肠道菌群被错怪？近万人研究：动脉粥样硬化竟然与口腔细菌有关！

Streptococcus Species Abundance in the Gut Is Linked to Subclinical Coronary Atherosclerosis in 8973 Participants From the SCAPIS Cohort

Sergi Sayols-Baixeras, Koen F. Dekkers, Gabriel Baldanzi, Daniel Jönsson, Ulf Hammar, Yi-Ting Lin, Shafqat Ahmad, Diem Nguyen, Georgios Varotsis, Sara Pita, Nynne Nielsen, Aron C. Eklund, Jacob B. Holm, H. Bjørn Nielsen, Ulrika Ericson, Louise Brunkwall, Filip Ottosson, Anna Larsson, Dan Ericson, Björn Klinge, Peter M. Nilsson, Andrei Malinovschi, Lars Lind, Göran Bergström, Johan Sundström, Johan Ärnlöv, Gunnar Engström, J. Gustav Smith, Marju Orho-Melander, Tove Fall

Circulation：2023/07/12

Background: Gut microbiota have been implicated in atherosclerotic disease, but their relation with subclinical coronary atherosclerosis is unclear. This study aimed to identify associations between the gut microbiome and computed tomography-based measures of coronary atherosclerosis and to explore relevant clinical correlates.

Methods: We conducted a cross-sectional study of 8973 participants (50 to 65 years of age) without overt atherosclerotic disease from the population-based SCAPIS (Swedish Cardiopulmonary Bioimage Study). Coronary atherosclerosis was measured using coronary artery calcium score and coronary computed tomography angiography. Gut microbiota species abundance and functional potential were assessed with shotgun metagenomics sequencing of stool, and associations with coronary atherosclerosis were evaluated with multivariable regression models adjusted for cardiovascular risk factors. Associated species were evaluated for association with inflammatory markers, metabolites, and corresponding species in saliva.

Results: The mean age of the study sample was 57.4 years, and 53.7% were female. Coronary artery calcification was detected in 40.3%, and 5.4% had at least 1 stenosis with >50% occlusion. Sixty-four species were associated with coronary artery calcium score independent of cardiovascular risk factors, with the strongest associations observed for Streptococcus anginosus and Streptococcus oralis subsp oralis (P<1×10-5). Associations were largely similar across coronary computed tomography angiography-based measurements. Out of the 64 species, 19 species, including streptococci and other species commonly found in the oral cavity, were associated with high-sensitivity C-reactive protein plasma concentrations, and 16 with neutrophil counts. Gut microbial species that are commonly found in the oral cavity were negatively associated with plasma indole propionate and positively associated with plasma secondary bile acids and imidazole propionate. Five species, including 3 streptococci, correlated with the same species in saliva and were associated with worse dental health in the Malmö Offspring Dental Study. Microbial functional potential of dissimilatory nitrate reduction, anaerobic fatty acid β-oxidation, and amino acid degradation were associated with coronary artery calcium score.

Conclusions: This study provides evidence of an association of a gut microbiota composition characterized by increased abundance of Streptococcus spp and other species commonly found in the oral cavity with coronary atherosclerosis and systemic inflammation markers. Further longitudinal and experimental studies are warranted to explore the potential implications of a bacterial component in atherogenesis.

背景：；肠道微生物群与动脉粥样硬化性疾病有关，但它们与亚临床冠状动脉粥样硬化的关系尚不清楚。本研究旨在确定肠道微生物组与基于计算机断层扫描的冠状动脉粥样硬化测量之间的相关性，并探索相关的临床相关性；我们对8973名参与者（50至65岁）进行了一项横断面研究，这些参与者来自基于人群的SCAPIS（瑞典心肺生物图像研究），没有明显的动脉粥样硬化疾病。采用冠状动脉钙化评分和冠状动脉计算机断层摄影血管造影术测量冠状动脉粥样硬化。通过粪便的鸟枪宏基因组学测序评估肠道微生物群的物种丰度和功能潜力，并通过调整心血管风险因素的多变量回归模型评估与冠状动脉粥样硬化的相关性。评估了相关物种与唾液中炎症标志物、代谢产物和相应物种的相关性。结果：；研究样本的平均年龄为57.4岁，53.7%为女性。40.3%的患者检测到冠状动脉钙化，5.4%的患者至少有1处>；50%闭塞。64个物种与冠状动脉钙评分相关，与心血管风险因素无关，其中观察到的相关性最强的是；血管病链球菌；以及；链球菌；口腔；subsp；口腔；（P<；1×10-5）。在基于冠状动脉计算机断层扫描血管造影的测量中，相关性基本相似。在64个物种中，19个物种，包括链球菌和其他常见于口腔的物种，与高敏C反应蛋白血浆浓度有关，16个与中性粒细胞计数有关。口腔中常见的肠道微生物种类与血浆吲哚丙酸酯呈负相关，与血浆仲胆汁酸和咪唑丙酸酯呈正相关。在马尔默后代牙科研究中，包括3个链球菌在内的5个物种与唾液中的同一物种相关，并与更差的牙齿健康相关。异化硝酸盐还原、厌氧脂肪酸β-氧化和氨基酸降解的微生物功能潜力与冠状动脉钙评分有关；这项研究提供了肠道微生物群组成的关联证据，其特征是增加了；链球菌；spp等常见于口腔内具有冠状动脉粥样硬化和全身炎症标志物。需要进一步的纵向和实验研究来探索细菌成分在动脉粥样硬化形成中的潜在意义。

动脉粥样硬化性心血管疾病（ASCVD）是导致全球人群死亡或残疾的最主要原因之一。既往研究提示，肠道菌群可通过三种不同潜在机制（干扰宿主代谢；提高炎症水平；直接感染斑块）促进动脉粥样硬化的进展，肠道菌群或许是ASCVD的“潜在凶手”之一。

不过，一项发表在《循环》（Circulation）上的大型研究或许将给我们带来不同见解。这项研究提示，链球菌以及其他口腔常见细菌与亚临床冠状动脉粥样硬化（即通过影像学的方法可以检测到病变，但患者无任何症状）之间存在密切关联。未来，我们或许有必要进一步探索口腔菌群与肠道菌群之间的关联。

截图来源：Circulation

当前这项研究旨在分析肠道菌群与亚临床冠状动脉粥样硬化之间的关联。研究人员基于大型队列SCAPIS对受试者进行筛选，并最终纳入8973例受试者（平均年龄为57.4岁；53.7%为女性）进行分析。

总体而言，受试者基线时未伴有心血管疾病（包括动脉粥样硬化性心血管疾病）。与此同时，40.3%的受试者存在冠状动脉钙化；5.4%的受试者至少存在1处冠状动脉狭窄（闭塞＞50%）。

基于宏基因组学测序技术，研究人员发现，共有64种肠道菌与冠状动脉钙化积分（钙化积分越高，就表示动脉粥样硬化越严重）相关。其中，51种肠道菌与冠状动脉钙化积分呈正相关，13种肠道菌与冠状动脉钙化积分呈负相关。

值得强调的是，Streptococcus anginosus和Streptococcusoralis subsp oralis这两种肠道菌与冠状动脉钙化积分之间的相关性最强（P＜1×10-5），且均为正相关。针对受试者临床特征的分析结果提示，上述这两种肠道菌丰度较高的受试者，心血管疾病风险因素通常更多。

进一步分析显示，在与冠状动脉粥样硬化相关的肠道菌中，部分肠道菌可对血浆代谢产物水平产生重要影响（与血浆丙酸吲哚水平呈负相关；与血浆次级胆汁酸、丙酸咪唑水平呈正相关），但这部分细菌也常见于口腔。此外，就全身性炎症标志物方面，有19种肠道菌与超敏C反应蛋白（hs-CRP）血浆水平相关，16种肠道菌与中性粒细胞计数相关，而链球菌和其他口腔中常见菌种与hs-CRP、中性粒细胞计数以及白细胞计数均明显相关。

研究人员基于MODS研究（包含435例受试者的粪便和唾液样本）中的数据进一步验证，5种冠状动脉粥样硬化相关的肠道菌在口腔唾液样本中同样存在，且这些细菌均与更差的牙齿健康相关。

总体而言，当前这项研究的分析结果证实，肠道菌（包括链球菌以及其他口腔常见细菌）与亚临床冠状动脉粥样硬化、全身性炎症标志物水平之间存在显著关联。分析数据进一步支持，口腔菌群与肠道菌群并非完全独立的菌群系统，口腔菌群或可异位定植于肠道。

论文强调，在肠道存在内皮功能障碍的情况下，口腔致病菌或许可借此进入人体的血液系统，并通过干扰宿主代谢、提高炎症水平等方式影响动脉粥样硬化过程的发生。此前很少有研究评估动脉粥样硬化相关肠道菌群与口腔菌群之间的相关性，当前这项研究的结果为我们带来重要见解。

参考资料

[1] Sergi Sayols-Baixeras et al.; Streptococcus species abundance in the gut is linked to subclinical coronary atherosclerosis in 8973 participants from the SCAPIS cohort. Circulation. 2023. DOI: 10.1161/CIRCULATIONAHA.123.063914