Dysbiotic interrelationship between gut Streptococcus and branched-chain amino acid levels in patients with advanced heart failure
S Xie, Z Chen, P K S Chan, E FungAbstract
Background/Introduction
Patients with advanced heart failure (AdvHF) have altered circulatory physiology that affects the gut-heart axis. Previous studies have shown that elevated circulating BCAA levels in HF patients were associated with adverse outcomes. However, few studies have investigated the interrelationship between gut dysbiosis and circulating branched-chain amino acids (BCAAs) in AdvHF.
Purpose
We aim to characterise the interrelationship between changes in gut microbiota and circulating BCAA levels in AdvHF.
Methods
This study included patients with a history of AdvHF (defined as HF with a history of previous hospitalisation, NYHA class III/IV and/or left ventricular ejection fraction ≤35%) and community-living older adults (controls) with no history of HF that were randomly selected from over 1,000 individuals in a longitudinal cohort. Serum metabolites were measured by targeted proton-NMR. Fresh stool samples were collected within a month of blood sampling, transported to the laboratory within two hours of defaecation, and stored at -80°C. Gut microbiota profiling was performed using 16S rRNA V3-V4 region sequencing. ANCOM-BC was used to identify phyla and genera significantly associated with AdvHF, controlling for age and sex. Associations between circulating metabolites and genus abundance were assessed using Spearman correlation.
Results
53 AdvHF patients and 100 controls were analysed (mean age, 73.2±8.6 vs. 76.6±7.9, p=0.025l; sex, 66% vs. 52%, p=ns; BMI, 25.3±4.6 vs. 24.1±3.2, p=ns; 6-min walking distance, 313.2±73.4 vs. 355.3±80.6 metres, p<0.001). Hypertension was prevalent in both groups (67.9% vs. 56%, p=ns). As expected, ischaemic heart disease (64.2% vs. 8%), diabetes mellitus (41.5% vs. 16%), atrial fibrillation (45.3% vs. 6%), myocardial infarction (26.4% vs. 1%), and chronic kidney disease (28.3% vs. 1%) were more common in AdvHF (all p<0.001). Alpha diversity of microbial community (Shannon index for dominance) and evenness (Simpson's index for abundance) were significantly different between the groups (AdvHF vs. control, p=0.013 and 0.048, respectively), but not by richness (number of genera). PERMANOVA identified significantly different overall gut microbial compositions between groups (R^2=0.015, p=0.025). Abundance of 5 families (4 increased, 1 decreased) and 19 genera (14 increased, 5 decreased) were significantly altered. In AdvHF, abundance of the Akkermansia and Streptococcus genera were consistently and significantly increased, whereas the Fusobacterium genus were reduced. Notably, in the control group where Streptococcus abundance was inversely associated circulating levels of total BCAAs, valine and leucine (p=0.0022 to 0.0089, respectively), the interrelationships disappeared in the AdvHF group.
Conclusion(s)
The dynamic interrelationship between gut Streptococcus and circulating levels of BCAAs is altered in AdvHF. Further characterisation by metagenomic sequencing is warranted.