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

Jungjae Park1, Olivia Orahood1, Maithili Banginwar1

  • 1Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, California, USA.

Insights

Early gut infection impacts the microbiota-gut-brain axis long-term. Intestinal epithelial NOD1 signaling is crucial for immune response, barrier repair, and preventing lasting gut-brain dysfunction, with probiotic muropeptides showing therapeutic potential.

Area of Science:

  • Microbiology
  • Immunology
  • Neuroscience

Background:

  • Early-life enteric infections can disrupt the microbiota-gut-brain (MGB) axis, leading to persistent health issues.
  • The role of specific host signaling pathways, like NOD1, in mediating these long-term effects remains incompletely understood.

Purpose of the Study:

  • To investigate the role of intestinal epithelial cell (IEC) NOD1 signaling in coordinating mucosal immunity, barrier repair, and neuroimmune outcomes following early-life infection.
  • To determine if IEC NOD1 signaling influences long-term MGB axis remodeling and associated cognitive deficits.
  • To explore the therapeutic potential of NOD2 ligands in mitigating infection-induced inflammation.

Main Methods:

  • Utilized a neonatal Enteropathogenic Escherichia coli (EPEC) infection model in wild-type (WT) and Nod1-deficient IEC (Nod1ΔIEC) mice.
  • Assessed ileal inflammation, barrier integrity, epithelial proliferation, and immune cell infiltration post-infection.
  • Evaluated long-term MGB axis effects in adulthood, including intestinal permeability, hippocampal inflammation, neurogenesis, and recognition memory.
  • Investigated the immunomodulatory effects of muropeptides derived from probiotic Lactobacillus species on EPEC-induced inflammation.

Main Results:

  • Neonatal EPEC infection in WT mice caused ileal inflammation, barrier defects, and reduced epithelial proliferation, which were blunted in Nod1ΔIEC mice.
  • In adult WT mice, neonatal infection led to persistent intestinal permeability, sustained inflammation, hippocampal inflammation, altered neurogenesis, and impaired recognition memory, largely absent in Nod1ΔIEC mice.
  • Microbially derived NOD2 ligands (muropeptides) from Lactobacillus attenuated EPEC-induced mucosal inflammation and chemokine induction without affecting bacterial load.

Conclusions:

  • IEC NOD1 signaling is a critical determinant of long-term MGB axis remodeling following early-life enteric infection.
  • Disruption of IEC NOD1 signaling prevents persistent gut-brain dysfunction and associated cognitive deficits.
  • Probiotic-derived muropeptides represent a potential therapeutic strategy for modulating host-directed immune responses to gut infections.

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