Deciphering the Gut-Brain Axis in Necrotizing Enterocolitis: Phenotypic Manifestations, Mechanistic Insights, and Therapeutic Strategies
Year: 2024
Type: dissertation
Abstract: Necrotizing enterocolitis (NEC) remains one of the most severe gastrointestinal (GI) emergencies affecting premature infants with low and extremely low weight at birth. NEC is characterized by inflammation in the small bowel and/or large bowel with varying degrees of mucosal injury including inflammation, dysbiosis, ischemia, and in extreme cases, intestinal perforation. Approximately half of NEC survivors suffer from poor neurodevelopmental outcomes, not associated with prematurity alone, suggesting a gut-brain connection.Our hypothesis posits that NEC-related brain damage results from systemic influences of bacterial ligands and neuroendocrine factors within this axis. We propose that remote ischemic conditioning (RIC) could be a non-surgical strategy to mitigate intestinal damage and foster brain resilience in NEC. We investigated the NEC brain injury phenotype in a mouse model, identifying neuroinflammation driven by microglia and astrocytes, alongside increased pro-inflammatory cytokines. These factors disrupt cell homeostasis, impacting the density of mature neurons, oligodendrocytes, and neural progenitors. Further exploration into the gut-brain axis revealed intestinal HMGB1, a TLR4 ligand, triggers inflammasome activation in microglial cells within the NEC brain, contributing to the spread of injury. Organoid studies and the NEC mouse model highlighted the crucial roles of gut hormones glucagon-like peptide (GLP) 1 and 2 in postnatal development of both gut and brain. Deficiencies in GLP signaling modulated brain immunity. Our findings also suggest RIC enhances memory performance and maintains blood-brain barrier (BBB) integrity, with mechanisms implicating GLP1, eNOS, pAkt, and FGF21 signaling pathways. Collectively, identifying the gut-brain axis in NEC provides novel molecular biomarkers for early diagnosis of brain injury during the onset of NEC, and establishes a preclinical framework for targeted therapeutic strategies, like RIC, to mitigate NDI during the infant management of NEC.
Source: TSpace (University of Toronto)
Author: Biouss, George
Institution: University of Toronto
Language: English
Topic: Infant Nutrition and Health
Subfield: Nutrition and Dietetics
Field: Nursing
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7132967200