2. Academic Validation
  3. Candida albicans accelerates atherosclerosis by activating intestinal hypoxia-inducible factor2α signaling

Candida albicans accelerates atherosclerosis by activating intestinal hypoxia-inducible factor2α signaling

  • Cell Host Microbe. 2024 May 13:S1931-3128(24)00137-9. doi: 10.1016/j.chom.2024.04.017.
Xuemei Wang 1,  Shuang Zhou 1,  Xiaomin Hu 2,  Chuan Ye 1,  Qixing Nie 1,  Kai Wang 1,  Sen Yan 3,  Jun Lin 1,  Feng Xu 4,  Meng Li 1,  Qing Wu 5,  Lulu Sun 6,  Bo Liu 7,  Yi Zhang 8,  Chuyu Yun 3,  Xian Wang 7,  Huiying Liu 1,  Wen-Bing Yin 9,  Dongyu Zhao 10,  Jing Hang 11,  Shuyang Zhang 12,  Changtao Jiang 13,  Yanli Pang 14
Affiliations

Affiliations

  • 1 Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Research on Major Immunology-related Diseases, Peking University, Beijing 100191, China; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China; Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
  • 2 Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.
  • 3 State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China; National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China.
  • 4 Clinical Pharmacology and Pharmacometrics, Janssen China Research & Development, Beijing, China.
  • 5 Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
  • 6 Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China; State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China.
  • 7 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China; Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
  • 8 Department of General Surgery, Cancer Center, Peking University Third Hospital, Beijing 100191, China; Center of Basic Medical Research, Institute of Medical Innovation and Research, Third Hospital, Peking University, Beijing 100191, China.
  • 9 State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
  • 10 State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China; Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
  • 11 State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China; National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China. Electronic address: [email protected].
  • 12 Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China. Electronic address: [email protected].
  • 13 Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Research on Major Immunology-related Diseases, Peking University, Beijing 100191, China; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China; Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Center of Basic Medical Research, Institute of Medical Innovation and Research, Third Hospital, Peking University, Beijing 100191, China. Electronic address: [email protected].
  • 14 State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China; National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China. Electronic address: [email protected].
PMID: 38754418 DOI: 10.1016/j.chom.2024.04.017
Abstract

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.

Keywords

Candida albicans; atherosclerosis; intestinal HIF-2α; intestinal fungal metabolites; intestinal fungi.

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