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

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 Sirt3 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, Nnmt knockdown, and Nnmt 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.

From Gut to Heart: Role of Indole-3-Propionic Acid in HFpEF

“…IPA, the product of degradation of tryptophan by gut microbiota, has been recently recognized for its beneficial role in mitigating systemic inflammation and oxidative damage. 9 Intriguingly, the study by Wang et al 8 proposes that gut microbiota dysbiosis occurring in the 2-hit mouse model of HFpEF 3 reduces plasmatic and cardiac IPA levels. Importantly, a reduction in IPA plasma levels was also found in 2 independent human cohorts of patients with HFpEF.…”

Modulating commensal bacteria to intervene in cancer immunotherapy

“… 7 Recent studies have also focused on the role of indole derivatives in regulating the physiological functions of organs and in the development of disease. Among these, IPA has been shown to promote nerve regeneration and repair, 8 prevent ejection fraction and heart failure, 9 and prolong survival in rats with traumatic colon injury, 10 but its role in cancer immunotherapy has not yet been clarified.…”