Reconstitution of gut microbiota by medicinal plant isoflavones ameliorates heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome with limited therapeutic options. Gut microbiota and microbiota-derived metabolites impact the progression and severity of HFpEF-related cardiometabolic dysfunctions. Here, we demonstrated that the isoflavone extract of Pueraria lobata (Iso-Pl), puerarin, or its microbial metabolite S-equol, improved left ventricular diastolic dysfunctions, reduced hypertension, and ameliorated metabolic disorders in an HFD and L-NAME-induced HFpEF mouse model. Antibiotic depletion and fecal microbiota transplantation experiments revealed an important contribution of gut microbiota to Iso-Pl efficacy. It reshaped gut microbiota composition and function, and reprogrammed microbial-mediated lysine and phenylalanine metabolism. Metabolomics analysis confirmed that Iso-Pl enhanced the production of beneficial metabolites, butyrate and S-equol, while reducing the lysine and phenylalanine-related trimethyllysine (TML) and phenylacetylglycine (PAGly) that have been reported to accumulate and aggravate HFpEF. Moreover, treatment with Iso-Pl, puerarin, and S-equol upregulated estrogen receptor β (ESR2) and activated the downstream eNOS-cGMP-PKG signaling axis in mice, while concurrently inhibiting the pro-inflammatory mitogen-activated protein kinase (MAPK) pathway. These activities collectively contributed to the alleviation of HFpEF by Iso-Pl. Collectively, our findings demonstrate that the cardioprotective effects of Iso-Pl are closely linked with the gut microbiota-dependent metabolic reprogramming and highlight P. lobata isoflavones as promising therapeutic agents for HFpEF.