# Associations Between Gut Microbiota and Mitochondrial Metabolites, with Growth Differentiation Factor-15 as a Marker of Oxidative Stress in Heart Failure vs. Healthy Ageing

## TL;DR

This study explores how gut microbes and mitochondrial metabolites relate to oxidative stress in heart failure and healthy aging, using GDF-15 as a marker.

## Contribution

The study identifies gut microbiota-derived metabolites and mitochondrial markers associated with GDF-15 in heart failure and aging.

## Key findings

- Higher GDF-15 levels correlate with heart failure severity, fat mass, and inflammation markers.
- Gut metabolites like hippuric acid and sarcosine show distinct patterns in heart failure versus healthy aging.
- Pyruvic and fumaric acid drive GDF-15 in heart failure, indicating mitochondrial stress.

## Abstract

Growth differentiation factor-15 (GDF-15) is an established marker of oxidative stress and a general stress-response mitokines. In this study, we aim to investigate the association of GDF-15 with the metabolic signature of gut and mitochondrial activity in HF and ageing population. A total of 25 HF (67.9 ± 10.0 years) and 29 age-matched healthy participants (HPs) (67.8 ± 11.1 years) were recruited and underwent detailed body composition assessment via dual X-ray absorptiometry; total fat mass and appendicular lean soft tissue index (ALSTI/body mass index (BMI)) were calculated. Utilizing semi-targeted Gas Chromatography–Mass Spectrometry on fasting plasma, a panel of gut microbial-derived (e.g., hippuric acid, indole derivatives, and sarcosine) and tricarboxylic acid cycle metabolites was identified. Results showed higher GDF-15 tertiles were associated with greater HF prevalence, fat mass, NT-proBNP, and TNF-α (p < 0.05). Gut-derived metabolites exhibited phenotype-specific patterns; 3-hydroxyindole predicted higher fat mass in HP; hippuric acid was inversely related in HF; and sarcosine correlated with GDF-15 only in HP. In HF, GDF-15 was strongly driven by pyruvic and fumaric acid, indicating disease-specific mitochondrial stress. In conclusion, these observed associations could be evaluated in future mechanistic studies as sensitive biomarkers of systemic oxidative stress markers, informing potential microbiome-targeted therapeutic avenues.