Chronic hypoxia plays a critical role in the pathogenesis of numerous diseases by triggering cellular and molecular adaptations that disrupt tissue homeostasis, impair gut eubiosis, promote inflammation, and contribute to progressive functional decline. These effects mimic key features of neurodegenerative diseases and share mechanistic overlap with adverse outcomes of airborne environmental exposures that compromise oxygen homeostasis through mechanisms involving Hypoxia-Inducible Factor 1-alpha (HIF-1α) stabilization, proteasome dysfunction, and gut-brain axis disruption. In this study, C57BL/6 mice were exposed to 12% O2 for 2 months and received oral probiotics supplementation, which rescued short-term memory deficits in the novel object recognition test, reduced hippocampal HIF-1α accumulation, restored prolyl hydroxylase domain protein 2 (PHD2) and ubiquitin-proteasome pathway, and attenuated neuroinflammation and apoptosis, while elevating brain-derived neurotrophic factor (BDNF). Probiotics also normalized plasma gut hormones (glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and leptin), enhanced ileal tight junction proteins (zonulin-1, occludin and claudin) in Ileal tissue, countered gut microbiota β-diversity shifts and restored beneficial bacterial metabolites with improved predicted metabolic pathways. These findings provide preclinical evidence that probiotics oral supplementation can restore gut-brain axis homeostasis, and mitigate chronic hypoxia related neuroinflammation, offering a potential therapeutic strategy against neurodegeneration triggered by oxygen‑depriving environmental and pathological conditions.
