Reoxygenation Mitigates Intermittent Hypoxia-Induced Systemic Inflammation and Gut Microbiota Dysbiosis in High-Fat Diet-Induced Obese Rats

Abstract

Menglu Dong,1 Xili Liang,1 Tian Zhu,1 Ting Xu,1 Liwei Xie,2,3 Yuan Feng1,4,5 1Sleep Medicine Center, Department of Psychiatric, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, People’s Republic of China; 3Department of Endocrinology and Metabolism, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 4Institute of Brain Disease, Nanfang Hospital of Southern Medical University, Guangzhou, People’s Republic of China; 5Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Science, Southern Medical University, Guangzhou, People’s Republic of ChinaCorrespondence: Liwei Xie, Email [email protected]; Yuan Feng, Sleep Medicine Center, Department of Psychiatric, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Baiyun District, Guangzhou, 510515, People’s Republic of China, Email [email protected]: Obstructive sleep apnea (OSA) is a prevalent sleep breathing disorder characterized by intermittent hypoxia (IH), with continuous positive airway pressure (CPAP) as its standard treatment. However, the effects of intermittent hypoxia/reoxygenation (IH/R) on weight regulation in obesity and its underlying mechanism remain unclear. Gut microbiota has gained attention for its strong association with various diseases. This study aims to explore the combined influence of IH and obesity on gut microbiota and to investigate the impact of reoxygenation on IH-induced alterations.Methods: Diet-induced obese (DIO) rats were created by 8-week high-fat diet (HFD) feeding and randomly assigned into three groups (n=15 per group): normoxia (NM), IH (6% O2, 30 cycles/h, 8 h/day, 4 weeks), or hypoxia/reoxygenation (HR, 2-week IH followed by 2-week reoxygenation) management. After modeling and exposure, body weight and biochemical indicators were measured, and fecal samples were collected for 16S rRNA sequencing.Results: DIO rats in the IH group showed increased weight gain (p=0.0016) and elevated systemic inflammation, including IL-6 (p=0.0070) and leptin (p=0.0004). Moreover, IH rats exhibited greater microbial diversity (p< 0.0167), and significant alterations in the microbial structure (p=0.014), notably the order Clostridiales, accompanied by an upregulation of bile acid metabolism predicted pathway (p=0.0043). Reoxygenation not only improved IH-exacerbated obesity, systemic inflammation, leptin resistance, and sympathetic activation, but also showed the potential to restore IH-induced microbial alterations. Elevated leptin levels were associated with Ruminococcaceae (p=0.0008) and Clostridiales (p=0.0019), while body weight was linked to Blautia producta (p=0.0377). Additionally, the abundance of Lactobacillus was negatively correlated with leptin levels (p=0.0006) and weight (p=0.0339).Conclusion: IH leads to gut dysbiosis and metabolic disorders, while reoxygenation therapy demonstrates a potentially protective effect by restoring gut homeostasis and mitigating inflammation. It highlights the potential benefits of CPAP in reducing metabolic risk among obese patients with OSA.Keywords: intermittent hypoxia, reoxygenation, high-fat diet-induced obese, gut microbiota, 16S rRNA

Keywords

• intermittent hypoxia
• reoxygenation
• high-fat diet-induced obese
• gut microbiota
• 16s rrna