Tomohiro Hayashi

BACKGROUND: It is increasingly recognized that gut microbiota play a pivotal role in the development of atherosclerotic cardiovascular disease. Previously, we have reported that the abundance of genus Bacteroides is lower in patients with coronary artery disease (CAD) than in patients without CAD with coronary risk factors or in healthy volunteers. However, it remains unclear which and how specific gut bacteria contribute to the progression of atherosclerosis. METHODS: We recruited patients with CAD patients and controls without CAD with coronary risk factors. We then compared gut microbial composition using 16S ribosomal RNA gene sequencing in fecal samples to detect species with differential abundance between 2 groups. Subsequently, we used atherosclerosis-prone mice to study the mechanisms underlying the relationship between such species and atherosclerosis. RESULTS: Human fecal 16S ribosomal RNA gene sequencing revealed a significantly lower abundance of Bacteroides vulgatus and Bacteroides dorei in patients with CAD. This significant differential abundance was confirmed by quantitative polymerase chain reaction. Gavage with live B. vulgatus and B. dorei attenuated atherosclerotic lesion formation in atherosclerosis-prone mice, markedly ameliorating endotoxemia followed by decreasing gut microbial lipopolysaccharide production, effectively suppressing proinflammatory immune responses. Furthermore, fecal lipopolysaccharide levels in patients with CAD were significantly higher and negatively correlated with the abundance of B. vulgatus and B. dorei. CONCLUSIONS: Our translational research findings identify a previously unknown link between specific gut bacteria and atherosclerosis. Treatment with live B. vulgatus and B. dorei may help prevent CAD. CLINICAL TRIAL REGISTRATION: URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000018051 . Unique identifier: UMIN000015703.

AIM: Recent studies have suggested that metabolic disorders such as obesity and type 2 diabetes are associated with gut microbiota. The association between atherosclerosis and gut microbiota has also been attracting increased attention. Our aim was to specify a characteristic trend of gut microbiota in coronary artery disease (CAD). METHODS: This study included 39 CAD patients, 30 age- and sex-matched no-CAD controls (Ctrls) with coronary risk factors and 50 healthy volunteers (HVs) without coronary risk factors. Bacterial DNA was extracted from their fecal samples and analyzed by terminal restriction fragment length polymorphism. RESULTS: A characteristic change of gut microbiota was observed in CAD patients, where the order Lactobacillales was increased (CAD, Ctrl vs. HV; 13.6%±12.0%, 6.2%±7.7% vs. 4.1%±5.9%; p＜0.001) and the phylum Bacteroidetes (Bacteroides＋Prevotella) was decreased (CAD, Ctrl vs. HV;35.5%±11.6%, 43.9%±11.2% vs. 47.4%±11.5%; p＜0.001). The CAD group was over-represented in enterotype "others" (III), compared with the Ctrl or HV group (p＜0.001, chi-squared test), although we could not deny the possibility that some drugs affect the gut flora types. CONCLUSIONS: Although this study had some limitations, we demonstrated that the incidence of CAD was linked with an alteration of gut microbiota. A prospective study is desired to clarify a causal relationship between CAD and gut microbiota.

BACKGROUND: Gut microbiome composition or circulating microbiome-related metabolites in patients with heart failure (HF) have not been investigated at different time points (i.e., in the decompensated (Decomp) and compensated (Comp) phases). METHODS AND RESULTS: We prospectively enrolled 22 patients admitted for HF and 11 age-, sex-, and comorbidity-matched hospitalized control subjects without a history of HF. Gut flora and plasma microbiome-related metabolites were evaluated by amplicon sequencing of the bacterial 16S ribosomal RNA gene and capillary electrophoresis time-of-flight mass spectrometry, respectively. HF patients were evaluated in both the Decomp and Comp phases during hospitalization. The phylum Actinobacteria was enriched in HF patients compared with control subjects. At the genus level, Bifiodobacterium was abundant while Megamonas was depleted in HF patients. Meanwhile, plasma concentration of trimethylamine N-oxide (TMAO), a gut microbiome-derived metabolite, was increased in HF patients (Decomp HF vs. control, P=0.003; Comp HF vs. control, P=0.004). A correlation analysis revealed positive correlations between the abundance of the genus Escherichia/Shigella and levels of TMAO and indoxyl sulfate (IS, a microbe-dependent uremic toxin) in Comp HF (TMAO: r=0.62, P=0.002; IS: r=0.63, P=0.002). Escherichia/Shigella was more abundant in Decomp than in Comp HF (P=0.030). CONCLUSIONS: Our results suggest that gut microbiome composition and microbiome-related metabolites are altered in HF patients.