Gut dysbiosis and neutrophil extracellular traps in chronic heart failure

Chronic heart failure (HF) patients have reduced microbiota diversity. Leakage of microbes and their metabolites into the bloodstream may activate neutrophils. Neutrophil extracellular traps (NETs) consist of chromatin and proteases, and may contribute to HF pathogenesis. We assessed associations between circulating NETs and 1) cardiac function, 2) the degree of gut microbiota diversity and 3) gut leakage and microbial metabolites in HF patients.

A cross-sectional study including 124 patients with chronic HF and left ventricular ejection fraction ≤40 %. Severe HF was defined as N-terminal pro-B-type natriuretic peptide concentrations above median. We measured citrullinated histone H₃ (CitH₃), myeloperoxidase- and double-stranded-DNA in the blood. Gut leakage markers included bacterial lipopolysaccharides and soluble cluster of differentiation 14. The microbial metabolites included circulating trimethylamine N-oxide and butyrate producing capacity. We used the Shannon diversity-index and a dysbiosis-index based on bacteria with altered relative abundance to characterize the gut microbiota profile.

Quartile 4 of CitH₃ was associated with more severe HF compared to quartiles 1-3, after adjustments for age, gender and hypertension (adjusted odds ratio [95 %CI] 3.21[1.18-8.69], p = 0.022). CitH₃ was moderately associated with hypertension (p = 0.04), higher CRP levels (p = 0.016) and lower Shannon diversity index_, (p = 0.039). No other NET marker associated with severe HF.

In chronic HF patients with reduced LVEF, high levels of CitH₃ were associated with disease severity, inflammation and reduced gut microbiota diversity. Our results suggest that enhanced release of NETs could be involved in progressive HF, although the contribution of the gut microbiota seems limited in this context.