近年来，我国心血管疾病的发病率和死亡率不断攀升，心肌纤维化（myocardial fibrosis，MF）作为心脏疾病发生、心功能恶化的重要病理基础，受到越来越多的关注。随着高通量测序等实验方法的发展，肠道菌群及其代谢产物在治疗消化系统、循环系统及免疫系统疾病等方面的作用逐渐显现。本文探讨了肠道菌群代谢产物之一的短链脂肪酸对MF的影响，以为MF的预防及治疗提供新方向。

心肌纤维化（myocardial fibrosis，MF）是指当心肌组织暴露在应激状态下，如缺血性损伤和慢性高血压时，成纤维细胞分化为肌成纤维细胞，产生过多的细胞外胶原和细胞外基质，从而导致心脏的病理性纤维化重塑[1-3]。MF可分为置换性纤维化和反应性纤维化。置换性纤维化通常发生在心肌梗死后，当心肌细胞因缺血性损伤而坏死时，身体的修复机制会在受损区域产生纤维组织来替代心肌细胞，从而形成瘢痕，这种类型的纤维化是局灶性的，只发生在特定的受损区域。反应性纤维化是MF的另一种形式，是由于各种非缺血性因素引起的心肌反应，包括压力负荷、炎症、代谢紊乱、药物毒性等，其特点是纤维组织的沉积较为弥漫，不局限于特定的心肌区域。两种MF对心脏的作用可能截然不同，如置换性纤维化在心肌梗死后促使肌成纤维细胞大量增生，形成有组织的胶原纤维网络，可以预防心肌梗死后心脏的破裂[4]；而反应性纤维化则是成纤维细胞驱动的细胞外胶原和基质长期、不受限制的或过度的激活、沉积，使心脏组织重构，最终引发心力衰竭[5]。在心肌梗死后，如何控制MF的发展至关重要。多项基础和临床研究表明，MF在一定程度上是可以预防和逆转的[6-11]。但目前对MF仍无有效的治疗方法，β受体阻滞剂和醛固酮受体拮抗剂等药物虽已被证实在治疗纤维化方面具有临床益处，但其对MF相关心功能指数的恢复作用仍有限，并不能为MF提供足够的临床干预[12-13]。

人体内有数以万亿计的微生物，其中肠道菌群是寄生在人肠道中的微生物群落，它们在肠道中形成了一个巨大的生态系统，与人类健康和疾病息息相关。其在人体中的作用就像一个内分泌器官，产生影响人体生理功能的生物活性代谢物，如短链脂肪酸（short-chain fatty acids，SCFA）、脂多糖、氧化三甲胺等[14]。其中，SCFA是由复杂碳水化合物和可消化纤维经结肠中的厌氧肠道微生物群细菌发酵而成。结肠中超过90%的SCFA由乙酸、丙酸和丁酸及其相应有机化合物组成，且三者比例固定，约为3  ∶  1  ∶  1，影响体内多种生理过程[15-16]。SCFA的生成涉及多种微生物，如丁酸产生菌、梭状芽孢杆菌、粪便杆菌、乳杆菌和枯草杆菌等丁酸的直接生产者[17]，以及间接产生丁酸并促进丁酸生产的物质，包括普氏杆菌科、梭菌科、放线杆菌、瘤胃球菌科、乳杆菌科、韦氏菌科、巨型芽孢杆菌和乳杆菌[18-19]。SCFA在心血管疾病和胃肠道疾病中均有一定疗效，近年来，国内外研究均发现SCFA与MF关系密切[20-21]。本文分析了肠道菌群代谢产物之一的SCFA对MF的影响，从免疫炎症、氧化应激、组蛋白去乙酰化酶（histone deacetylase，HDAC）抑制三个方面探讨SCFA在MF中的作用，及对MF预防及治疗的前景。

1 SCFA在MF中的作用

1.1 炎症与免疫

研究表明，心肌梗死后，梗死区以促炎的巨噬细胞M1样极化为主，3 d逐渐转为抗炎的M2样极化巨噬细胞，以缓解心肌梗死区的免疫炎症 [22-23]。心肌梗死和心肌修复与巨噬细胞极化的调节有关[24]。施珺菁等研究发现，对心肌缺血模型小鼠进行电针干预可以降低小鼠心肌细胞中巨噬细胞数量，同时促进巨噬细胞向M2型极化，以此抑制心肌梗死后的炎症反应，缓解纤维化[25]。巨噬细胞的极化决定了心肌梗死后炎症期向炎症消退期的过渡，促进心肌梗死后巨噬细胞抗炎的M2样极化可以改善心肌梗死后的心脏损伤[26]。Zhang等将8至10周龄的雄性C57BL/6小鼠进行麻醉并制作心肌梗死模型，手术后连续14天空腹使用乳酸钠进行治疗，结果表明，乳酸钠可通过改善射血分数和缩短分数减轻心肌梗死心功能障碍，降低心肌细胞凋亡，从而抑制纤维化[27]。丙酸通过抑制JNK/P38/NF-κB信号通路的激活、抑制心肌巨噬细胞M1极化以及促进心肌巨噬细胞M2极化，导致不同表型的巨噬细胞旁分泌因子诱导激活不同的成纤维细胞表型[28]。孙奇林等将30只18月龄的C57BL/6J小鼠随机分为对照组、老年糖尿病组和老年经黄芪多糖治疗组，经过16周的干预后发现，黄芪多糖可使老年糖尿病鼠心肌JNK、P38 MAPK及NF-κB水平下降，改善MF[29]。心肌巨噬细胞M2极化可以抑制心肌梗死边界区和非梗死区炎症浸润和纤维化扩张，从而缓解MF[30]。此外，丁酸也可以通过促进巨噬细胞M2的极化，减轻心肌细胞细胞线粒体死亡，从而减轻心肌细胞的损伤，增加心肌成纤维细胞的损伤和死亡，减轻梗死后的纤维化[31-32]。有研究表明，SCFA可以与大肠上皮或大肠固有层内T细胞中的G蛋白偶联受体43（G protein-coupled receptor43，GPR43）结合，诱导T细胞极化为调节性T细胞（regulatory T cells，Treg），也可以与Gpr109a结合，降低白细胞介素6（interleukin-6，IL-6）、白细胞介素8（interleukin-8，IL-8）和肿瘤坏死因子-α（tumour necrosis factor-α，TNF-α）等促炎因子的水平，从而调节宿主的免疫系统[33]。

有研究对野生型和敲除载脂蛋白E2的小鼠分别注射持续14天和28天的血管紧张素Ⅱ以诱导高血压，同时向其饮食中添加丙酸盐，结果显示野生型小鼠对心律失常的易感性显著降低，敲除载脂蛋白E2的小鼠主动脉硬化面积显著减少，丙酸可通过调节性T细胞减弱心肌中T细胞对血管紧张素Ⅱ的反应，抑制辅助性T细胞17（T helper cell 17，Th17）释放促炎因子，抑制心脏成纤维细胞的分化和胶原纤维的合成，从而抑制MF[34]。此外，当通过粪便移植肠道微生物群或使用SCFA重建免疫系统后，发现可以恢复梗死周围区的免疫活性，并提高心肌梗死后的生存率[35]。

1.2 氧化应激

1.2.1 丙二醛

在一项动物实验中，经高脂肪饮食喂养6周后的大鼠心脏出现了梗死、炎症浸润和纤维化，而添加了丁酸钠的高脂肪饮食治疗组却显示出正常的心脏组织结构，证明丁酸钠可以阻止心脏组织梗死、炎症浸润和轻度纤维化[15]。实验还发现，经高脂肪饮食喂养6周后的雌鼠血浆中的丙二醛（malondialdehyde，MDA）水平升高，谷胱甘肽（glutathione，GSH）含量下降，喂食丁酸盐后雌性大鼠的血浆皮质酮水平降低，MDA是脂质过氧化的产物，而GSH是一种重要的抗氧化剂，说明高脂肪饮食喂养后大鼠体内产生氧化应激和抗氧化衰竭；皮质酮是抗氧化或炎症应激的抗炎激素，说明丁酸盐通过降低心肌组织的氧化应激来阻止MF[15]。Nrf2是一种保护细胞免受氧化应激的调节剂，丁酸可以通过激活Nrf2信号通路，促进Nrf2 mRNA的表达增加来增强抗氧化作用，以此阻止氧化应激和抗氧化衰竭导致的MF[36]。同时，在糖尿病大鼠中，血清和心脏中的MDA、丙氨酸氨基转移酶（alanine transaminase，ALT）升高，表明心肌组织损伤；心脏GSH/GSH二硫化物比值升高，表明心肌组织因氧化损伤，证实组织氧化应激可以激活炎症反应，促进细胞浸润、纤维化和正常组织结构的丧失[37]。

SCFA还可以通过抑制HDAC，改善外周胰岛素敏感性、治疗高胰岛素血症，从而减轻心肌组织氧化应激及MF进展。Mikelsaar等认为，SCFA可以通过由GSH过氧化物酶和GSH还原酶组成的完整GSH系统，增加心脏中的超氧化物歧化酶（superoxide dismutase，SOD）和GSH巯基转移酶（glutathione S-transferase，GST）活性抗氧化，从而保护细胞免受氧化应激[38]。

1.2.2 活性氧

在压力负荷引起的MF组织或细胞中，会出现线粒体能量代谢失衡和氧化应激损伤，严重时会加重线粒体结构损伤，导致线粒体自噬或线粒体融合/裂变机制失衡[39-40]。如果线粒体受损结构不能完全修复，则会进一步影响线粒体能量代谢，加剧活性氧（reactive oxygen species，ROS）的过量产生，而ROS可以直接激活心肌成纤维细胞，诱导其分化和增殖，促进细胞外基质合成，引发MF[41]。

线粒体来源的ROS也是调节NOD样受体热蛋白结构域相关蛋白3（NOD-like receptor thermal protein domain associated protein 3，NLRP3）炎症小体激活的一个关键信号。糖尿病患者心肌细胞的能量代谢功能受到严重影响，导致线粒体功能障碍、胰岛素抵抗、内质网应激、心肌细胞凋亡。以上因素往往相互影响，导致心肌肥厚或缺血，心脏舒张和收缩功能异常最终发展为MF和心力衰竭[42-43]。受损心肌还能释放大量NLRP3炎性小体，是NLRP3炎性小体的激活刺激因子[44]。NLRP3的激活会加速心肌梗死后的心脏重构和心功能障碍，NLRP3蛋白的表达增加和炎性小体的组装导致caspase-1介导的成熟和白细胞介素-1β（interleukin-1β，IL-1β）的释放，从而引发炎症和热解，在MF过程中起着至关重要的作用[45]。在肌成纤维细胞中，NLRP3炎性小体激活可引起活化的IL-1β增加，最终刺激胶原合成、细胞外基质蛋白表达和肌成纤维细胞分化，参与MF和心肌梗死后的疤痕修复[46]。而在阵发性或持续性房颤患者的心房心肌细胞中，NLRP3炎性小体活性升高，肌浆网Ca²⁺释放改变，心房有效不应期缩短，从而导致心房肥厚和MF[47]。乙酸可以通过GPR43抑制NLRP3炎性小体的激活，随后通过三磷酸信号通路进一步激活可溶性腺苷酸环化酶（soluble adenylyl cclase，sAC），促进NLRP3炎性小体的泛素化，进而利用自噬途径诱导NLRP3降解，缓解MF[48-49]。因此，SCFA可以作为通过细胞线粒体代谢的能量来源改善线粒体损伤，显著减少ROS和NO的过量产生，阻止MF进展。

1.2.3 HDAC抑制剂

研究表明，组蛋白乙酰化有助于DNA与组蛋白解离，使核小体结构松弛，促进转录因子与DNA结合位点结合，激活基因转录。这一过程受到组蛋白乙酰转移酶（histone acetyltransferase，HAT）和HDAC的调控[50-52]。而醋酸盐具有相当大的HDAC抑制特性，因此在表观遗传调节中发挥着重要作用[53]。在糖尿病大鼠中，补充丁酸钠可抑制HDAC活性，通过IL-6/STAT3信号通路减少心肌细胞胶原纤维和α-平滑肌肌动蛋白的表达，抑制成纤维细胞和肌成纤维细胞的分化，从而起到抗MF的作用[54]。也有研究认为，SCFA通过抑制HDAC改善外周胰岛素敏感性，进而阻止MF[38]。

2 治疗

2.1 饮食干预

研究发现，膳食纤维可以调节肠道菌群结构，改变肠道菌群组成。高纤维饮食可以使SCFA的主要生产者——拟杆菌科家族成员的丰度显著增加[55]。SCFA受体信号可能影响免疫细胞的迁移并抑制炎性细胞因子的产生。膳食纤维可以增加SCFA，通过其免疫与抗炎作用发挥对心梗后心肌的保护作用，主要表现为保护心功能、缩小梗塞面积、减轻不良重构及降低心梗死亡率。

肠道菌群对饮食的改变反应强烈，食用高热量食物会使肠道黏膜氧化应激，导致肠道生态失调，对肠道屏障有益的菌群数量减少，产生内毒素的菌群数量增加，内毒素通过受损的肠道屏障入血，进而损害相应靶器官[56-57]。在对29例超重个体的临床研究中发现，与传统的西方饮食相比，地中海饮食（即低热量、低脂肪饮食）能更大程度降低口服葡萄糖的胰岛素敏感性和低密度脂蛋白胆固醇水平，还使得瘤胃球菌、粪球菌、溶胆链球菌和黄酮因子的丰度减少，丁酸肠单胞菌和嗜粘杆菌的丰度增加[58]。Guo等在一项临床试验中发现，间歇性禁食可能通过增加SCFA的产生和降低循环系统中脂多糖（lipopolysaccharide，LPS）的水平发挥心血管保护作用[59]。

2.2 菌群移植

粪便微生物群移植（fecal microbiota transplantation，FMT）是一种新兴的治疗方式，通过将供体微生物群移植至受体肠道内，重建受体肠道微生态结构，从而治疗与肠道微生物群失调相关的慢性病。Battson等将肥胖小鼠的盲肠菌群移植到正常对照组小鼠的盲肠后发现，与接受相同菌群移植的肥胖小鼠组相比，正常对照组小鼠的肠通透性增大且盲肠SCFA含量升高，心脏缺血再灌注后的梗死面积减小[60]。

2.3 益生菌

益生菌已被证明可以减少心肌梗死面积、动脉粥样硬化斑块面积，以及降低梗死后心肌肥厚和心力衰竭的发生率[61-63]。研究表明，丁酸盐水平在心力衰竭患者中降低[64]，补充含有植物乳杆菌的益生菌混合物可以改善代谢综合征，从而避免其引起的心脏损害，同时植物乳杆菌的益生菌混合物可以丰富拟杆菌属[65]，促进SCFA的产生，减轻炎症和心肌肥厚，并改善心肌梗死后的心功能[66-67]。

3 小结

MF导致的心肌重构常伴随多种心血管疾病，并促使其加速发展，直至心衰。因此，抑制MF至关重要。然而，目前治疗MF药物的临床疗效并不理想。近年来，肠道菌群及其代谢产物在免疫、抗氧化、抗肿瘤等方面显示出了独特的作用。SCFA作为一种肠道菌群代谢产物，为MF的治疗提供了新思路。但是，目前仍缺少SCFA抗MF的直接证据，对于心梗后如何控制MF不过度进展的研究也较少。因此，寻找SCFA如何直接影响MF及对其机制进行研究将为未来MF的治疗提供新的参考。

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