mouse gut metagenome Targeted Locus (Loci)

Heart Failure with preserved Ejection Fraction (HFpEF) is a common, complex disease with multiple comorbidities, including obesity, diabetes, and hypertension. To understand these relationships, we performed multi-omics analyses of metabolic remodeling of heart tissue in a HFpEF mouse model. We found that indole-3- propionic acid (IPA), a metabolite derived from gut bacteria, was substantially decreased in both heart tissue and circulation in HFpEF mice as compared to controls. IPA was similarly reduced in plasmas of two independent cohorts of HFpEF patients as compared to controls. In HFpEF mice, IPA supplementation attenuated gut dysbiosis, intestinal barrier damage, and metabolic remodeling, and protected against diastolic dysfunction. Mechanistically, IPA restored nicotinamide, NAD + /NADH and SIRT3 in the heart of HFpEF mice, mitigating inflammation and oxidative stress. Nicotinamide supplementation or suppression of NNMT, an enzyme that catalyzes nicotinamide degradation, resulted in a similar protective effect on the heart as IPA, including attenuated metabolic and diastolic dysfunction. Notably, nicotinamide, IPA, or the combination of the two, all reduced diastolic dysfunction to the same extent, suggesting that they affect a common pathway. Together, our findings reveal protective effects of gut microbe-heart crosstalk mediated by IPA in the progression of HFpEF and suggest potential therapeutic strategies.