Abstract Body (Do not enter title and authors here): Background: Diabetic cardiomyopathy (DCM) is one of the most serious complications of diabetes mellitus (DM). However, studies exploring the roles of gut microbiome in DM and cardiovascular disease remain limited.
Hypothesis: Gut microbiota dysbiosis is associated with the development of DCM.
Methods: We collected fecal and serum samples from 18 DCM patients and 13 matched control subjects for metagenomic and metabolomic analysis. Fecal microbiota transplantation (FMT) with samples from both groups was performed on the pseudo-germ-free (PGF) rats. Then, we analyzed rat gut microbiota by 16S rDNA sequencing, and examined cardiac parameters and blood glucose indicators of PGF rats. Serum and myocardium metabolomic analysis was performed on DCM rats and compared with human samples.
Results: Linear Discriminant Analysis Effect Size (p＜0.05, LDA≥2.0) of the metagenomics data identified 11 gut microbiota, which can be used as the DCM patient’s biomarkers. After FMT, compared to control-PGF rats, DCM-PGF rats showed significant differences in the composition of gut microbiota (α-diversity, simpson p=0.015, shannon p=0.011; β-diversity p= 0.005). Moreover, DCM-PGF rats had higher fasting blood glucose levels (p=0.036), intraperitoneal glucose tolerance test showed higher blood glucose levels at 15 and 30 minutes (p=0.000, 0.030), left ventricular (LV) end systolic diameter was larger (p=0.009), diastolic and systolic LV anterior wall thickness, and systolic LV posterior wall thickness were thicker (p=0.011, 0.035, 0.036), fibrosis area was larger (p=0.022). When comparing metabolic profiles of serum of DCM patients, serum of DCM rats and the myocardium of DCM model with the corresponding controls, we identified 2 shared differential metabolites: Hydroxybutyric acid and 15,16-DiHODE. Spearman correlation analysis of these two metabolites with differential gut microbiota species in DCM patients vs. control subjects showed that Hydroxybutyric acid and 15,16-DiHODE are strongly correlated with 7 species (p＜0.05, r＞|0.5|) and with 23 species (p＜0.05, r＞|0.5|) respectively.
Conclusions: Our study found that DCM patients have their characteristic altered gut microbiota and serum metabolites, which may be responsible for the development of DCM. Gut microbiota is expected to be a potential target for therapeutic intervention in DCM.