The gut microbiota is closely linked to atherosclerosis. However, the role of intestinal fungi, essential members of the complex microbial community, in atherosclerosis is poorly understood. Herein, we show that gut fungi dysbiosis is implicated in patients with dyslipidemia, characterized by higher levels of Candida albicans (C. albicans), which are positively correlated with plasma total cholesterol and low-density lipoprotein-cholesterol (LDL-C) levels. Furthermore, C. albicans colonization aggravates atherosclerosis progression in a mouse model of the disease. Through gain- and loss-of-function studies, we show that an intestinal hypoxia-inducible factor 2α (HIF-2α)-ceramide pathway mediates the effect of C. albicans. Mechanistically, formyl-methionine, a metabolite of C. albicans, activates intestinal HIF-2α signaling, which drives increased ceramide synthesis to accelerate atherosclerosis. Administration of the HIF-2α selective antagonist PT2385 alleviates atherosclerosis in mice by reducing ceramide levels. Our findings identify a role for intestinal fungi in atherosclerosis progression and highlight the intestinal HIF-2α-ceramide pathway as a target for atherosclerosis treatment.

肠道微生物群与动脉粥样硬化密切相关。然而，肠道真菌是复杂微生物群落的重要成员，在动脉粥样硬化中的作用却知之甚少。在此，我们发现肠道真菌失调与血脂异常患者有关，其特征是白色念珠菌（C. albicans）水平较高，与血浆总胆固醇和低密度脂蛋白胆固醇（LDL-C）水平呈正相关。此外，白色念珠菌的定植会加剧小鼠模型中的动脉粥样硬化进展。通过功能获得和功能丧失研究，我们表明肠道缺氧诱导因子 2α (HIF-2α)-神经酰胺途径介导白色念珠菌的作用。从机制上讲，白色念珠菌的代谢产物甲酰甲硫氨酸可激活肠道 HIF-2α 信号传导，从而促进神经酰胺合成增加，从而加速动脉粥样硬化。给予 HIF-2α 选择性拮抗剂 PT2385 通过降低神经酰胺水平来减轻小鼠动脉粥样硬化。我们的研究结果确定了肠道真菌在动脉粥样硬化进展中的作用，并强调肠道 HIF-2α-神经酰胺途径作为动脉粥样硬化治疗的靶点。