Indole-3-Propionic Acid Protects Against Heart Failure With Preserved Ejection Fraction

Overview

Journal Circ Res

Specialty Cardiology & Vascular Diseases

Date 2024 Jan 24

PMID 38264909

Authors

Yu-Chen Wang

Yen Chin Koay

Calvin Pan

Zhiqiang Zhou

Wilson Tang

Jennifer Wilcox

Xinmin S Li

Alexia Zagouras

Francine Marques

Hooman Allayee

Federico E Rey

David M Kaye

John F OSullivan

Stanley L Hazen

Yang Cao

Aldons J Lusis

Affiliations

Soon will be listed here.

Abstract

Background: Heart failure with preserved ejection fraction (HFpEF) is a common but poorly understood form of heart failure, characterized by impaired diastolic function. It is highly heterogeneous with multiple comorbidities, including obesity and diabetes, making human studies difficult.

Methods: Metabolomic analyses in a mouse model of HFpEF showed that levels of indole-3-propionic acid (IPA), a metabolite produced by gut bacteria from tryptophan, were reduced in the plasma and heart tissue of HFpEF mice as compared with controls. We then examined the role of IPA in mouse models of HFpEF as well as 2 human HFpEF cohorts.

Results: The protective role and therapeutic effects of IPA were confirmed in mouse models of HFpEF using IPA dietary supplementation. IPA attenuated diastolic dysfunction, metabolic remodeling, oxidative stress, inflammation, gut microbiota dysbiosis, and intestinal epithelial barrier damage. In the heart, IPA suppressed the expression of NNMT (nicotinamide N-methyl transferase), restored nicotinamide, NAD/NADH, and SIRT3 (sirtuin 3) levels. IPA mediates the protective effects on diastolic dysfunction, at least in part, by promoting the expression of SIRT3. SIRT3 regulation was mediated by IPA binding to the aryl hydrocarbon receptor, as knockdown diminished the effects of IPA on diastolic dysfunction in vivo. The role of the nicotinamide adenine dinucleotide circuit in HFpEF was further confirmed by nicotinamide supplementation, knockdown, and overexpression in vivo. IPA levels were significantly reduced in patients with HFpEF in 2 independent human cohorts, consistent with a protective function in humans, as well as mice.

Conclusions: Our findings reveal that IPA protects against diastolic dysfunction in HFpEF by enhancing the nicotinamide adenine dinucleotide salvage pathway, suggesting the possibility of therapeutic management by either altering the gut microbiome composition or supplementing the diet with IPA.

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References

Dodd D, Spitzer M, Van Treuren W, Merrill B, Hryckowian A, Higginbottom S . A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. Nature. 2017; 551(7682):648-652. PMC: 5850949. DOI: 10.1038/nature24661. View

Cao Y, Aquino-Martinez R, Hutchison E, Allayee H, Lusis A, Rey F . Role of gut microbe-derived metabolites in cardiometabolic diseases: Systems based approach. Mol Metab. 2022; 64:101557. PMC: 9399267. DOI: 10.1016/j.molmet.2022.101557. View

Hogg K, Swedberg K, McMurray J . Heart failure with preserved left ventricular systolic function; epidemiology, clinical characteristics, and prognosis. J Am Coll Cardiol. 2004; 43(3):317-27. DOI: 10.1016/j.jacc.2003.07.046. View

Dunlay S, Roger V, Redfield M . Epidemiology of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2017; 14(10):591-602. DOI: 10.1038/nrcardio.2017.65. View

Sundaresan N, Gupta M, Kim G, Rajamohan S, Isbatan A, Gupta M . Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J Clin Invest. 2009; 119(9):2758-71. PMC: 2735933. DOI: 10.1172/JCI39162. View

Verbrugge F, Omote K, Reddy Y, Sorimachi H, Obokata M, Borlaug B . Heart failure with preserved ejection fraction in patients with normal natriuretic peptide levels is associated with increased morbidity and mortality. Eur Heart J. 2022; 43(20):1941-1951. PMC: 9649913. DOI: 10.1093/eurheartj/ehab911. View

Komatsu M, Kanda T, Urai H, Kurokochi A, Kitahama R, Shigaki S . NNMT activation can contribute to the development of fatty liver disease by modulating the NAD metabolism. Sci Rep. 2018; 8(1):8637. PMC: 5988709. DOI: 10.1038/s41598-018-26882-8. View

Agus A, Planchais J, Sokol H . Gut Microbiota Regulation of Tryptophan Metabolism in Health and Disease. Cell Host Microbe. 2018; 23(6):716-724. DOI: 10.1016/j.chom.2018.05.003. View

Nikolajevic Starcevic J, Janic M, Sabovic M . Molecular Mechanisms Responsible for Diastolic Dysfunction in Diabetes Mellitus Patients. Int J Mol Sci. 2019; 20(5). PMC: 6429211. DOI: 10.3390/ijms20051197. View

10.

Wikoff W, Anfora A, Liu J, Schultz P, Lesley S, Peters E . Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci U S A. 2009; 106(10):3698-703. PMC: 2656143. DOI: 10.1073/pnas.0812874106. View

11.

Hage C, Lofgren L, Michopoulos F, Nilsson R, Davidsson P, Kumar C . Metabolomic Profile in HFpEF vs HFrEF Patients. J Card Fail. 2020; 26(12):1050-1059. DOI: 10.1016/j.cardfail.2020.07.010. View

12.

Venkatesh M, Mukherjee S, Wang H, Li H, Sun K, Benechet A . Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. Immunity. 2014; 41(2):296-310. PMC: 4142105. DOI: 10.1016/j.immuni.2014.06.014. View

13.

Bhanpuri N, Hallberg S, Williams P, McKenzie A, Ballard K, Campbell W . Cardiovascular disease risk factor responses to a type 2 diabetes care model including nutritional ketosis induced by sustained carbohydrate restriction at 1 year: an open label, non-randomized, controlled study. Cardiovasc Diabetol. 2018; 17(1):56. PMC: 5928595. DOI: 10.1186/s12933-018-0698-8. View

14.

Turnbaugh P, Ley R, Mahowald M, Magrini V, Mardis E, Gordon J . An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006; 444(7122):1027-31. DOI: 10.1038/nature05414. View

15.

Jia C, Hu Y, Kelly D, Kim J, Li M, Zhang N . Accounting for technical noise in differential expression analysis of single-cell RNA sequencing data. Nucleic Acids Res. 2017; 45(19):10978-10988. PMC: 5737676. DOI: 10.1093/nar/gkx754. View

16.

DeGroot D, Denison M . Nucleotide specificity of DNA binding of the aryl hydrocarbon receptor:ARNT complex is unaffected by ligand structure. Toxicol Sci. 2013; 137(1):102-13. PMC: 3924043. DOI: 10.1093/toxsci/kft234. View

17.

Dittenhafer-Reed K, Richards A, Fan J, Smallegan M, Fotuhi Siahpirani A, Kemmerer Z . SIRT3 mediates multi-tissue coupling for metabolic fuel switching. Cell Metab. 2015; 21(4):637-46. PMC: 4393847. DOI: 10.1016/j.cmet.2015.03.007. View

18.

Zheng S, Chan F, Nabeebaccus A, Shah A, McDonagh T, Okonko D . Drug treatment effects on outcomes in heart failure with preserved ejection fraction: a systematic review and meta-analysis. Heart. 2017; 104(5):407-415. PMC: 5861385. DOI: 10.1136/heartjnl-2017-311652. View

19.

Hubbard T, Murray I, Perdew G . Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation. Drug Metab Dispos. 2015; 43(10):1522-35. PMC: 4576673. DOI: 10.1124/dmd.115.064246. View

20.

Parodi-Rullan R, Chapa-Dubocq X, Javadov S . Acetylation of Mitochondrial Proteins in the Heart: The Role of SIRT3. Front Physiol. 2018; 9:1094. PMC: 6090200. DOI: 10.3389/fphys.2018.01094. View