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

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.