UC Davis

Diarrheal diseases, such as those caused by enteric pathogens, including Enteropathogenic E. coli (EPEC), pose a significant problem in developing countries. In prior studies, we found that neonatal infection-induced disruption of colonization of the gut microbiome causes long-term impacts on microbiota-gut-brain (MGB) axis signaling in mice. Additional studies have also demonstrated a crucial role for innate immune Nod-like receptors (NLRs) expressed on intestinal epithelial cells (IEC), which recognize bacterial peptidoglycan (PGN), in regulating stress-induced behavioral deficits. We therefore hypothesized that IEC Nod1 receptors, activated by EPEC-derived PGN, modulate disrupted MGB axis signaling following early-life infection. On postnatal day (P)7, Villin Cre+ (Nod1ΔIEC) and littermate Cre- (WT) mice were infected with EPEC (or vehicle control [Luria Bertani broth]). Acute gastrointestinal (GI) inflammation, histological damage, and EPEC colonization were assessed at 1-week post-infection (P14) and behavior, inflammation (ileum, hippocampus), serum corticosterone, and neurogenesis were assessed in adulthood (P42-56). We found that the absence of IEC Nod1 receptors prevents EPEC-induced GI inflammation and altered IEC kinetics at P14, with no impact on bacterial burden. This was coupled with an absence of EPEC-induced altered hippocampal neurogenesis and neuroinflammation in adulthood, both known to regulate cognitive function. Increased serum corticosterone levels were also found in adult mice following early-life infection, suggesting stress may modulate impairments along the MGB axis via IEC Nod1 receptors. Finally, to investigate a potential therapeutic, we administered probiotic bacteria-derived muropeptides to neonatal mice for 7 days following EPEC infection (P7-14). In preliminary studies, we found a potential role for muropeptides in ameliorating EPEC-induced GI inflammation through increased anti-inflammatory cytokine expression. Taken together, these results demonstrate a novel role for IEC Nod1 receptors in modulating EPEC-induced MGB axis dysregulation.