Gut microbiota, endotoxemia, inflammation, and oxidative stress in patients with heart failure, left ventricular assist device, and transplant

Abstract

Background: Gut microbial imbalance may contribute to endotoxemia, inflammation, and oxidative stress in heart failure (HF). Changes occurring in the intestinal microbiota and inflammatory/oxidative milieu during HF progression and following left ventricular assist device (LVAD) or heart transplantation (HT) are unknown. We aimed to investigate variation in gut microbiota and circulating biomarkers of endotoxemia, inflammation, and oxidative stress in patients with HF (New York Heart Association, Class I-IV), LVAD, and HT.

Methods: We enrolled 452 patients. Biomarkers of endotoxemia (lipopolysaccharide and soluble [sCD14]), inflammation (C-reactive protein, interleukin-6, tumor necrosis factor-α, and endothelin-1 adiponectin), and oxidative stress (isoprostane) were measured in 644 blood samples. A total of 304 stool samples were analyzed using 16S rRNA sequencing.

Results: Gut microbial community measures of alpha diversity were progressively lower across worsening HF class and were similarly reduced in patients with LVAD and HT (p < 0.05). Inflammation and oxidative stress were elevated in patients with Class IV HF vs all other groups (all p < 0.05). Lipopolysaccharide was elevated in patients with Class IV HF (vs Class I-III) as well as in patients with LVAD and HT (p < 0.05). sCD14 was elevated in patients with Class IV HF and LVAD (vs Class I-III, p < 0.05) but not in patients with HT.

Conclusions: Reduced gut microbial diversity and increased endotoxemia, inflammation, and oxidative stress are present in patients with Class IV HF. Inflammation and oxidative stress are lower among patients with LVAD and HT relative to patients with Class IV HF, whereas reduced gut diversity and endotoxemia persist in LVAD and HT.

Keywords: gut dysbiosis; heart failure; heart transplantation; inflammation; left ventricular assist device; oxidative stress.

Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Variation in circulating biomarkers of inflammation, oxidative stress, and endotoxemia across disease categories (HF Class I, II, III, IV, LVAD, and HT). (A) CRP. (B) IL-6. (C) TNF-α. (D) ET-1. (E) Adiponectin. (F) LPS. (G) sCD14. (H) Isoprostane. All p-values for linear trend across HF Class I – IV < 0.01 and all p-values for any difference across all patient categories < 0.001. Light bars: unadjusted. Dark bars: Adjusted for age, sex, and race/ethnicity. CRP, C-reactive protein; ET-1, endothelin-1; HF, heart failure; HT, heart transplantation; IL-6, interleukin-6; LPS, lipopolysaccharide; LVAD, left ventricular assist device; sCD14, soluble CD14; TNF-α, tumor necrosis factor-α.

Figure 2

Measures of alpha diversity across patient categories. (A) Shannon Index and (B) number of observed OTUs. Light bars: unadjusted. Dark bars: adjusted for age, sex, race/ethnicity, and antibiotic use. Multivariable adjusted p-values for any difference in Shannon Index = 0.48 and number of observed taxa = 0.66; both p-values derived from 5 df F-test. p-values for linear trend across HF Class I–IV for Shannon Index = 0.03 and number of observed taxa = 0.10. HF, heart failure; HT, heart transplantation; LVAD, left ventricular assist device; OTU, operationalized taxonomic unit.

Figure 3.

(A) Two principle coordinates are plotted, derived from the Bray-Curtis measure of beta diversity, summarizing similarity of gut microbial communities across patient categories. PCoA 1 explains 5.3% and PCoA 2 explains 3.7% of variation in microbial communities. p-value derived from PERMANOVA Adonis test of any difference across category = 0.09. (B) Means values of the first principle coordinate derived from the Bray-Curtis measure of beta diversity across patient category. Light bars: unadjusted. Dark bars: adjusted for age, sex, race/ethnicity, and antibiotic use. p-value for any difference across patient category <0.0001. The p-value for linear trend among patients with HF < 0.0001. HF, heart failure; HT, heart transplantation, LVAD, left ventricular assist device; PCoA, principal coordinates analysis; PERMANOVA, permutational multivariate analysis of variance.

Figure 4

Stacked bar chart summarizing gut microbiota phylum-level relative abundance across disease categories HF Class I, II, III, IV, LVAD, and HT. HF, heart failure; HT, heart transplantation; LVAD, left ventricular assist device.

Figure 5

LEfSe results summarizing top taxa differentially abundant between patient categories. Colored circles and shaded branches indicate taxa that are enriched in a particular patient category with p < 0.05. HF, heart failure; HT, heart transplantation; LEfSe, linear discriminant analysis for effect size; LVAD, left ventricular assist device.