Farnesoid X receptor-dependent microbiome-bile acid signaling mediates obstructive sleep apnea-induced atherosclerosis
Intermittent hypoxia and hypercapnia (IHC), a hallmark of obstructive sleep apnea (OSA), accelerates atherosclerosis, yet the underlying mechanisms remain unclear. The gut microbiota and metabolites, specifically bile acids, change with IHC and thus the bile acid receptor farnesoid X receptor (FXR) might mediate IHC-induced atherosclerosis. In this study, ApoE-/- and ApoE-/- FXR-/- mice were exposed to IHC or room air and fed with a high-fat, high-cholesterol diet for 10 weeks. Markers of atherosclerosis, fecal microbiome, and metabolome were then examined via Sudan IV staining, absolute abundance shotgun metagenomics, and untargeted liquid chromatography tandem mass spectrometry (LC-MS/MS). IHC markedly increased aortic atherosclerosis in ApoE-/-mice, an increase that was abolished by FXR deficiency. In addition, IHC reshaped gut microbial composition, promoting enrichment of bile acid-modifying taxa and increasing levels of microbial hydroxysteroid dehydrogenase (hsdh). The bile acid pool was also remodeled and associated with aortic atherosclerosis via FXR-dependent metabolic signals in ApoE-/- mice. Knockout of FXR disrupted microbiome shift under IHC and uncoupled microbial bile acid metabolism from vascular lesion development, thereby protecting against aortic atherosclerosis. These findings show that FXR has a central role in linking IHC, microbial bile acid metabolism, and cardiovascular pathology.