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Updated: Jun 26, 2025
An Ex vivo Assay to Study Candida albicans Hyphal Morphogenesis in the Gastrointestinal Tract
Published on: July 1, 2020
Candida albicans accelerates atherosclerosis by activating intestinal hypoxia-inducible factor2α signaling
Xuemei Wang1, Shuang Zhou1, Xiaomin Hu2
1Department 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.
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.
Insights
Gut fungi imbalance, specifically Candida albicans, is linked to higher cholesterol and atherosclerosis. Targeting the gut
Area of Science:
- Microbiology
- Cardiovascular Science
- Metabolic Disease
Background:
- The gut microbiota's role in atherosclerosis is established, but intestinal fungi's contribution remains unclear.
- Dyslipidemia, a risk factor for atherosclerosis, involves altered lipid profiles.
- Candida albicans is a common gut fungus with potential pathogenic roles.
Purpose of the Study:
- To investigate the role of intestinal fungi, particularly Candida albicans, in atherosclerosis.
- To elucidate the molecular mechanisms linking Candida albicans to atherosclerosis progression.
- To explore the therapeutic potential of targeting the identified pathway.
Main Methods:
- Analysis of gut fungi and plasma lipids in dyslipidemia patients.
- Colonization of a mouse atherosclerosis model with Candida albicans.
- Gain- and loss-of-function studies to investigate the hypoxia-inducible factor 2α (HIF-2α)-ceramide pathway.
- Administration of HIF-2α antagonist PT2385 in mice.
Main Results:
- Gut fungi dysbiosis, with increased Candida albicans, correlates with higher total cholesterol and LDL-C in dyslipidemia patients.
- Candida albicans colonization exacerbates atherosclerosis in mice.
- Candida albicans activates intestinal HIF-2α signaling via formyl-methionine, increasing ceramide synthesis and accelerating atherosclerosis.
- PT2385 treatment reduces ceramide levels and alleviates atherosclerosis in mice.
Conclusions:
- Intestinal fungi, specifically Candida albicans, play a significant role in atherosclerosis progression.
- The intestinal HIF-2α-ceramide pathway is a key mediator of Candida albicans' effects on atherosclerosis.
- Targeting the HIF-2α-ceramide pathway presents a potential therapeutic strategy for atherosclerosis.
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