Abstract Body (Do not enter title and authors here): Background: Without timely intervention, pressure-overloading left ventricular (poLV) remodeling may become progressive and readily degenerate into heart failure. The relative risk is especially high in children with congenital heart disease who are awaiting surgical correction.
Aims: The aims of this study were to identify a plasma metabolite that is clinically and mechanically linked to poLV remodeling and heart failure in children and investigate a safe, efficacious treatment that blocks its action.
Methods: We used multi-omics including untargeted metabolomics on the plasma of poLV children and neonatal ascending aorta constriction (nAAC) mice, whole-transcriptome resequencing and single-nucleus RNA sequencing of mouse and human LV samples, and metagenomics analysis of mouse gut microbiota to disclose the gut microbiota-kynurenine (Kyn)-remodeling axis. Aryl hydrocarbon receptor (AHR) knockout mice and germ-free (GF) mice as well as fecal microbiota transplantation were used to clarify its mechanism.
Results: Abnormally elevated plasma kynurenine (Kyn) was detected in both the patient cohort and the mouse model. Plasma Kyn levels were clinically associated with the cardiac functions and the degree of remodeling. Excessive Kyn induced the hypertrophy and fibrosis phenotypes both in vitro and in vivo, which was blocked by AHR inhibitors and by AHR knockout, respectively. It was demonstrated that Kyn affected both cardiomyocytes and cardiac fibroblasts by promoting AHR nuclear translocation, initiating ADAMTS2 transcription which accelerates hypertrophy, and inducing FN1 and COL1A1 which exacerbate fibrosis. There were significant alterations in the gut microbiota of nAAC mice.Transplantation of nAAC mouse feces to GF mice augmented their Kyn level, indicating the existence of a gut microbiota-Kyn relationship. Oral probiotic supplementation reconstructed the gut microbiota in the nAAC mice, modulated the Kyn-AHR axis, and alleviated poLV remodeling.
Conclusions: Plasma Kyn levels were strongly correlated with cardiac remodeling and function in pediatric patients and mice with poLV. Kyn is a pathological signal from an altered gut microbiota to activates AHR and its gene targets in poLV remodeling heart, promoting hypertrophy and fibrosis in respective cells. Oral probiotics reshaped the gut microbiota, lowered Kyn levels, and showed great potential at delaying cardiac remodeling and preventing heart failure.