Dapagliflozin-affected endothelial dysfunction and altered gut microbiota in mice with heart failure

Abstract

Aim To investigate the potential microbiome profile of a mouse model with heart failure (HF) during dapagliflozin treatment. Method An HF model was constructed in 8-week-old male mice, and cardiac tissues were analyzed using histological staining. Hemodynamic indexes were measured, and fecal samples were collected for 16S rDNA sequencing. Chao1, Shannon, and Simpson were used for α-diversity analysis. b-Diversity analysis was conducted using principal coordinate analysis (PCoA) and non-metric multidimensional scaling (NMDS) based on the Bray–Curtis distance. Linear discriminant analysis coupled with effect size measurements (LEfSe) was used to identify signature gut microbiota, and phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) was used to predict the function of altered gut microbiota. Result Dapagliflozin treatment reduced inflammation, infarction area, and cardiac fibrosis in HF mice. It also increased endothelial-dependent dilation and inflammation in mice with HF. Dapagliflozin decreased the ratio of Firmicutes/Bacteroidetes, which was increased in HF mice. There was no significant statistical difference in α-diversity among the control, HF, and HF+dapagliflozin groups. Desulfovibrio, AF12, and Paraprevotella were enriched in HF+dapagliflozin, while Rikenella and Mucispirillum were enriched in HF based on LEfSe. KEGG analysis revealed that altered gut microbiota was associated with fermentation, amino acid biosynthesis, nucleoside and nucleotide biosynthesis/degradation, fatty acid and lipid biosynthesis, carbohydrate biosynthesis/degradation, and cofactor/prosthetic group/electron carrier/vitamin biosynthesis. Conclusion Understanding the microbiome profile helps elucidate the mechanism of dapagliflozin for HF. The signature genera identified in this study could be used as a convenient method to distinguish between HF patients and healthy individuals.

Current Role of SLGT2 Inhibitors in the Management of the Whole Spectrum of Heart Failure: Focus on Dapagliflozin

“…These clinical beneficial effects of dapagliflozin rely on several pathophysiologica mechanisms that have been investigated in different experimental and clinical studies Thus, experimental studies have shown in different animal models with HF that dapagli flozin inhibits ventricular remodeling, attenuates cardiometabolic dysregulation and dia betes-induced diastolic dysfunction, reduces cardiac fibrosis and inflammation, improve These clinical beneficial effects of dapagliflozin rely on several pathophysiological mechanisms that have been investigated in different experimental and clinical studies. Thus, experimental studies have shown in different animal models with HF that dapagliflozin inhibits ventricular remodeling, attenuates cardiometabolic dysregulation and diabetesinduced diastolic dysfunction, reduces cardiac fibrosis and inflammation, improves aorta sympathetic tone and endothelial dysfunction [109][110][111][112][113][114][115][116][117][118]. The impact of dapagliflozin on cardiac remodeling has been confirmed in patients with chronic HF in the DAPA-MODA study, with significant improvements in left atrial volume, left ventricular geometry parameters and natriuretic peptides levels, after only 6 months of treatment [119].…”

Gut–Kidney–Heart: A Novel Trilogy

“…Paraprevotella has been identified as a noteworthy bacterium implicated in cardiac structural and functional impairment in a rat model of heart failure. Desulfovibrio, as a detrimental genus, has a role as a pivotal sulfate-reducing bacterium in the gut microbiota, introducing hydrogen sulfide and lipopolysaccharide into compromised tissues [177]. Another antidiabetic drug that appears to be able to modulate the microbiome is acarbose, an intestinal alpha-glucosidase inhibitor.…”

Effects and mechanisms of nutritional interventions on extradigestive complications in obese patients

“…Obesity is a metabolic disease correlated to an increased risk of multiple extradigestive complications. Nutritional intervention, a crucial management tool, can positively affect weight management, associated disease risk control, and the occurrence of extradigestive complications in patients with obesity by modifying the dietary structure and providing appropriate nutrients[ 1 - 5 ]. The global prevalence of obesity is increasing and is closely related to the development of extradigestive complications, such as cardiovascular disease (CVD), type 2 diabetes mellitus, and non-alcoholic fatty liver disease (NAFLD).…”