A Rat Model of Chronic Heart Failure Combined with Intestinal Dysfunction and Alterations in the Microbiome and Metabolomics

Abstract

Abstract Intestinal dysfunction (ID) is considered a critical comorbidity of chronic heart failure (CHF) and can exacerbate the condition. The pathophysiology underlying chronic heart failure combined with intestinal dysfunction (CHF&ID) remains elusive, and animal models are lacking. In this study, we compared four modeling methods, abdominal aortic constriction (AAC), transverse aortic constriction (TAC), TAC combined with cecum ligation (TAC + CL), and AAC combined with cecum ligation (AAC + CL), to establish a rat CHF&ID model. The results demonstrated that TAC + CL elicited a significant elevation in B-type natriuretic peptide (BNP) and trimethylamine N-oxide (TMAO) levels, accompanied by a notable decrease in heart function as assessed by echocardiography. Moreover, this method induced myocardial fibrosis, and cardiomyocyte hypertrophy in rats. Additionally, it was found to induce mechanical barrier damage to the small intestinal, including disorganization of epithelial structure, and increased diamine oxidase (DAO) and lipopolysaccharide (LPS) in rats. Afterward, analysis of the cecal intestinal microbiota using 16S rRNA sequencing technology revealed significant alterations in CHF&ID rats, characterized by an increased abundance of Bacteroides, Ruminococcaceae_UCG-005, NK4A214_group, Family_XIII_AD3011_group, Lachnospiraceae_UCG-010, and Bifidobacterium (p < 0.05), as well as a decreased abundance of Roseburia, Oscillibacter and Tuzzerella (p < 0.05). Detection of serum metabolites by the LC‒MS coupling technique revealed that LysoPC (0:0/18:2(9Z,12Z)), LysoPC (18:3(9Z,12Z,15Z)/0:0), PC (17:1(9Z)/0:0), glycoursodeoxycholic acid were upregulated. Correlation analysis showed that the intestinal microbiota was significantly associated with several lipid metabolites, cardiac remodeling and leaky gut indicators. These results suggest that intestinal microbiota disorders and serum metabolites crosstalk with each other to induce the development of CHF&ID.