楚志芬

河北医科大学第一医院

【摘要】肠屏障通透性病理性升高（即“肠漏”）是多种肠道及全身性疾病的核心驱动因素。在调控肠屏障通透性的诸多因素中，产丁酸菌作为维系肠道菌群生态稳定的“基石功能群”，通过其核心代谢产物丁酸在维持肠屏障完整性中发挥关键作用。本文系统综述了产丁酸菌（以酪酸梭菌为代表）降低肠屏障通透性的分子机制：在直接层面，产丁酸菌分泌的丁酸通过激活GPR109A/AMPK/PGC-1α信号轴促进紧密连接组装；同时作为组蛋白去乙酰化酶抑制剂（HDAC）上调紧密连接蛋白基因转录，并协同调控FXR、AhR及凋亡-自噬轴等多通路维持紧密连接稳态。在间接层面，丁酸通过提供肠上皮细胞约70%的能量需求、调节免疫微环境（诱导Treg、抑制NF-κB/NLRP3、促进M2极化）、增强化学屏障和重塑肠道菌群稳态等方式间接维护屏障完整性。本文还梳理了产丁酸菌匮乏与肠道通透性升高在肠道疾病谱系及肠-肝轴、肠-脑轴、肠-心轴、肠-肺轴相关多系统疾病中的病理关联及临床干预证据，为肠屏障通透性的微生态调控研究提供理论参考。

【关键词】肠屏障通透性；肠漏；产丁酸菌；酪酸梭菌；丁酸；紧密连接；AMPK

1 引言

心脑血管病、2型糖尿病、肥胖、肿瘤、阿尔茨海默病、炎症性肠病、肠易激综合征等——这些看似互不相关的肠内外疾病，实际上均与肠屏障通透性的病理性升高（即“肠漏”）密切相关[1-3]。

完整的肠黏膜屏障允许水、电解质和小分子营养物质通过，同时精准限制肠腔内细菌内毒素、未消化大分子及条件致病菌穿过肠壁进入血液循环[4]。肠漏发生后，有害物质穿过肠壁进入血液循环，随血流到达全身：入肝诱发炎症和纤维化，侵入血管驱动动脉粥样硬化，透过血脑屏障加重神经退行性病变[1, 2]。

肠屏障功能完整性直接决定通透水平，当肠黏膜屏障受损时，肠漏即发生。近年来，肠道菌群及其代谢产物已被确立为维持肠屏障完整、调控黏膜通透性的关键因素[4, 5]。然而，在数以千计的肠道微生物中，究竟是哪一类菌群在这一调控网络中发挥了重要作用？2024年，Wu等发表于Cell的研究给出了明确答案：产丁酸菌是维持菌群生态稳定的“基石功能群”，其丰度下降直接导致微生态失衡和肠屏障损伤[6]。产丁酸菌的核心代谢产物丁酸，一方面为结肠上皮提供约70%能量以维持上皮完整，另一方面通过多信号通路调控紧密连接组装与黏膜炎症，维持肠道选择性通透稳态[4, 5, 7]。在众多产丁酸菌中，酪酸梭菌（Clostridium butyricum）因其高产丁酸、优异定植能力和长达近百年的安全应用历史，成为研究最为深入的代表菌株[8]。

现有研究虽已广泛证实丁酸具备肠屏障修复效应，但产丁酸菌通过丁酸多通路协同调控肠屏障通透性的完整分子网络仍缺乏系统梳理，各通路间的逻辑关系及协同效应尚待明确。本文以酪酸梭菌为代表菌株，系统综述产丁酸菌经丁酸降低肠屏障通透性的直接与间接分子机制，梳理相关疾病的临床证据，以期为肠屏障功能障碍相关疾病的微生态干预提供理论参考。

2 肠屏障通透性的结构基础与评价体系

2.1 肠屏障四层结构及肠漏局部级联损伤

图 1健康的肠屏障四层结构

肠屏障由机械、化学、免疫和生物四层协同构成，四层屏障的完整性共同决定通透水平，其中机械屏障是调控通透性的核心，由单层柱状肠上皮细胞及细胞间的紧密连接复合体构成[9, 10]。化学、免疫和生物三层屏障则通过间接途径影响通透性：化学屏障主要由黏液层和抗菌肽构成，黏液层以杯状细胞分泌的黏蛋白2（MUC2）为主要成分，其糖基化交联结构形成致密的凝胶网络，将肠腔内容物与上皮细胞物理隔离[11]。免疫屏障通过肠道相关淋巴组织及免疫细胞平衡促炎、抗炎因子的分泌，避免过度炎症损伤，进而维持紧密连接结构稳定[12]。生物屏障依托肠道共生菌群，通过生态位竞争、分泌保护性代谢产物维持微生态稳态，间接保护肠屏障完整[12, 13]。

图 2肠漏状态下的肠道屏障

肠漏发生后，肠腔内毒素及细菌抗原持续穿透上皮刺激黏膜，诱发局部慢性炎症，炎症介质进一步反向破坏四层屏障，形成“肠漏→炎症→屏障破坏→肠漏加重”恶性循环：机械屏障受损表现为紧密连接蛋白表达下调与分布异常，旁细胞途径失控开放[4, 14]；化学屏障出现黏液层变薄、MUC2与抗菌肽分泌不足，肠腔有害物质直接接触上皮[11]；免疫屏障存在促炎因子（TNF-α、IL-6、IL-1β）过量分泌与抗炎因子（IL-10）不足，Treg/Th17比例失调[12]；生物屏障伴随菌群多样性降低、产丁酸菌等有益菌耗竭、条件致病菌过度增殖，肠道微生态的定植抗力随之丧失[12, 13]。四层屏障损伤相互促进、级联放大，最终导致肠屏障整体功能破坏[2, 14]。

2.2 机械屏障的核心：紧密连接复合体

紧密连接（TJ）复合体是机械屏障的核心功能单元，由Occludin、Claudin跨膜蛋白与ZO-1、ZO-2架蛋白协同组装，定位于极化肠上皮细胞侧膜顶端，直接决定旁细胞途径物质转运通量[9, 15]。物质经孔隙、泄漏两条选择性旁细胞通路跨上皮转运，两条通路在分子截留、电荷筛选上存在差异，并受炎症信号动态调控[4]。当紧密连接复合体解离或相关蛋白表达下调、分布异常时，旁细胞途径通透性升高，原本仅允许小分子通过的通道变得“失控”，脂多糖（LPS）、未消化蛋白质等大分子物质穿过肠上皮进入血液循环，即形成“肠漏”[2, 4, 14]。

2.3 肠屏障通透性的评价体系

肠屏障通透性的评估已形成多层次的指标体系，但目前尚无公认的单一“金标准”方法[16, 17]。体内常用指标包括：乳果糖/甘露醇（L/M）比值、血浆D-乳酸、二胺氧化酶（DAO）和LPS水平[18-22]，升高均提示肠道屏障受损；连蛋白（Zonulin）被视为有前景的血清学标志物，但其检测特异性仍存争议[23, 24]。体外常用方法包括：Caco-2细胞单层模型的跨上皮电阻（TEER）和荧光标记葡聚糖（FD4）通量[25]，以及Ussing chamber技术[26, 27]；组织学层面通过免疫荧光观察ZO-1、Occludin的定位与表达变化[4]。

3 产丁酸菌匮乏是通透性升高的核心枢纽

药物、失衡膳食、身心应激、环境污染物等多种外部刺激均能诱发肠屏障通透性升高[28-30]。上述因素各不相同，但靶点一致，均导致产丁酸菌丰度不足，丁酸水平降低，从而引起肠屏障功能受损，通透性病理性升高。抗生素直接导致产丁酸菌减少[31]；高脂饮食通过改变肠道pH值和胆汁酸代谢谱抑制产丁酸菌定植[30]；炎症环境损害产丁酸菌赖以生存的严格厌氧生态位[29]。

产丁酸菌分泌的丁酸兼具三重屏障保护功能：为结肠上皮细胞提供主要能量来源[14]，抑制组蛋白去乙酰化酶活性[32]，激活GPR109A等屏障保护性受体[33]。丁酸不足时，上述三重保护机制同时失效：肠上皮能量供应下降，紧密连接蛋白合成受阻，肠屏障完整性受损[2, 14]。LPS经破损肠壁进入血液循环，激活TLR4/NF-κB通路释放促炎因子，诱发全身慢性低度炎症[34]。炎性因子反过来加速屏障损伤，同时产丁酸菌匮乏与黏液层变薄共同加剧LPS驱动的炎症反应[34]。由此构成“产丁酸菌匮乏→丁酸不足→肠屏障破损（肠漏）→内毒素移位→全身低度炎症→屏障进一步破坏→多脏器慢性病变”的级联[4]。

4 产丁酸菌通过丁酸修复紧密连接的直接分子机制

肠屏障通透性升高源于紧密连接复合体的结构破坏与功能失调[16, 17][4, 33, 34]。产丁酸菌（尤其是酪酸梭菌）通过其核心代谢产物丁酸多通路调控紧密连接分子信号，重塑紧密连接结构，抑制病理状态下大分子旁细胞渗漏，恢复肠屏障通透稳态。

4.1 激活GPR109A/AMPK/PGC-1α信号轴

酪酸梭菌分泌的丁酸通过激活GPR109A发挥屏障保护作用[35]。邓桂清等（2024）在急性胰腺炎小鼠模型中建立了从酪酸梭菌到GPR109A/AMPK/PGC-1α通路的完整证据链：酪酸梭菌干预后，模型小鼠的GPR109A受体表达显著回升，5'-腺苷单磷酸活化蛋白激酶（AMPK）磷酸化水平升高，PGC-1α表达增加，同时肠道紧密连接蛋白ZO-1和Occludin表达上调，炎症因子IL-6和IL-1β下降[36]。体外实验中，沉默肠上皮细胞GPR109A受体能加剧LPS诱导的紧密连接蛋白下降和炎症因子浸润。产丁酸菌分泌的丁酸通过激活AMPK-PGC1α通路增强线粒体生物合成[37]；该通路在肾脏组织中同样被证实能改善线粒体功能障碍[38]。上述线粒体生物合成增强为肠上皮细胞提供了充足的能量储备，进而为AMPK执行紧密连接组装等屏障保护功能奠定了代谢基础。

4.2 激活AMPK促进紧密连接组装与膜定位

AMPK是丁酸经GPR109A受体激活后的核心下游靶点[39, 40]。Peng等（2009）利用Caco-2细胞单层模型首次发现，产丁酸菌的代谢产物丁酸能显著增加AMPK磷酸化水平，伴随TEER升高和细胞旁通透性降低；丁酸并不改变紧密连接蛋白的总表达量，而是通过促进ZO-1和Occludin向细胞周边的重新分布来增强屏障功能[41]。AMPK缺失会延迟紧密连接的重新组装和膜定位，导致TEER和屏障功能的建立受损[42]。

AMPK激活后通过多条下游通路发挥作用。Miao等（2016）发现产丁酸菌分泌的丁酸通过激活AMPK，一方面抑制肌球蛋白II调节轻链（MLC2）磷酸化，另一方面促进蛋白激酶Cβ2（PKCβ2）磷酸化，双途径促进紧密连接的重组装[43]。Xu等（2023）进一步揭示，丁酸通过SP1和AMPK双通路上调肠道Claudin-23的表达，将AMPK调控的紧密连接蛋白从经典的ZO-1/Occludin扩展至Claudin家族成员[44]。Li等（2022）证实，丁酸通过激活AMPK诱导线粒体自噬，缓解氧化应激诱导的肠上皮屏障损伤和线粒体功能障碍[45]。此外，PPAR-γ为丁酸激活AMPK的重要上游调控节点：LPS损伤模型中，PPAR-γ拮抗剂能抵消丁酸的屏障保护作用，提示PPAR-γ激活是AMPK磷酸化的前提[46]。

4.3 抑制HDAC上调紧密连接蛋白基因转录

产丁酸菌分泌的丁酸是天然组蛋白去乙酰化酶（HDAC）抑制剂，能穿透肠上皮细胞核，通过抑制HDAC活性重塑染色质构象，解除紧密连接蛋白基因启动子的表观沉默，提升紧密连接蛋白转录水平[47, 48]。动物实验证实，酪酸梭菌能抑制HDAC活性，显著上调紧密连接蛋白ZO-1、claudin-3和occludin的表达[49]。

不同HDAC亚型介导丁酸的屏障保护效应。2024年《Immunity》研究表明，丁酸通过抑制肠道干细胞HDAC3，能够减少IL-25释放、阻断ILC2介导的2型炎症，减轻炎症对紧密连接的破坏[47]；靶向抑制HDAC8阻断NF-κB信号过度激活，直接上调紧密连接蛋白表达，发挥屏障保护作用[48]。自闭症谱系障碍小鼠模型研究进一步证实，酪酸梭菌能抑制HDAC1，上调离子通道Trek1，同步修复肠道高通透性、改善模型动物异常行为[50]。

除直接激活紧密连接编码基因外，丁酸还通过HDAC通路上调肌动蛋白结合蛋白Synaptopodin（SYNPO）。SYNPO与ZO-1共定位于紧密连接区，是维持上皮屏障的关键骨架蛋白；动物实验证实，补充丁酸能恢复菌群耗竭所致的SYNPO缺失，而Synpo基因敲除小鼠表现为通透性升高及结肠炎修复延迟[51]。

4.4 抑制Zonulin/MLCK通路阻断紧密连接解离

Zonulin是目前已知唯一能调控紧密连接可逆解离的生理性调节因子[52]，激活后触发MLCK磷酸化→肌球蛋白轻链收缩→紧密连接解离→通透性升高。产丁酸菌的代谢产物丁酸主要靶向通路下游MLCK相关分子，该抑制效应与 4.2 中 AMPK 介导的 MLC2 调控机制一致，阻断肌球蛋白轻链磷酸化，防止紧密连接解离[43]；在LPS诱导的肠上皮损伤模型中，丁酸还能抑制RhoA/ROCK2/MLCK信号轴，恢复ZO-1和Occludin的正常表达与膜定位[53]。临床研究亦证实，丁酸能显著降低老年受试者血浆Zonulin和LBP水平[54]。

4.5 协同调控FXR、AhR与凋亡-自噬轴、Akt/mTOR通路

除前述经典信号通路外，酪酸梭菌及其代谢产物丁酸还能同步激活多条上皮内源通路，协同稳定紧密连接、降低旁细胞通透性。

FXR信号通路：法尼醇X受体（FXR）是胆汁酸代谢与肠屏障交互的关键枢纽。酪酸梭菌产生的丁酸能通过调节胆汁盐水解酶（BSH）重塑胆汁酸池以激活FXR[55]；DSS肠损伤模型中，肠道特异性FXR敲除能完全消除酪酸梭菌上调紧密连接、抑制炎症的保护效应[56]。

AhR通路：芳香烃受体（AhR）是菌群代谢物介导黏膜免疫与屏障稳定的新型关键受体。丁酸通过HDAC抑制放大内源配体对AhR的激活[57]，协同激活GPR41、GPR109A等多条受体信号，稳固紧密连接结构、缓解肠道局部炎症[5]。

凋亡-自噬轴：Zheng等（2025）研究证实，丁酸经AMPK-Akt通路抑制肠上皮过度凋亡、诱导保护性自噬，减少上皮细胞丢失所导致的紧密连接解离[58]。

PI3K/Akt/mTOR通路：酪酸梭菌能激活PI3K/Akt/mTOR信号，直接上调ZO-1和Occludin表达[59]；该通路在不同能量状态下与AMPK通路协同调控紧密连接组装效率。

5 产丁酸菌降低肠屏障通透性的间接机制

5.1 能量供给：丁酸为结肠上皮细胞供能

酪酸梭菌产生的丁酸是结肠上皮细胞主要能量来源，通过β-氧化为细胞提供ATP以维持其基础生理活动。Donohoe等（2011）表明，无菌小鼠结肠上皮细胞中NADH/NAD⁺和ATP水平显著下降，线粒体呼吸功能受损；而定植产丁酸菌能恢复这些指标至正常水平[60]。Gasaly等（2021）进一步指出，成熟结肠上皮细胞中丁酸的氧化能提供其70%–80%的能量需求[61]。当肠道中丁酸浓度充足时，肠上皮细胞能够维持正常的有氧代谢状态；而在产丁酸菌匮乏的病理状态下，丁酸供应不足迫使肠上皮细胞转向以糖酵解为主的代谢模式，导致能量产出效率下降，紧密连接蛋白的合成与更新受阻，屏障修复能力受损，TEER降低、旁细胞途径通透性升高。

5.2 免疫调节：抑制NF-κB/NLRP3、诱导Treg、促进M2巨噬细胞极化

酪酸梭菌的代谢产物丁酸通过多种途径发挥免疫调节作用。促进Treg分化方面，丁酸作为HDAC抑制剂上调Foxp3基因表达[61]，同时经ACSS2转化为丁酰辅酶A促进诱导性调节T细胞（iTreg）分化[62]，iTreg通过分泌IL-10抑制炎症反应[63]。

抑制NF-κB/NLRP3通路方面，丁酸通过HDAC抑制和GPR109A激活双重途径抑制NF-κB信号通路，使TNF-α、IL-6、IL-1β等促炎因子减少[61]；还能通过抑制NLRP3炎症小体减轻肠道炎症。

促进M2巨噬细胞极化是丁酸发挥免疫调节作用的重要机制之一。产丁酸菌分泌的丁酸通过H3K9乙酰化激活STAT6信号通路[64]；同时通过TGR5/β-arrestin2通路抑制M1样极化、促进巨噬细胞向抗炎M2表型极化，从而缓解肠道炎症[65]。炎症微环境的改善能降低促炎因子对紧密连接的破坏作用，从而间接降低肠屏障通透性。

5.3 化学屏障增强：促进MUC2黏液层分泌与抗菌肽表达

黏液层以杯状细胞分泌的MUC2为主要骨架，与抗菌肽共同构成肠道化学屏障，将肠腔有害物质与上皮物理隔离，维持肠道选择性通透稳态。与其他短链脂肪酸相比，产丁酸菌分泌的丁酸能通过三重途径协同强化化学防御：激活HIF-1α通路诱导上皮保护性自噬，经Wnt/ERK通路调控杯状细胞分化，同时活化PPAR-γ上调MUC2表达、增厚黏液层[66, 67]。

酪酸梭菌亦能通过多条通路重塑黏液屏障：Zhu等（2025）证实酪酸梭菌通过抑制Notch信号通路促进MUC2分泌，缓解吲哚美辛诱导肠黏膜损伤[68]；动物实验还发现，酪酸梭菌能激活IL-22/Reg3信号轴，上调抗菌肽表达，修复创伤性脑损伤所致的肠道屏障损伤[69]。黏液层增厚与抗菌肽分泌构成化学隔离带，减少肠腔有害物质与上皮的直接接触，从而防止通透性被动升高。

5.4 微生态重塑：促进有益菌、抑制致病菌、恢复菌群稳态

以酪酸梭菌为代表的产丁酸菌是肠道微生态的基石功能群。酪酸梭菌凭借其“生态锚定性、功能唯一性和不可替代性”在菌群生态中占据核心地位[6]。一方面，酪酸梭菌分泌多糖水解酶分解多糖为低聚糖，为双歧杆菌、乳杆菌等有益菌提供发酵底物；其耗氧代谢降低结肠氧分压，为专性厌氧菌营造适宜定植环境[70]。另一方面，酪酸梭菌通过竞争黏附位点、分泌丁酸及抑菌物质，抑制幽门螺杆菌、致病性大肠杆菌及艰难梭菌等有害菌的黏附与增殖[71-74]，从而减少致病菌及其毒素对上皮的攻击，维持屏障完整性。

菌群与肠屏障之间存在双向正反馈。完整的肠黏膜是肠道菌群稳定定植的前提[75]，酪酸梭菌通过分泌丁酸修复肠上皮屏障，为有益菌群提供稳定的定植环境。有益菌通过交叉喂养将其代谢产生的乳酸、乙酸供给酪酸梭菌，促进酪酸梭菌增殖，进一步提升肠道丁酸水平[76, 77]，丁酸反过来持续巩固肠黏膜结构，由此形成“酪酸梭菌丰度升高→丁酸充足→肠屏障完整→有益菌增殖→产丁酸菌丰度进一步升高”的闭环。

综上所述，酪酸梭菌通过促进有益菌增殖、抑制致病菌定植、驱动菌群-屏障正向反馈三重机制恢复肠道稳态，从根源阻断产丁酸菌匮乏所致肠屏障损伤的级联效应[78]。

6 产丁酸菌匮乏与通透性升高的病理关联及临床应用

产丁酸菌匮乏所致的肠道通透性升高，通过“LPS入血→激活TLR4/NF-κB通路→促炎因子释放→紧密连接进一步破坏”的恶性循环，将局部肠道屏障损伤转化为全身性慢性炎症[2, 14]。该病理链条是多种肠内外疾病的共同驱动机制。基于此，本节分别阐述产丁酸菌匮乏在肠道疾病及肠外疾病中的临床关联与干预证据。

6.1 肠道疾病6.1.1 抗生素相关性腹泻（AAD）

抗生素广泛使用导致产丁酸菌丰度下降，丁酸水平降低，引发肠上皮能量匮乏及紧密连接蛋白表达下调[79]。酪酸梭菌对青霉素类、头孢菌素类等常用抗生素具有天然耐受性，其芽孢能抵抗胃酸并定植于结肠。刘克锋等（2022）纳入29项RCT（共4096例患儿）的Meta分析显示，酪酸梭菌活菌制剂能使婴幼儿AAD发生风险降低71%（RR=0.29，95%CI: 0.25-0.34，P<0.01）[80]。其核心机制在于酪酸梭菌通过产生丁酸修复肠上皮损伤、上调紧密连接蛋白表达，从而恢复屏障功能、降低通透性[81]。

6.1.2 肠易激综合征（IBS）

腹泻型肠易激综合征（IBS-D）患者产丁酸菌减少与慢性应激及肠道菌群整体失衡相关，肠道低度炎症持续存在[82]。机制层面，王娇娇等（2025）发现丁酸通过抑制PI3K/Akt通路，上调ZO-1和Occludin表达，修复IBS小鼠肠道屏障、降低通透性[83]；酪酸梭菌还能通过NLRP6抑制结肠低度炎症，缓解IBS内脏高敏感性[84]。江学良等（2016）纳入240例IBS-D患者的RCT显示，酪酸梭菌CGMCC0313-1治疗28天后临床总有效率达99.2%[85]。Di Pierro等（2025）的前瞻性真实世界研究（n=205）证实，酪酸梭菌CBM588治疗8周后，腹泻发作减少>80%[86]。

6.1.3 炎症性肠病（IBD）

炎症性肠病（IBD）为高度活跃的组织破坏性炎症，产丁酸菌匮乏加剧肠上皮能量代谢障碍，屏障通透性升高，内毒素及细菌抗原持续穿透黏膜下层。Liu等（2020）在DSS结肠炎模型中证实，酪酸梭菌能降低FITC-葡聚糖通量、上调紧密连接蛋白表达，降低肠道通透性[59]。李延鸿等（2019）Meta分析显示，美沙拉嗪联合酪酸梭菌的疗效优于单用美沙拉嗪，临床缓解率及应答率均显著提高，且复发率低、不良反应少[87]。临床研究证实，英夫利昔单抗联合酪酸梭菌能更有效降低克罗恩病患者C-反应蛋白、血沉水平，改善肠黏膜屏障功能[88]。

6.1.4 腺瘤性息肉与结直肠癌（CRC）

腺瘤性息肉是结直肠癌（CRC）最重要的癌前病变。产丁酸菌匮乏导致丁酸供给不足，诱发持续性肠屏障损伤与内毒素移位，长期慢性炎症环境下NF-κB、Wnt/β-catenin通路异常激活，同时丁酸不足造成HDAC丧失了对促癌基因的表观抑制，致使三类促癌因子以产丁酸菌匮乏为共同源头协同驱动“正常肠上皮→异常隐窝病灶→腺瘤→结直肠癌”恶性演进[89, 90]。酪酸梭菌分泌的丁酸通过HDAC抑制诱导肿瘤细胞凋亡[91]。临床研究亦证实，提升肠道丁酸水平能够减轻家族性腺瘤性息肉病患者的息肉负荷[92]。

史新龙等（2020）研究显示，直肠癌患者围手术期应用酪酸梭菌制剂能恢复菌群平衡，降低肠黏膜通透性，修复肠屏障功能[93]。2025年《Cancer Cell》研究进一步揭示，酪酸梭菌通过SecD蛋白与肿瘤细胞表面GRP78受体结合，抑制PI3K/Akt-NF-κB通路，协同增强抗PD-1免疫治疗疗效[94]。

6.2 肠道外多系统疾病

肠屏障损伤导致的内毒素入血并非局限于肠道局部，而是通过循环系统影响全身多个器官系统。各轴疾病的共同干预逻辑在于：补充酪酸梭菌修复肠道屏障、降低通透性，从源头减少内毒素移位及其引发的全身炎症损伤。

肠-肝轴：肠道来源的LPS经门静脉入肝后激活Kupffer细胞TLR4/NF-κB通路，驱动肝细胞损伤与纤维化[95]。肝硬化患者肠道产丁酸菌丰度显著降低，丁酸合成相关基因（BCoAT）表达下降，肠道通透性标志物（LBP、I-FABP）显著升高[96]。补充酪酸梭菌能通过修复肠屏障减轻肝脏损伤[81]。

肠-脑轴：产丁酸菌减少导致丁酸水平降低，肠道通透性升高，LPS及炎症因子入血后，损伤血脑屏障并进一步侵入中枢激活神经炎症[97]。这一机制在临床中得到印证：阿尔茨海默病（AD）患者产丁酸菌丰度降低，且与认知功能损伤呈负相关[98]；帕金森病（PD）患者产丁酸菌丰度亦显著降低[99]。补充酪酸梭菌能通过修复肠道屏障发挥神经保护作用[100]。动物实验中，酪酸梭菌灌胃能显著改善APP/PS1转基因AD小鼠的认知功能，减少Aβ沉积和小胶质细胞活化，降低TNF-α和IL-1β水平[95, 96]。

肠-心轴：产丁酸菌匮乏引起肠漏，LPS入血激活TLR4/NF-κB通路，驱动血管炎症与动脉粥样硬化[101]。临床研究证实，冠心病、高血压、心衰及心梗患者肠道产丁酸菌丰度显著降低[102]。动物实验表明，酪酸梭菌灌胃能恢复肠屏障完整性,重塑菌群稳态，抑制LPS/TLR4/NF-κB信号，减轻动脉粥样硬化斑块形成[103]；亦能显著降低自发性高血压大鼠收缩压并抑制炎症[104]。补充酪酸梭菌通过修复肠道屏障，从源头阻断LPS移位驱动的血管损伤。

肠-肺轴：产丁酸菌丰度较高的异基因造血干细胞移植患者发生病毒性下呼吸道感染风险显著降低（丰度最高者风险降低5倍）[105]，补充酪酸梭菌通过维护肠道屏障，阻断LPS及炎症因子易位，经肠-肺轴发挥肺部保护作用。

代谢性疾病：产丁酸菌减少导致肠道通透性升高，LPS入血后诱发系统性炎症，加重胰岛素抵抗，参与2型糖尿病及肥胖的发生发展[100, 106]；补充酪酸梭菌能有效改善上述代谢紊乱。临床研究证实，2型糖尿病患者粪便丁酸水平与肥胖及血糖水平呈显著负相关[107]。

7 总结与展望

产丁酸菌丰度不足是肠屏障通透性病理性升高（“肠漏”）的关键始动因素，其通过“产丁酸菌匮乏→丁酸不足→紧密连接破坏→肠道通透性升高→慢性炎症级联”的链条，诱发并驱动肠道疾病及肠外多系统疾病的发生发展。酪酸梭菌作为产丁酸菌的代表菌株，在直接修复紧密连接（激活AMPK促进组装、抑制HDAC上调基因转录、阻断Zonulin/MLCK通路、协同调控FXR/AhR/凋亡-自噬/Akt/mTOR通路）和间接支持屏障修复（提供能量、调节免疫、促进黏液分泌、重塑菌群稳态）两个层面发挥关键作用。临床研究证实，酪酸梭菌通过修复肠道屏障降低病理性通透性，对肠道病变及肠源性肝、神经、心血管及代谢损伤均具干预价值。随着对“产丁酸菌-丁酸-紧密连接-通透性”调控网络理解的深入，以酪酸梭菌为核心的微生态干预策略能够从源头阻断肠屏障功能障碍相关疾病。

我国在酪酸梭菌的基础研究与产业化应用方面已取得重要进展。其中，酪酸梭菌菌株CGMCC0313-1具有自主知识产权，相关技术已获得中美两国发明专利授权（ZL 200610086642.3，US 7785581）。基于该菌株开发的酪酸梭菌活菌制剂展现出良好的安全性与应用前景，酪酸梭菌活菌胶囊与酪酸梭菌活菌散等微生态制剂已实现规模化生产，并经国家药品监督管理局批准为绿标OTC药品[108-109]。上述成果为以酪酸梭菌为代表的产丁酸基石菌在调控肠屏障通透性的作用机制及临床转化，提供了可靠的菌株资源与制剂保障。

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