Probiotic Supplementation Rescues Memory, Reduces Neuroinflammation, and Restores Gut-Brain Axis in Chronic Hypoxia Mice

Chronic hypoxia is a critical factor in the pathogenesis of numerous diseases, triggering cellular and molecular adaptations that disrupt tissue homeostasis. It impairs gut eubiosis, promotes inflammation, and contributes to progressive functional decline, mimicking key features of neurodegenerative diseases. Mechanistically, chronic hypoxia involves Hypoxia-Inducible Factor 1-alpha (HIF-1α) stabilization, proteasome dysfunction, and gut-brain axis disruption. Current strategies often fall short in comprehensively addressing these multifaceted damages, highlighting a need for interventions that can restore systemic homeostasis.

C57BL/6 mice were subjected to chronic hypoxia (12% O2) for 2 months to induce pathological conditions. During this period, mice received daily oral probiotics supplementation (specific strain/dose not detailed in abstract) via gavage. The study assessed various endpoints including short-term memory using the novel object recognition test, hippocampal HIF-1α accumulation, prolyl hydroxylase domain protein 2 (PHD2) levels, and the ubiquitin-proteasome pathway. Additionally, neuroinflammation, apoptosis, and brain-derived neurotrophic factor (BDNF) were measured. Gut-brain axis integrity was evaluated by analyzing plasma gut hormones (GLP-1, GIP, leptin), ileal tight junction proteins (zonulin-1, occludin, claudin), and gut microbiota β-diversity and metabolic pathways.

Probiotic supplementation significantly rescued short-term memory deficits in the novel object recognition test in hypoxic mice. They observed a marked reduction in hippocampal HIF-1α accumulation, alongside a restoration of PHD2 and the ubiquitin-proteasome pathway. Probiotics also attenuated neuroinflammation and apoptosis, while elevating BDNF levels in the brain. The intervention normalized plasma levels of key gut hormones, including glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and leptin. Furthermore, probiotics enhanced ileal tight junction proteins (zonulin-1, occludin, claudin) in ileal tissue, indicating improved gut barrier function. > Probiotics countered gut microbiota β-diversity shifts and restored beneficial bacterial metabolites, with improved predicted metabolic pathways, demonstrating a comprehensive impact on gut-brain axis homeostasis.