Chronic Intermittent Hypoxia Participates in the Pathogenesis of Atherosclerosis and Perturbs the Formation of Intestinal Microbiota

Chronic intermittent hypoxia (CIH) is the prominent signature of highly prevalent obstructive sleep apnea (OSA) pathophysiology, which leads to increased risk and aggravation of atherosclerotic cardiovascular diseases. However, whether intestinal microbiota is implicated in the mechanisms linking CIH to arteriosclerosis (AS) pathogenesis remains unclear. The association of CIH with the development of altered gut microbiota (GM) may provide the opportunity to develop preventive strategies for atherosclerotic cardiovascular risk reduction. Animal models of apolipoprotein E-deficient (apoE(-/-)) mice treated with high-fat diet (HFD) and subjected to CIH conditions was applied to mimic the AS observed in patients with OSA. The physiological status and atherosclerotic lesion formation were confirmed by histological analysis. 16S rDNA sequencing of fecal samples was conducted to determine the changes in gut microbial composition. Morphometric analysis demonstrated that CIH caused aggravated atherosclerotic lesions and facilitated AS in apoE(-/-) mice treated with HFD. The gut bacteria was significantly varied in AS and AS+CIH mice compared with that in the control mice. Significantly perturbed GM profiles were detected in AS mice with and without CIH, with altered microbial α- and β- diversity and shifts in bacterial compositions at phylum and genus levels. While the difference between AS and AS+CIH was observed at different bacteria taxa levels. Aggravation of reduced Sutterella and increased Halomonas, Halomonadaceae and Oceanospirillales was noted in CIH-treated AS mice. The correlation of intestinal bacterial parameters with pathological changes in artery indicated complicated interactions under CIH-induced GM dysbiosis. Furthermore, the gut microbial functions in the potential ability of replication recombination and repair proteins, glycan biosynthesis and metabolism, as well as metabolism of cofactors and vitamins were identified to be further suppressed by CIH. Our findings demonstrated a causal effect of CIH on GM alterations in AS mice and suggested that the disordered GM features in AS development were deteriorated by CIH, which may be associated with AS aggravation. Preventative strategies targeting gut microbiome are highly recommended for intervention of OSA-related AS.