Pueraria lobata isoflavones and their microbial metabolites improved heart failure with preserved ejection fraction in mice through gut microbiota-dependent metabolic reprogramming.
Does isoflavone extract of Pueraria lobata (Iso-Pl) improve left ventricular diastolic dysfunctions and metabolic disorders in an HFD and L-NAME-induced HFpEF mouse model?
Pueraria lobata isoflavones ameliorate HFpEF in a mouse model through gut microbiota-dependent metabolic reprogramming and activation of the ESR2/eNOS-cGMP-PKG signaling axis.
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. • Pueraria lobata Isoflavone (Iso-Pl) improves HFpEF in microbiota-depended manner. • Iso-Pl reshapes gut microbiota and reprograms lysine/phenylalanine metabolism. • Iso-Pl increases butyrate and S -equol, decreases TML and PAGly. • Puerarin, or Iso-Pl microbial metabolite S -equol improve HFpEF. • Iso-Pl and S -equol upregulate ESR2/eNOS-cGMP-PKG and inhibit the MAPK pathway.
Lin et al. (2026) studied this question. Pueraria lobata isoflavones and their microbial metabolites improved heart failure with preserved ejection fraction in mice through gut microbiota-dependent metabolic reprogramming.