Fuzi decoction treats chronic heart failure by regulating the gut microbiota, increasing the short-chain fatty acid levels and improving metabolic disorders.

Fuzi decoction (FZD) is clinically used to treat chronic heart failure (CHF) in China, but the mechanism underlying FZD treatment in CHF remains unclear. Here, we investigated the potential mechanism underlying FZD treatment of CHF in rats. First, the compounds in FZD-containing serum of rats were identified, and 16 S rRNA sequencing and GC-MS-based untargeted metabolomics analysis were then performed. The levels of fecal short-chain fatty acids (SCFAs) were determined and compared, and fecal microbiota transplantation (FMT) was used to verify the role of the gut microbiota. Our results identified 27 in FD-containing serum. FZD increased the Firmicutes-to-Bacteroidetes ratio and the Lactobacillus abundance and affected the β diversity of the gut microbiota in rats with CHF. Differential species analysis showed that Lactobacillus and Prevotella were biomarkers of FZD treatment of CHF. Untargeted metabolomics analysis revealed that FZD affected valine, leucine and isoleucine biosynthesis; galactose metabolism; and aminoacyl-tRNA biosynthesis in rats with CHF. Furthermore, FZD significantly increased the acetic acid, propionic acid, butyric acid and isopentanoic acid levels in the feces of rats with CHF. Correlation analysis showed that the butyric acid and Lactobacillus levels had the strongest correlation in the control, sham and high-dose FZD (HFZD) groups, and many microbiota components were closely related to differentially abundant metabolites. FMT revealed that the fecal microbiota obtained from the HFZD group changed the heart rate; the brain natriuretic peptide (BNP), acetic acid, propionic acid, butyric acid, and metabolite levels; and the gut microbiota in rats with CHF. In summary, our study revealed that the mechanism of action of FZD in CHF treatment may be related to improvements in the gut microbiota, elevations in the SCFA content and the regulation of valine, leucine, and isoleucine biosynthesis; galactose metabolism; and other metabolic pathways.