We propose that incomplete development of the mucus barrier during early neonatal life and the capacity of colonizing K1 to interfere with mucus barrier maturation provide opportunities for neuropathogen translocation into the bloodstream. The newborn infant is particularly vulnerable to systemic bacterial infection during the first 4 weeks of life, and mortality and morbidity associated with neonatal bacterial meningitis (NBM) and accompanying sepsis remain significant despite advances in antibacterial chemotherapy and supportive care (1, 2). In the developed world, Escherichia coli and group B streptococci are responsible for the majority of cases of NBM, and bacteria isolated from the cerebrospinal fluid of infected neonates invariably elaborate a protective polysaccharide capsule. Of neuroinvasive E. coli isolates, 80 to 85% express the K1 capsule (3, 4), a homopolymer of ␣-2,8-linked polysialic acid (polySia) that mimics the molecular structure of the polySia modulator of neuronal plasticity in mammalian hosts (5) and enables these strains to evade detection by a neonatal innate immune system undergoing a process of age-dependent maturation (6).Risk factors for NBM include obstetric and perinatal complications, premature birth, and low birth weight, particularly in low socioeconomic groups (7), but predisposition to infection is critically dependent on vertical transmission of the causative agent from mother to infant at or soon after birth (8). Although many aspects of the pathogenesis of E. coli K1 in NBM are unclear, maternally derived E. coli K1 bacteria are known to colonize the neonatal gastrointestinal (GI) tract (8, 9, 10), which is sterile at birth but rapidly acquires a complex microbiota that eventually converges toward a profile characteristic of the adult GI tract (11). E. coli K1 bacteria then translocate from the lumen of the small intestine or colon into the systemic circulation before entering the central nervous system (CNS) across the blood-brain barrier at the cerebral microvascular endothelium of the arachnoid membrane (12) or the blood-cerebrospinal fluid (CSF) barrier at the choroid plexus epithelium (13).Many of the temporal and spatial aspects of NBM can...