Chronic intermittent hypoxia exacerbates hepatic steatosis in a microbiota-dependent manner in lean mice

Chronic intermittent hypoxia (CIH), a hallmark pathological feature of obstructive sleep apnea (OSA), is extensively linked to hepatic steatosis in high-fat-diet-induced mice. However, the association between CIH and hepatic steatosis in lean mice, as well as the potential involvement of gut microbiota-related mechanisms, remains poorly understood. Four hundred participants in the Shanghai Sleep Health Study were included to assess the association between apnea-hypopnea index (AHI) and hepatic steatosis index (HSI). To characterize CIH-associated phenotypes and explore microbiota-related alterations in lean mice, liver histology, inflammatory cytokine profiling, metagenomic sequencing with antibiotic intervention, plasma untargeted metabolomics, and liver transcriptomics were performed. As a result, AHI was positively associated with HSI in non-obese participants. In lean mice, 16-week CIH alone induced hepatic steatosis and inflammation, accompanied by significant alterations in gut microbiota composition. Antibiotic treatment attenuated hepatic steatosis and inflammation in 16-week CIH-exposed mice. Metagenomic analysis revealed CIH-associated depletion of Bacteroides uniformis, which was reversed by antibiotic treatment. Plasma metabolomic profiling identified deoxycholic acid as a metabolite exhibiting opposite, phenotype-aligned alterations between CIH and CIH plus antibiotic groups and showing the strongest correlation with Bacteroides uniformis abundance. In parallel, liver transcriptomics revealed coordinated alterations in bile acid-related metabolic pathways and PPAR signaling consistent with CIH-induced and antibiotic-sensitive metabolic remodeling. Together, these findings indicate that prolonged CIH exposure induces hepatic lipid accumulation in lean mice and is associated with coordinated, antibiotic-sensitive alterations in gut microbiota composition, bile acid metabolism, and hepatic transcriptional programs, suggesting a potential involvement of gut microbiota-bile acid-liver interactions in CIH-associated hepatic steatosis.IMPORTANCEObstructive sleep apnea (OSA) is increasingly recognized as a contributor to metabolic dysfunction, yet its role in hepatic steatosis independent of obesity remains incompletely understood. This study shows that chronic intermittent hypoxia (CIH), a defining pathological feature of OSA, is sufficient to induce hepatic steatosis and inflammation in lean mice, independent of dietary manipulation. These findings broaden current understanding of OSA-associated liver disease beyond the context of obesity and metabolic syndrome. By integrating metagenomic sequencing, plasma metabolomics, and liver transcriptomics, this work highlights coordinated alterations in gut microbial composition, bile acid profiles, and hepatic lipid-related transcriptional programs associated with CIH exposure. Depletion of Bacteroides uniformis and elevation of deoxycholic acid were linked to CIH-induced hepatic phenotypes and were sensitive to antibiotic intervention, supporting a contributory role of gut microbiota-bile acid interactions in this process. Together, these findings underscore the potential importance of gut microbiota-host metabolic crosstalk in OSA-associated hepatic steatosis and suggest that microbiota- or bile acid-targeted strategies may warrant further investigation as adjunctive approaches for risk stratification and therapeutic intervention in OSA-related liver disease.