肠-血管轴: 从血管功能到结构的层级调控

摘要

肠-血管轴是血管结构稳态的保护性代谢信号通路. 肠源性信号分子咪唑丙酸、氧化三甲胺和短链脂肪酸可对血管系统进行从功能到结构的层级调控, 以维持其稳定性. 本文系统探讨了肠道代谢物对血管内皮细胞"功能层"及平滑肌细胞、细胞外基质"结构层"的作用机制, 阐述了微血管、中等肌性动脉及大弹性动脉对这些分子的不同反应, 描述了肠源性炎症在主动脉夹层及主动脉瘤发生中的作用, 旨在为心血管疾病的肠源性机制提供新视角, 为靶向肠-血管轴干预提出新方向.

关键词: 肠-血管轴; 肠道代谢物; 主动脉夹层; 主动脉瘤

核心提要: 肠-血管轴层级调控是指肠道菌群及其代谢物(如咪唑丙酸、氧化三甲胺和短链脂肪酸等)通过受损的肠道屏障作用于血管内皮细胞功能层以及血管平滑肌细胞和细胞外基质结构层, 以调控血管系统稳态.

Gut-vascular axis: Hierarchical regulation from vascular function to structure

Cui-Hong Tian, Xue-Rui Tan

Cui-Hong Tian, Department of Cardiology, First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China

Xue-Rui Tan, Human Phenome Institute of Shantou University Medical College, Shantou 515041, Guangdong Province, China

Supported by: China Postdoctoral Science Foundation, No. 2025M772244; Key Disciplinary Project of Clinical Medicine under the High-level University Development Program, Guangdong, No. 2024-2025; Special Fund from the Central Government for Guiding Local Scientific and Technological Development in 2024, No. STKJ2024068; Guangdong Medical Leading Talent, the First Affiliated Hospital of Shantou University Medical College, No. 2019-2022.

Corresponding author: Xue-Rui Tan, Professor, Chief Physician, Human Phenome Institute of Shantou University Medical College, No. 22 Xinling Road, Jinping District, Shantou 515041, Guangdong Province, China. tanxuerui@vip.sina.com

Received: February 25, 2026
Revised: March 20, 2026
Accepted: March 23, 2026
Published online: March 28, 2026

Abstract

The gut-vascular axis is a critical protective metabolic signaling pathway for vascular structural homeostasis. Gut-derived signaling molecules, such as imidazole propionate, trimethylamine N-oxide, and short-chain fatty acids, hierar-chically regulate the vascular system at the functional and structural levels to maintain vascular stability. This review systematically explores the mechanisms by which these gut metabolites act on the functional level of vascular endothelial cells and the structural level of vascular smooth muscle cells and extracellular matrix, further elaborates the distinct responses of microvessels, medium-sized muscular arteries, and large elastic arteries to these molecules, and describes the contribution of gut-derived inflammation to the pathogenesis of aortic dissection and aortic aneurysms, aiming to provide a novel perspective on the gut-originated mechanisms underlying cardiovascular diseases and propose new directions for targeted interventions via the gut-vascular axis.

Key Words: Gut-vascular axis; Gut metabolites; Aortic dissection; Aortic aneurysm

0 引言

血管系统分为不同层次, 包含器官组织中进行物质交换的微血管、调控组织局部血流的肌性动脉和维持全身血流动力学稳定的大弹性动脉. 研究表明[1-3], 不同血管层级的解剖学特征、功能特性及细胞组成存在显著差异. 微血管因内皮表面积大、网络分布密集, 是最直接、最灵敏的代谢及炎症信号感应器[4]. 肌性动脉富含平滑肌细胞, 能主动、精确地调节器官血流量[5,6]. 大弹性动脉以由弹力蛋白、胶原蛋白等物质构成的细胞外基质(extracellular matrix, ECM)为主要结构支架, 承受心脏搏动带来的周期性高流量、高压力[7,8]. 结构的异质性使不同血管层级对代谢、炎症及力学刺激的敏感性不同.

"肠-血管轴"的提出[9], 为肠道微生物及其代谢物整合于血管层级体系的研究提供了思想框架. 该概念明确区分了血管的两个重要层次, 即由内皮细胞构成的"功能层"以及由平滑肌细胞和ECM构成的"结构层". 肠道菌群代谢物如咪唑丙酸(imidazole propionate, ImP)[10,11]、氧化三甲胺(trimethylamine N-oxide, TMAO)[12,13]和短链脂肪酸(short-chain fatty acids, SCFAs)[14,15], 以不同方式与两层相互作用. 功能层作为血管壁的第一道屏障, 直接接触循环中的代谢物, 更易发生一氧化氮(nitric oxide, NO)生物利用度的快速变化和炎症激活[16,17]; 而结构层主要感应慢性炎症信号和基质降解酶, 易发生血管重塑, 甚至出现动脉瘤或夹层等极端表型[18-20].

镁治疗降低ImP的研究证实, ImP与胰岛素抵抗密切相关[21], 而微血管功能障碍是糖尿病血管病变早期可检测的表现[22], 间接提示了ImP与糖尿病微血管病变的关系. 持续的微循环障碍可导致大血管壁滋养管缺血损伤, 造成结构层缺血缺氧. 肠源性炎症因子[如脂多糖(lipopolysaccharide, LPS)]长期作用于平滑肌细胞, 促使其发生表型转换、基质金属蛋白酶(matrix metalloproteinases, MMPs)异常激活、ECM降解、血管重塑, 进而发展为主动脉夹层或主动脉瘤等[23,24]. 这些证据提示, 在肠-血管轴框架下进行疾病早期干预及靶向治疗具有巨大的潜在临床价值. 本综述将以肠-血管轴的层级框架为主线, 系统讨论肠道对血管功能及结构稳态的调控作用, 并提出未来的研究方向及临床转化路径.

1 肠道端的始动因素

肠道微生态失衡导致的菌群、代谢物与屏障之间的相互作用, 是肠-血管轴的始动环节. 特定的饮食成分如组氨酸、胆碱和左旋肉碱、膳食纤维, 可被肠道菌群代谢产生一系列具有生物活性的小分子, 成为连接肠道与血管的关键信使[9,25].

1.1 典型肠道代谢物来源与功能

ImP是由肠道细菌(如厚壁菌门、放线菌门)通过尿刊酸还原酶等代谢膳食组氨酸而生成的一种组氨酸衍生物. 在肥胖和2型糖尿病人群中, 血浆ImP水平显著升高, 并与胰岛素抵抗密切相关[26]. TMAO的产生更为复杂, 肠道细菌(如厚壁菌门、变形菌门)将膳食来源的胆碱、卵磷脂和左旋肉碱转化为三甲胺, 三甲胺被吸收后经门静脉进入肝脏, 被黄素单加氧酶(flavin-containing monooxygenases, FMOs)家族(主要是FMO3)氧化生成TMAO[27]. 血浆TMAO浓度与2型糖尿病和中心性肥胖以及炎症、内皮功能障碍呈正相关[28]. SCFAs(包括乙酸、丙酸和丁酸)主要由肠道菌群(如厚壁菌门、拟杆菌门)发酵膳食纤维产生. 与上述两者相反, SCFAs是肠道健康和宿主能量代谢的重要调节分子, 被认为具有血管保护作用[29,30].

1.2 肠道屏障的完整性

肠道屏障的完整性是维持健康的生理基础. 肠道屏障由物理屏障(肠上皮细胞、紧密连接)、化学屏障(黏液层、抗菌肽)、免疫屏障(肠道相关淋巴组织)和微生物屏障(共生菌群)等共同构成. 肠道屏障受损, 即"肠漏", 可引起菌群组分LPS、肽聚糖、细菌DNA等进入血液循环, 触发全身低度炎症反应, 即"代谢性内毒素血症"[31]. LPS作为Toll样受体4(toll-like receptor 4, TLR4)的经典配体, 进入循环后可激活血管壁上的免疫细胞及结构细胞, 直接启动炎症级联反应[32].

2 血管功能层与结构层的分层调控

血管系统的不均质性使不同血管层级对肠源性信号的反应存在显著差别, 故肠源性信号对血管功能层及结构层的调控及选择性响应明显不同.

2.1 内皮功能层的调控

内皮细胞是血管功能的核心调控单元. 内皮型一氧化氮合酶(endothelial nitric oxide synthase, eNOS)及其产物NO是最关键的功能分子. NO不仅介导血管舒张, 还具有抑制血小板聚集、白细胞黏附和平滑肌细胞增殖的多重保护作用. 肠道代谢物通过调节eNOS活性, 影响着从微循环到大动脉的整体血管功能.

ImP在糖尿病中升高, 与饮食、菌群相关[33]. 微血管是ImP作用的感应器. 肠道细菌以组氨酸为原料合成ImP, 激活p38γ丝裂原活化蛋白激酶(p38γ mitogen-activated protein kinase, p38γ MAPK), 继而干扰肝细胞、肌细胞、脂肪细胞中的胰岛素信号通路[34]. 胰岛素介导的血管扩张在组织微循环阻力血管的调节中发挥重要作用.

大动脉中TMAO具有双重致病作用. 首先, TMAO可促进血管超氧化物(超氧阴离子)生成, 使NO氧化失活, eNOS"解偶联", 从而降低NO的生物利用度. TMAO还可下调内皮细胞中沉默信息调节因子1的表达, 抑制eNOS活性. 此外, 在冠状动脉、脑动脉等易发生动脉粥样硬化的血管中, TMAO可促进内皮细胞表达血管细胞黏附分子-1和细胞间黏附分子-1, 使单核细胞浸润内膜, 加剧局部炎症[35]. 与此同时, TMAO可增强巨噬细胞清道夫受体CD36的表达, 促进泡沫细胞形成, 加速易损斑块破裂, 增加急性心脑血管事件的风险[36].

2.2 中膜与外膜结构层的调控

由于大弹性动脉需要承受巨大的血流动力学压力, 因此平滑肌细胞及ECM的完整性是维持大弹性动脉结构稳定的根本前提, 而肠源性信号在其中的作用具有慢性积累的特点.

正常血管中膜平滑肌细胞为收缩表型, 高表达α-平滑肌肌动蛋白、平滑肌22α等收缩蛋白, 且处于低增殖、低迁移、低合成活性的状态. 肠道来源的LPS可激活平滑肌细胞表面TLR4, 启动髓样分化因子88依赖性信号通路, 激活核因子κB(nuclear factor kappa B, NF-κB), 诱导平滑肌细胞向合成表型转化[37]. 合成型平滑肌细胞收缩蛋白表达下调, 增殖和迁移能力增强, 大量合成并分泌ECM成分(如胶原蛋白、蛋白聚糖), 从而造成血管壁内膜增生、中膜增厚, 即发生典型的病理性重塑[38].

肠源性炎症是MMPs极强的激活剂. MMPs是一类锌依赖性内肽酶, 其中MMP-2和MMP-9对弹力蛋白、胶原蛋白均具有极高的亲和力. LPS与辅助性T细胞17(T helper 17 cell, Th17)分泌的白细胞介素-17(interleukin-17, IL-17)均能通过激活NF-κB及MAPK信号通路上调血管壁细胞中MMP-2和MMP-9的表达水平及活性[39]. 过度活化的MMPs会不可逆地降解ECM中的弹力蛋白及胶原蛋白, 减弱主动脉壁拉伸强度, 导致主动脉扩张、引起夹层[40]. 因此, MMPs介导的ECM降解实质上是主动脉夹层及主动脉瘤形成的共同通路.

外膜是血管支撑结构, 也是血管免疫活性区域[41]. 在高血压中, 肠道菌群失调可促进Th17细胞在肠道相关淋巴组织中分化, 释放IL-17, 放大血管炎症反应[42].

3 肠-血管轴在主动脉夹层及主动脉瘤等极端表型中的角色

主动脉夹层和主动脉瘤是血管结构损伤最典型且死亡率极高的两种形式, 被认为是血管损伤的极端表型. 传统观点认为其病因主要是遗传(如马凡综合征、洛伊-迪茨综合征)及机械应力因素(如高血压), 但仍有大量散发病例不能用上述因素充分解释. 近年研究表明[43-45], "肠-血管轴失调"可能解释这些"不明原因"的散发病例. 临床研究表明[43,44], 血浆TMAO水平与腹主动脉瘤患者最大主动脉直径呈正相关. 动物实验表明[45], 抗生素可通过清除肠道菌群抑制腹主动脉瘤形成; 将腹主动脉瘤倾向小鼠的粪菌移植给无菌小鼠后, 后者腹主动脉瘤易感性明显提高.

肠道代谢物可诱导氧化应激, 上调缺氧诱导因子-1α水平, 继而诱导多种炎症因子及MMPs表达增高[46], 这些分子改变是包括主动脉在内的不同动脉病变的重要特征[47]. 其次, 肠道来源的LPS及Th17细胞分泌的IL-17等炎症因子直接作用于中膜平滑肌细胞和外膜成纤维细胞, 激活NF-κB、MAPK通路, 诱导MMPs表达, 过度降解ECM中的弹力蛋白及胶原蛋白, 降低主动脉壁的机械强度[39,40]. 当两种因素叠加时, 主动脉壁在原有血流动力学压力下更易于进行性扩张形成动脉瘤或发生内膜撕裂形成夹层.

4 静脉系统

虽然过去对肠-血管轴的讨论很少涉及静脉系统, 但从解剖学角度认识, 静脉系统在"轴"内有独特地位. 静脉系统特别是门静脉及肝静脉直接接收肠血液回流, 较早暴露于高浓度的肠源性代谢物及炎症因子, 因而可视为肠-血管轴的"下游"器官[32].

直接暴露于肠源性代谢物可导致静脉血管内皮活化, 引起局部炎症及血栓前状态. 肠源性LPS激活静脉内皮细胞上的TLR4, 促进组织因子表达, 同时抑制血栓调节蛋白及硫酸乙酰肝素等抗凝物质的表达, 使局部微环境极有利于凝血[48]. 因此, 肠道屏障破坏后的细菌易位是"肠系膜静脉血栓"的重要原因之一[49]. 此外, 慢性炎症及血流动力学改变可诱导静脉壁ECM重塑[38]. 严重下肢静脉曲张患者的静脉壁中MMPs活性增高, 弹力蛋白含量下降, 胶原沉积紊乱, 使静脉顺应性显著降低, 影响心脏充盈及全身血流动力学, 增加动脉系统的脉动负荷, 间接损害动脉健康[50]. 因此, 肠-血管轴中动、静脉相互联系、互为整体.

5 靶向干预

基于肠-血管轴的层级调控模式, 可设计功能增强与结构保护兼顾的疾病干预方案. 由于ImP明确的致微血管功能障碍和结构重塑作用, 因而开发尿刊酸还原酶抑制剂从源头抑制肠道ImP的生成, 是改善微血管功能并减轻其对结构层间接损害的新策略[51,52]. 乳酸杆菌、双歧杆菌、阿克曼氏菌等益生菌可通过抑制产三甲胺和ImP菌群的丰度, 同时促进产SCFAs菌群的丰度, 重塑肠道菌群[26,53-56]. 粪菌移植技术在该领域展现出较大潜力, 但其安全性和长期疗效仍需大规模临床试验加以验证. 增加膳食纤维摄入或直接补充SCFAs(尤其是丁酸), 能激活内皮细胞G蛋白偶联受体GPR41、GPR43, 促进NO生成, 减轻氧化应激反应, 改善内皮功能[57]. 基于TLR4在LPS诱导的血管炎症及MMPs激活中的核心作用, 使用TLR4拮抗剂TAK-242阻断TLR4信号通路或用重组LPS结合蛋白中和LPS是抑制动脉内膜增生的有效治疗策略[58]. 此外, 动物研究表明[59], TLR4基因敲除或药理学抑制能显著抑制腹主动脉瘤进展.

随着合成生物学的发展, 生产"原位"产生血管保护性分子的工程益生菌有望成为新兴领域. 把表达SCFAs合成酶、MMPs抑制剂或NO合酶的基因回路导入安全性极好的益生菌(大肠杆菌Nissle 1917)中, 让其在肠道内持续、稳定地释放保护性分子, 以实现肠-血管轴的局部、精准调控, 同时最大限度地避免全身性副作用, 从"系统性给药"向"局部生物制造"转变[60].

6 未来前景

鉴于肠-血管轴在血管病变中的重要作用, 未来研究应着重于以下几个方面: (1)建立"血管床特异性"的肠-血管轴模型: 传统二维细胞培养不能再现血管真实的三维结构及细胞间精细互作, 而诱导多能干细胞来源的内皮细胞及平滑肌细胞, 配合微流控芯片技术, 可构建出能良好的模拟微血管、肌性动脉及大动脉生物力学特性及血流环境的"血管-器官芯片"模型, 有利于解构不同血管层级对肠道信号的响应机制[61]; (2)验证新型临床生物标志物: TMAO作为生物标志物已有较多应用, 但其个体间变异很大, 且易受肾功能影响. ImP等新兴分子作为动脉粥样硬化早期预测因子的临床价值逐渐凸显[10,11]; (3)探索双向调控机制: 当前研究仍以"肠道到血管"的单向研究为主, 缺乏系统、有层次地考察血管功能、结构的改变对肠道影响的反向研究. 动脉硬化所致的慢性肠道缺血是否会破坏肠道屏障？心力衰竭所致的肠道淤血、水肿是否改变肠道菌群组成？"血管对肠道"的反向调控机制是什么？这些问题的完整阐释有利于完善肠-血管轴的双向理论框架; 和(4)推动临床转化: 系统整合微生物组学、代谢组学及血管生物学等领域的研究成果, 开发以调节肠-血管轴为靶点的精准干预策略, 如小分子药物(TLR4拮抗剂、ImP合成酶抑制剂)、工程益生菌、个性化营养方案, 以推动临床转化.

7 结论

肠-血管轴是以功能调控为基础、以结构为延伸的严谨而有层次的调控网络, 是维持血管稳态的重要防线. 肠道菌群产生的ImP、TMAO、SCFAs等代谢物及LPS等炎症因子会通过受损的肠道屏障作用于血管内皮功能层及平滑肌/ECM结构层, 诱发毛细血管稀疏、动脉粥样硬化、主动脉夹层或主动脉瘤等血管病变. 靶向肠-血管轴有望成为改善血管病变的有效干预策略.

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备注

学科分类: 胃肠病学和肝病学

手稿来源地: 广东省

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科学编辑: 刘继红 制作编辑:张砚梁