Circulating metabolites in patients with chronic heart failure are related to increased lipid utilisation but not to gut microbiota alterations

Abstract Background The gut microbiota produces numerous metabolites that can enter the circulation and exert their effects outside the gut. Some have been implicated in the pathogenesis of chronic heart failure (HF). Several studies have reported altered gut microbiota composition and circulating metabolites in patients with chronic HF compared to healthy controls (HC). However, limited data is available on the potential interplay between the dysbiotic features of the gut microbiota and the altered circulating metabolome in these patients. Purpose To examine differences in circulating metabolites between patients with chronic HF and HC, and their association with cardiac function and gut dysbiosis. Methods We included 123 patients, aged 18-75 years, with stable chronic HF and left ventricular ejection fraction (LVEF) <40%, and 51 HC. We collected fasting blood samples for metabolomic and lipidomic analyses, which were performed using liquid chromatography tandem mass spectrometry. A web-based platform was utilised for data preprocessing, filtering, pathway analysis, and metabolite annotation. Principal component analysis and orthogonal partial least squares discriminant analysis were used to explore differences in plasma metabolic profiles. Over-representation analysis was performed to identify the pathways in which relevant metabolites were involved. Stool samples were sequenced using 16S ribosomal RNA gene amplification. We calculated a dysbiosis index for each sample based on different abundances of microbial taxa in patients vs. controls. Results After adjusting for age and sex, we identified 73 enriched metabolites and 27 enriched lipids (odds ratio≥2 and p<0.05), and 124 depleted metabolites and 6 depleted lipids (odds ratio≤0.5 and p<0.05) in HF patients compared to HC. The enriched metabolites were involved in pathways related to lipid metabolism (beta oxidation, glycerolipid, sex hormone, and fatty acid metabolism), pyrimidine metabolism, Warburg effect, citric acid cycle, and pentose phosphate pathway. The depleted metabolites were involved in pathways related to lipid biosynthesis (fatty acids, steroids, bile acids), amino acid metabolism (glycine, serine, taurine, hypotaurine, cysteine, selenoamino acids), polyamine biosynthesis (spermidine, spermine), sulphate/sulphite metabolism, propanoate and pyruvate metabolism, carbohydrate metabolism (galactose, amino sugars, glycolysis), transfer of acetyl groups into mitochondria, urea cycle, and beta oxidation of very long chain fatty acids (Figure 1). LVEF, N-terminal pro B-type natriuretic peptide, and the dysbiosis index were not significantly related to any metabolite. Conclusions In patients with chronic HF, energy metabolism is significantly altered compared to HC, with a notable shift towards lipid utilisation. However, the alterations in circulating metabolites were not related to markers of cardiac function and appear to be unrelated to gut dysbiosis.Figure 1