UCLA researchers in the Department of Medicine, Division of Cardiology have identified the protective effects of gut-heart crosstalk mediated by 3-propionic acid (IPA) in the progression of heart failure with preserved ejection fraction (HFpEF). IPA supplementation could rescue the IPA deficiency associated heart defects, protect against heart malfunction, and serve as a treatment for HFpEF.
BACKGROUND: Heart failure is one of the leading causes of death and disease with over 500,000 cases diagnosed each year in the United States and over 60 million worldwide. Heart failure with preserved ejection fraction (HFpEF) refers to the condition of which the heart pumps less blood out to the body than is needed, also termed diastolic dysfunction. HFpEF is found in approximately ~50% heart failure cases. HFpEF is a complex disorder with multiple comorbidities such as obesity, diabetes, hypertension, and inflammation. HFpEF remains an unsolved biological and clinical problem of immense significance, but microbe-derived metabolites and mechanisms associated with the gut microbiota may provide a clue to the development of potential therapies. In humans, gut microbes metabolize tryptophan into various indole derivatives, including indole-3-propionic acid (IPA). IPA has been implicated in reduction of inflammation and cell oxidative damage, as well as reported to improve glucose metabolism and attenuate steatohepatitis. Not surprisingly, elevated concentrations of IPA in human blood plasma were correlated with a lower risk of type 2 diabetes. However, the underlying relationship between IPA and cardiometabolic diseases, especially HFpEF, remains to be identified.
INNOVATION: UCLA researchers have demonstrated that IPA benefit diastolic function in HFpEF by revealing the link between diet, gut bacteria, and metabolic homeostasis. Metabolic profiling of heart tissue with a HFpEF mouse models revealed that IPA was dramatically decreased in both heart tissue and circulation. This was accompanied by metabolic remodeling, gut dysbiosis, increased oxidative stress and inflammation in the heart. In these models, IPA supplementation increased IPA levels in the heart and circulation and attenuated diastolic dysfunction induced by the HFpEF diet. Furthermore, IPA supplementation mitigated gut microbiota dysbiosis and intestinal epithelial barrier damage, reduced body mass and improved metabolic homeostasis. In the heart, IPA restored nicotinamide, NAD+/NADH and SIRT3 levels induced by HFpEF, attenuating inflammation and oxidative stress. The cardioprotective impact of IPA has now been elucidated, opening the door for potential use in clinical settings.
POTENTIAL APPLICATIONS:
- Therapy for heart failure with preserved ejection fraction (HFpEF)
- Early preventative treatment
- Administration following heart events or surgery
ADVANTAGES:
- Treatment is based on metabolite naturally produced in the body
- Highlights and provides avenue for increasing NAD+/NADH and SIRT3 levels
DEVELOPMENT-TO-DATE: The therapeutic effect of this invention was validated in 30 inbred strains of mice, including both male and female mice. The first description of the complete invention was completed at 04/18/2020 and additional findings were submitted for publication in academic journals.
Related papers (from the inventors only): Wang YC, Koay YC, Pan C, Zhou Z, Tang W, Wilcox J, Li XS, Zagouras A, Marques F, Allayee H, Rey FE, Kaye DM, O'Sullivan JF, Hazen SL, Cao Y, Lusis AJ. Indole-3-Propionic Acid Protects Against Heart Failure With Preserved Ejection Fraction. Circ Res. 2024 Feb 16;134(4):371-389. doi: 10.1161/CIRCRESAHA.123.322381. Epub 2024 Jan 24. PMID: 38264909; PMCID: PMC10923103.
Keywords: 3-propionic acid, IPA, heart failure with preserved ejection fraction, HFpEF, Clostridium sporogenes, nicotinamide, NAD+/NADH, gut microbiota dysbiosis, diastolic dysfunction