肠道菌群与冠状动脉疾病的发生风险
胡嘉禄 , 姚志峰 , 唐敏娜 , 唐春 , 赵晓璠 , 苏曦 , 卢淡泊 , 李秋荣 , 王张生 , 颜彦 , 王则能
工程（英文） ›› 2021, Vol. 7 ›› Issue (12) : 1715 -1724.
肠道菌群与冠状动脉疾病的发生风险
胡嘉禄 , 姚志峰 , 唐敏娜 , 唐春 , 赵晓璠 , 苏曦 , 卢淡泊 , 李秋荣 , 王张生 , 颜彦 , 王则能
工程（英文） ›› 2021, Vol. 7 ›› Issue (12) : 1715 -1724.
肠道菌群与冠状动脉疾病的发生风险
Gut Microbiota Community Shift with Severity of Coronary Artery Disease
在过去的几年中，小规模队列研究发现肠道菌群随冠状动脉疾病出现而改变。既往研究中所发现的冠状动脉疾病患者肠道中富集或减少的微生物群，在其他冠状动脉疾病队列中是否具有可重复性，有待进一步研究和验证。本研究共纳入78 名受试者，其中19 例受试者无冠状动脉狭窄（Ctrl 组），14 例受试者冠状动脉狭窄程度小于50%（LT50 组），45 例受试者冠状动脉狭窄程度大于50%（GT50 组）。采集受试者粪便标本，并提取DNA 进行16S 核糖体RNA 基因测序。对可执行的分类操作单位（operational taxonomic units, OTU）进行分析以确定不同类群的分类单元，采用多变量logistic 回归分析检验所定义的分类单元是否能独立预测冠状动脉疾病风险。结果显示，δ-变形杆菌纲、梭杆菌属、嗜胆菌属、放线菌属和梭菌XIX属在Ctrl 组中富集；普雷沃氏菌科、副拟杆菌属和芽孢杆菌属在LT50 组中富集；罗氏菌属和丁酸单胞菌属在GT50 组中富集。δ-变形杆菌纲、梭杆菌属、嗜胆菌属和脱硫弧菌科种群的增加与冠状动脉疾病风险降低相关。在相对丰度高于中位数的个体中，冠状动脉疾病风险分别降低为相对丰度低于中位数的个体的0.26 倍、0.21 倍、0.18 倍和0.26 倍（p < 0.05），而普雷沃氏菌科种群的增加与冠状动脉疾病风险增加相关，冠状动脉疾病风险增加5.63 倍（p < 0.01）。使用20 种微生物群联合诊断LT50组与Ctrl组、GT50组与Ctrl组、LT50组+GT50组与Ctrl组、GT50组与Ctrl组+LT50组，受试者工作特征（ROC）曲线下的面积均高于0.88。然而，除拟杆菌属外，既往研究所报道的在冠状动脉疾病或健康对照组受试者中富集的肠道菌群在本队列并未观察到。总之，冠状动脉疾病与健康对照组受试者具有不同的菌群特征。不同队列研究所发现的冠状动脉疾病富集的肠道菌群特征不具有重复性，提示肠道菌群较难应用于冠状动脉疾病的早期诊断和预防。综合本研究与既往研究结果，只有拟杆菌属丰度减少是冠状动脉疾病进展的可靠标志物。
Gut microbiota community shift with coronary artery disease (CAD) has been reported in several limited cohorts during the past several years. However, whether the enriched or decreased microbiota taxa with CAD can be reproducible deserves further investigation and validation. In this study, 78 human subjects were recruited. Of these, 19 were diagnosed without stenosis in coronary artery (control group, referred to herein as Ctrl), 14 with stenosis less than 50% (LT50), and 45 with stenosis greater than 50% (GT50). Fecal samples were collected and DNA was extracted to perform 16S rRNA gene sequencing. The operational taxonomic units (OTUs) were analyzed to identify taxa specific to different groups; next, multivariate logistic regression was employed to test whether the defined taxa could independently predict CAD risk. We found that Deltaproteobacteria, Fusobacterium, Bilophila, Actinomyces, and Clostridium XIX were enriched in Ctrl; Prevotellaceae, Parabacteriodes, and Butyricicoccus were enriched in LT50; and Roseburia and Butyricimonas were enriched in GT50. Further analysis revealed that increased populations of Deltaproteobacteria, Fusobacterium, Bilophila, and Desulfovibrionaceae were associated with a 0.26-fold, 0.21-fold, 0.18-fold, and 0.26-fold decreased risk of CAD, respectively (p < 0.05), and an increased Prevotellaceae population was associated with a 5.63-fold increased risk of CAD (p < 0.01). A combination of the 20 microbial taxa achieved an area under the receiver operating characteristic (ROC) curve of higher than 0.88 for all discriminations between LT50 vs Ctrl, GT50 vs Ctrl, LT50 + GT50 vs Ctrl, and GT50 vs Ctrl + LT50. However, the microbial taxa previously reported as enriched in CAD patients or healthy controls could not be observed in our cohort except for Bacteroides. In conclusion, CAD patients showed a different microbial taxa signature than the healthy controls. However, the non-reproducibility of the microbiota taxa enriched in CAD across different cohorts limits the use of this signature in early diagnosis and prevention. Only decreased Bacteroides abundance was found to be a reliable marker to indicate CAD progression.
| Variables | Control | LT50 | GT50 |
|---|---|---|---|
| (n = 19) | (n = 14) | (n = 45) | |
| Age (year) | 61.4 ± 7.5 | 60.6 ± 10.8 | 61.7 ± 9.0 |
| Sex (male %) | 68.4 | 64.3 | 84.4 |
| BMI | 24.2 ± 4.3 | 23.4 ± 3.4 | 24.7 ± 2.4 |
| DM (%) | 47.4 | 14.3 a | 15.6 b |
| HBP (%) | 78.9 | 57.1 | 44.4 a |
| Leukocyte (× 109 L-1) | 7.8 ± 3.8 | 6.1 ± 2.3 | 7.0 ± 2.5 |
| TC (mmol·L-1) | 4.1 ± 0.8 | 4.5 ± 1.2 | 3.8 ± 1.0 |
| LDL-C (mmol·L-1) | 2.3 ± 0.7 | 2.5 ± 0.9 | 1.9 ± 0.8 c |
| HDL-C (mmol·L-1) | 1.3 ± 0.4 | 1.3 ± 0.3 | 1.2 ± 0.4 |
| TG (mmol·L-1) | 1.2 ± 0.8 | 1.8 ± 1.5 | 2.0 ± 1.7 a |
| ApoA1 (g·L-1) | 1.5 ± 0.2 | 1.5 ± 0.3 | 1.5 ± 0.4 |
| ApoB (g·L-1) | 0.8 ± 0.2 | 0.8 ± 0.3 | 0.7 ± 0.2 |
| ApoE (mg·L-1) | 38.5 ± 13.0 | 40.5 ± 13.8 | 37.1 ± 18.5 |
| LP(a) (mg·L-1) | 367.6 ± 392.3 | 264.9 ± 362.0 | 312.2 ± 356.0 |
| Hb (g·L-1) | 134.6 ± 19.0 | 135.7 ± 15.4 | 138.3 ± 12.4 |
| Albumin (g·L-1) | 38.1 ± 2.2 | 39.2 ± 3.4 | 41.6 ± 5.8 |
| ALT (U·L-1) | 24.9 ± 26.9 | 24.9 ± 24.6 | 31.3 ± 21.2 |
| AST (U·L-1) | 65.6 ± 142.8 | 20.9 ± 7.5 | 28.3 ± 14.3 |
| Glycosylated hemoglobin (%) | 7.2 ± 2.4 | 5.9 ± 0.8 | 6.1 ± 0.6 |
| Alkaline phosphatase (U·L-1) | 57.4 ± 13.8 | 60.3 ± 19.6 | 65.8 ± 26.3 |
| Bilirubin (ng·mL-1) | 15.9 ± 17.4 | 10.4 ± 4.1 | 13.0 ± 8.7 |
| Bile acid (mmol·L-1) | 4.6 ± 3.4 | 4.2 ± 2.2 | 4.1 ± 3.0 |
| Urea (mmol·L-1) | 6.5 ± 3.2 | 5.9 ± 3.0 | 4.9 ± 1.8 |
| eGFR (mL·min·(1.73 m2)-1) | 79.9 ± 15.1 | 84.1 ± 12.8 | 85.3 ± 15.8 |
| Uric acid (mmol·L-1) | 314.6 ± 113.9 | 380.7 ± 165.5 | 326.3 ± 78.2 |
| Glucose (mmol·L-1) | 6.3 (5.2–7.4) | 5.3 (5.1–6.1) | 5.7 (5.0–6.7) |
| Na+ (mmol·L-1) | 141.7 ± 5.3 | 141.6 ± 3.2 | 141.7 ± 1.9 |
| K+ (mmol·L-1) | 4.0 ± 0.5 | 4.1 ± 0.2 | 3.9 ± 0.6 |
| Cl- (mmol·L-1) | 100.9 ± 5.6 | 103.7 ± 3.9 | 103.0 ± 2.9 |
| Taxa | Model | Phenotype | ||
|---|---|---|---|---|
| Ctrl | LT 50 | GT 50 | ||
| Bacteroidaceace/Bacteroides | A | 1.00 | 0.35 (0.08–1.45) | 0.40 (0.13–1.25) |
| B | 1.00 | 0.36 (0.05–2.86) | 0.11 (0.01–0.84) a | |
| Deltaproteobacteria | A | 1.00 | 0.27 (0.06–1.17) | 0.26 (0.08–0.85) a |
| B | 1.00 | 9.50 × 10-4 (2.40 × 10-7–3.78) | 0.12 (0.02–0.77) a | |
| Desulfovibrionaceace/Desulfovibrionales | A | 1.00 | 0.27 (0.06–1.17) | 0.26 (0.08–0.85) a |
| B | 1.00 | 9.50 × 10-4 (2.40 × 10-7–3.78) | 0.12 (0.02–0.77) a | |
| Fuscobacteria/Fuscobacteriia/Fusobacteriales | A | 1.00 | 0.19 (0.04–0.84) a | 0.26 (0.08–0.85) a |
| B | 1.00 | 0.02 (5.10 × 10-4–0.85) a | 0.09 (0.01–0.62) a | |
| Fuscobacteriaceae | A | 1.00 | 0.13 (0.03–0.63) a | 0.21 (0.07–0.66) b |
| B | 1.00 | 2.00 × 10-7 (1.00 × 10-7–3487.00) | 0.09 (0.01–0.61) b | |
| Fuscobacterium | A | 1.00 | 0.08 (0.01–0.46) b | 0.21 (0.07–0.66) b |
| B | 1.00 | 1.40 × 10-7 (1.00 × 10-7–3487.00) | 0.09 (0.01–0.61) b | |
| Bilophila | A | 1.00 | 0.20 (0.04–0.92) a | 0.18 (0.05–0.62) b |
| B | 1.00 | 1.70 × 10-3 (5.20 × 10-5–0.54) a | 0.07 (0.08–0.61) a | |
| Actinomyces | A | 1.00 | 2.29 (0.56–9.37) | 0.43 (0.13–1.40) |
| B | 1.00 | 0.95 (0.10–9.53) | 0.35 (0.07–1.82) | |
| Clostridium XIX | A | 1.00 | 0.23 (0.04–1.32) | 0.21 (0.06–0.74) a |
| B | 1.00 | 0.23 (0.02–3.66) | 0.14 (0.02–0.92) a | |
| Prevotellaceae | A | 1.00 | 5.08 (1.08–23.06) a | 5.63 (1.61–19.71) b |
| B | 1.00 | 29.02 (1.41–599.10) a | 588.00 (4.70–73579.00) a | |
| Parabacteroides | A | 1.00 | 7.00 (1.49–32.82) a | 3.20 (0.99–10.38) |
| B | 1.00 | 22.65 (1.37–374.14) a | 11.20 (1.45–87.25) a | |
| Butyricicoccus | A | 1.00 | 4.07 (0.85–19.43) | 0.81 (0.28–2.39) |
| B | 1.00 | 101.40 (1.21–8488.20) a | 5.79 (0.90–37.26) | |
| Clostridium sensu stricto | A | 1.00 | 7.94 (1.60–39.42) a | 2.07 (0.67–6.42) |
| B | 1.00 | 483.60 (0.46–512841.00) | 2.66 (0.44–15.95) | |
| Anaerobacter | A | 1.00 | 7.00 (1.49–32.82) a | 3.20 (0.99–10.38) |
| B | 1.00 | 9.57 (0.84–109.00) | 6.51 (1.03–41.07) a | |
| Roseburia | A | 1.00 | 1.63 (0.39–6.82) | 3.25 (1.04–10.13) a |
| B | 1.00 | 2.07 (0.20–21.14) | 3.40 (0.65–17.78) | |
| Butyricimonas | A | 1.00 | 2.81 (0.61–12.97) | 6.80 (1.93–23.98) |
| B | 1.00 | 0.93 (0.10–8.75) | 4.91 (0.90–26.69) | |
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