期刊
JOURNAL OF THE AMERICAN HEART ASSOCIATION
卷 10, 期 22, 页码 -出版社
WILEY
DOI: 10.1161/JAHA.121.022722
关键词
gut microbiome; intermittent fasting; Lactobacillus; lipotoxicity; metabolism; metabolomics; pulmonary arterial hypertension; right ventricular function
资金
- National Institutes of Health (NIH) [F32 HL154533]
- NIH [T32 HL144472, K08 HL140100]
- University of Minnesota Clinical and Translational Science award [NIH UL1 TR002494]
- University of Minnesota Medical School Academic Investment Educational Program Grant
- University of Minnesota Institute for Engineering in Medicine COVID--19 Rapid Response Grant
- University of Minnesota Medical School and College of Science and Engineering
- Cardiovascular Medical Research and Education Fund
- University of Minnesota Futures Grant
- Lillehei Heart Institute Cardiovascular Seed Grant
- University of Minnesota Faculty Research Development Grant
- United Therapeutics Jenesis Award
- American Lung Association Innovative Award [IA-816386]
Intermittent fasting (IF) improves right ventricular function, increases survival rate, reduces cardiomyocyte hypertrophy and fibrosis, prevents lipid accumulation, and enhances gut microbiota profile in pulmonary arterial hypertension (PAH), suggesting it may be a non-pharmacological approach to combat RV dysfunction in PAH.
Background Intermittent fasting (IF) confers pleiotropic cardiovascular benefits including restructuring of the gut microbiome and augmentation of cellular metabolism. Pulmonary arterial hypertension (PAH) is a rare and lethal disease characterized by right ventricular (RV) mitochondrial dysfunction and resultant lipotoxicity and microbiome dysbiosis. However, the effects of IF on RV function in PAH are unexplored. Therefore, we investigated how IF altered gut microbiota composition, RV function, and survival in the monocrotaline model of PAH. Methods and Results Male Sprague Dawley rats were randomly allocated into 3 groups: control, monocrotaline-ad libitum feeding, and monocrotaline-IF (every other day feeding). Echocardiography and invasive hemodynamics showed IF improved RV systolic and diastolic function despite no significant change in PAH severity. IF prevented premature mortality (30% mortality rate in monocrotaline-ad libitum versus 0% in monocrotaline-IF rats, P=0.04). IF decreased RV cardiomyocyte hypertrophy and reduced RV fibrosis. IF prevented RV lipid accrual on Oil Red O staining and ceramide accumulation as determined by metabolomics. IF mitigated the reduction in jejunum villi length and goblet cell abundance when compared with monocrotaline-ad libitum. The 16S ribosomal RNA gene sequencing demonstrated IF changed the gut microbiome. In particular, there was increased abundance of Lactobacillus in monocrotaline-IF rats. Metabolomics profiling revealed IF decreased RV levels of microbiome metabolites including bile acids, aromatic amino acid metabolites, and gamma-glutamylated amino acids. Conclusions IF directly enhanced RV function and restructured the gut microbiome. These results suggest IF may be a non-pharmacological approach to combat RV dysfunction, a currently untreatable and lethal consequence of PAH.
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