Candida albicans accelerates atherosclerosis by activating intestinal hypoxia-inducible factor2α signaling.
Cell Host Microbe
; 32(6): 964-979.e7, 2024 Jun 12.
Article
in En
| MEDLINE
| ID: mdl-38754418
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Candida albicans
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Signal Transduction
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Ceramides
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Atherosclerosis
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Basic Helix-Loop-Helix Transcription Factors
Limits:
Animals
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Female
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Humans
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Male
Language:
En
Journal:
Cell Host Microbe
Journal subject:
MICROBIOLOGIA
Year:
2024
Document type:
Article