Chronic intermittent hypoxia (CIH), a core pathophysiological feature of obstructive sleep apnea (OSA), is closely associated with multi-system damage, including cognitive dysfunction, metabolic disorders, and cardiovascular complications (Qi et al., 2024; Allaband et al., 2021). Studies have demonstrated that CIH can induce extensive cellular apoptosis, particularly in brain regions critical for learning and memory such as the hippocampus and prefrontal cortex, which may represent a key mechanism underlying OSA-related neurocognitive impairment (Moujalled et al., 2021). Beyond the central nervous system, CIH also promotes apoptosis in peripheral organs such as the lung and heart, though its systemic regulatory mechanisms remain incompletely understood.

n recent years, the role of the gut microbiota and its metabolites in chronic diseases has gained increasing attention. Through the “gut-organ axis,” gut microbiota bidirectionally communicate with distant organs, participating in the regulation of systemic inflammation, metabolic homeostasis, and cell fate (Li et al., 2019). OSA patients frequently exhibit altered gut microbial composition, which correlates with disease severity (Zhang et al., 2022a). Metabolomic analyses further reveal significant disturbances in metabolic profiles among OSA patients, partially reversible upon effective treatment, suggesting that metabolites may serve as critical mediators in OSA pathogenesis (Zhang et al., 2022b). However, how CIH modulates the gut microbiota-metabolite network to influence pulmonary apoptosis remains unclear.

Mitochondria, central to cellular energy metabolism and apoptosis regulation, play a pivotal role in CIH-induced tissue injury. CIH can trigger mitochondrial dynamics imbalance, excessive reactive oxygen species production, and activation of the mitochondrial apoptotic pathway, ultimately leading to cell death (Chen et al., 2015; Czabotar and Garcia-Saez, 2023). Studies indicate that CIH induces mitochondrial dysfunction in the brain, further driving neuroinflammation and synaptic damage, thereby contributing to cognitive decline (Yan et al., 2021; Bouhamida et al., 2022). Our preliminary work, through functional prediction analysis of the gut microbiota in OSA patients, revealed significant enrichment of apoptosis-related pathways, suggesting that gut microbes may influence host apoptosis via specific metabolites (Zeng et al., 2025). Nevertheless, whether the “gut microbiota-metabolite-mitochondria” axis plays a regulatory role in CIH-induced pulmonary apoptosis has not yet been systematically investigated.

Notably, mitochondrial dysfunction and systemic metabolic disturbances represent common pathological bases for multi-organ injury in OSA. Although this study focuses on lung tissue, the “microbiota-metabolite-mitochondrial dynamics” regulatory axis identified here may have broader relevance, offering a novel mechanistic perspective for understanding OSA-associated neurocognitive dysfunction. For instance, the differential microbes or metabolites identified in this study may also be implicated in central nervous system pathology in future research. Therefore, employing a CIH mouse model and integrating 16S rRNA sequencing, targeted metabolomics, and molecular pathological techniques, this study systematically investigates whether CIH modulates the gut microbiota and associated metabolites, thereby affecting mitochondrial dynamics and ultimately inducing pulmonary apoptosis. The findings are expected not only to provide new mechanistic insights into OSA-related lung injury but also to offer potential experimental evidence for targeting the “gut-lung axis” and “gut-brain axis” in therapeutic interventions. A graphical summary of the study design and major outcomes is provided as F.igure 1.