2022, Vol. 49
嗜黏蛋白阿克曼菌在疾病中的保护性作用及机制研究进展
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文章信息
- 陶晴, 王嫘, 彭宇明, 高千
- TAO Qing, WANG Lei, PENG Yuming, GAO Qian
- 嗜黏蛋白阿克曼菌在疾病中的保护性作用及机制研究进展
- Protective effect of Akkermansia muciniphila in diseases and the mechanisms
- 微生物学通报, 2022, 49(5): 1912-1926
- Microbiology China, 2022, 49(5): 1912-1926
- DOI: 10.13344/j.microbiol.china.210812
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文章历史
- 收稿日期: 2021-09-06
- 接受日期: 2021-12-21
- 网络首发日期: 2022-01-28
陶晴, 王嫘, 彭宇明, 高千. 嗜黏蛋白阿克曼菌在疾病中的保护性作用及机制研究进展[J]. 微生物学通报, 2022, 49(5): 1912-1926.
TAO Qing, WANG Lei, PENG Yuming, GAO Qian. Protective effect of Akkermansia muciniphila in diseases and the mechanisms[J]. Microbiology China, 2022, 49(5): 1912-1926.
嗜黏蛋白阿克曼菌在疾病中的保护性作用及机制研究进展
南京大学医学院转化医学中心 江苏省分子医学技术重点实验室, 江苏 南京 210093
摘要: 嗜黏蛋白阿克曼菌(Akkermansia muciniphila，Akk)是人类肠道正常存在的常见共生菌，丰度约占肠菌的1%−3%。Akk是极少数已知在肠道平衡态下仍能引发T细胞依赖性免疫作用的肠菌，提示该菌可能参与正常肠道免疫耐受过程。疾病和模型动物研究表明，Akk在改善宿主代谢功能和免疫应答方面具有重要作用，近期引起广泛关注。目前相关研究大多集中在Akk与疾病的相关性上，尚无系统阐述其作用机制的研究。本文对Akk与人体几大重要系统疾病和免疫之间的关联及其作用机制进行论述，以期为Akk的有效利用提供证据和思路。
关键词:
嗜黏蛋白阿克曼菌 肠道免疫稳态 代谢性疾病 神经性疾病 癌症
Protective effect of Akkermansia muciniphila in diseases and the mechanisms
Jiangsu Key Laboratory for Molecular Medicine, Translational Medicine Center, Medical School of Nanjing University, Nanjing 210093, Jiangsu, China
Abstract: The intestinal symbiotic Akkermansia muciniphila comprises 1%–3% of gut microbiota, which induces T cell-dependent immune response during intestinal homeostasis. Thus, it may be involved in immune tolerance of normal gut. Experiments on disease and model animals have proven the vital role of this bacterial species in improving metabolic functions and immune response of the hosts, which has attracted the interests of scholars. Previous studies mainly focused on the correlation between A. muciniphila and diseases, but the mechanisms have not been systematically explored. This study aims to discuss the relationships of A. muciniphila with diseases in major human systems and immunity and the mechanisms, which is expected to provide evidence and routes for effective utilization of this bacterial species.
Keywords:
Akkermansia muciniphila gut immune homeostasis metabolic disease neurological disease cancer
肠道菌群平衡在人类健康中起重要作用，其组成和丰度变化会明显影响肠道局部或全身组织和器官功能。嗜黏蛋白阿克曼菌(Akkermansia muciniphila，Akk)是众多肠道细菌中丰度相对较高的一种以嗜肠黏膜表面黏液为生的共生菌，定殖于黏液层，与肠壁相互作用，在调节肠壁通透性和维持肠道屏障功能中起重要作用，其存在和丰度变化影响机体代谢和免疫状态。研究发现，该菌具有抗感染、免疫调节、促进代谢、抗肿瘤等作用，成为肠菌研究中的“明星菌”，具有重要的转化价值。
1 Akk是常见肠道共生菌2004年，荷兰科学家阿克曼(Antoon D. L. Akkermans)及其团队在使用纯化的黏蛋白作为生长培养基中唯一的碳源时，首次从人类粪便中分离出一种新的粘液降解菌并将此菌命名为嗜黏蛋白阿克曼菌(Akkermansia muciniphila，Akk)[1]。Akk是疣微菌门成员中的一种，疣微菌门还包括突柄杆菌属、Rubritalea及疣微菌属，但Akk是疣微菌门唯一能被培养的肠道菌代表。2017年，研究人员先后对2个菌株Akkermansia muciniphila ATCC BAA-835和Akkermansia glycaniphila PytT进行了全基因组测序[2]。A. muciniphila ATCC BAA-835的完整基因组是由一条2 664 102 bp的环状染色体组成，平均GC含量为55.8%，该基因组共有2 176个预测的蛋白质编码序列，总编码能力为88.8%[3]。Akkermansia glycaniphila PytT基因组由一条3 074 121 bp的染色体组成，包含2 532个CDS、21个tRNA基因和3个完整的rRNA操纵子，同时，基因组结果分析显示该基因组具有降解黏蛋白和有氧呼吸的功能[4]。2020年日本科学家从健康日本男性粪便中分离出携带质粒pJ30893的Akk JCM 30893菌株，其染色体长2 845 645 bp，GC含量为55.6%，编码2 332个蛋白质编码基因和54个tRNA、3个5S rRNA、3个16S rRNA和3个23S rRNA基因[5]。截至目前，pJ30893质粒与公开数据库中的任何基因组都没有显著的相似性。2021年Karcher等通过来自NCBI的188个分离基因组(119个标记为Akkermansia muciniphila和69个标记为Akkermansia spp.)、来自人与动物构成的2 226个宏基因组和6个来自人类肠道分离株的新基因组，共2 420个基因组对嗜黏蛋白阿克曼菌属进行了大规模群体基因组学分析[6]。基因组学结果显示，Akkermansia菌株大致可分为5个候选物种，Akk、SGB9223、SGB9224、SGB9227和SGB9228，尽管16S rRNA基因序列很相似，但它们显示出显著的全基因组差异，这5个候选物种在给定宿主内表现出强烈的共排斥，在亚种上进行系统发育的分层。同时，5个候选物种广泛定殖于不同年龄的宿主，分布于不同的地理位置[6]。Akk的全基因组测序结果发现，许多基因编码黏蛋白降解酶，包括糖苷酶和硫酸酯酶，这些酶在黏蛋白降解中发挥重要作用，它们会释放聚糖以促进黏蛋白降解细菌的生长并影响肠道微生物[7]。Liu等通过转录组学和代谢组学研究发现，当黏蛋白在BHI培养基中达到一定浓度时，Akk才能在基因和代谢物水平上显著响应培养环境，并通过改变对碳水化合物和氨基酸的影响来改变其代谢特征[7]。Akk发挥代谢特性主要归因于黏蛋白降解酶。Akk是一种革兰氏阴性厌氧菌，广泛分布于动物和人肠道中，在盲肠中数量最多，可在黏膜的不同部位及粪便样品中检出，约占人体肠道微生物总量的1%–3%，其最适生长温度和酸碱度分别是37 ℃和pH 6.5[8]。Akk以粘液为碳、氮和能量来源，产生乙酸、丙酸等短链脂肪酸及较小的1, 2-丙二醇和琥珀酸酯等产物[9]。影响Akk生长的另一因素是氧[10-11]。有报道指出，Akk并非严格厌氧菌，相反地，该菌能从低氧环境中获益。如在含有低水平氧气的粘液层中，Akk产生的乙酸可转化为丙酸，可致ATP和NADH的含量增加，促进Akk的生长[12]。最近的研究进一步发现，胆汁也会影响Akk的生长[13]，其丰度与小鼠体内循环的原发性胆汁酸呈正相关[14]。与不含胆汁的培养基相比，添加0.1%−1.0%的猪胆汁提取物促进Akk生长[13]。进一步研究发现，添加0.5%或更高浓度的纯化胆汁盐会抑制Akk生长，而添加0.1%的纯化胆汁盐不会抑制生长[15]。因此，Akk的肠内丰度也要考虑胆汁代谢的影响。
针对Akk代谢功能的研究发现，该菌能够合成除L-苏氨酸以外的所有必需氨基酸。此外，Akk能降解多种单糖，如葡萄糖、N-乙酰氨基葡萄糖、N-乙酰半乳糖胺和岩藻糖[10]，其意义不明。Akk在胃肠道中定殖后具有抗酸能力，在新生儿胃中具有降解人乳寡糖的能力[16]。研究发现，Akk不编码可以将果糖-6-磷酸转化为氨基葡萄糖-6-磷酸的6-磷酸葡糖胺合成酶，其膜蛋白Amuc_1822上的Amuc-NagB在生理条件下无法从果糖-6-磷酸生成氨基葡萄糖-6-磷酸，影响肽聚糖的形成，后者对细胞壁的形成十分关键[17]。相反地，Amuc-NagB能有效催化上述反应的逆反应[17]。为了克服这种缺陷，需要在培养基中添加N-乙酰氨基葡萄糖以用于Akk的生长[17]。
Akk与宿主的关系还体现在参与肠黏膜的完整性和宿主免疫耐受上[18]。Akk可以促进肠道上皮细胞的增生和黏液层的增厚、改善肠道炎症状态、促进肠黏膜修复，其在粘液层中的定殖既保护了上皮细胞，也为其他定殖共生菌的生长提供了能量[19]。当肠内Akk水平较低时可致肠屏障功能减弱、肠黏液层变薄、通透性增加，甚至黏膜损伤，使毒素更易侵入宿主[20]。目前尚不清楚关于Akk刺激肠粘液分泌增加的机制。
此外，Akk会随增龄而变化。该菌定殖始于幼儿时期，但在老年人群中数量明显减少[21-22]。不仅如此，在怀孕期间，Akk在超重孕妇肠道内丰度高于正常体重孕妇[23-24]。Akk也存在于产妇母乳中，因此母乳可能作为一种载体将Akk从母亲转移到婴儿，这也解释了新生儿胃肠道内有Akk的存在[25-26]。婴儿肠道内Akk的定殖有利于婴儿肠道菌群的建立，可能也与其免疫功能的成熟相关[11]。
2 Akk改善代谢性疾病症状常见的代谢性疾病包括肥胖、2型糖尿病(diabetes mellitus type 2，T2DM)和脂肪肝等，近年有逐年增高趋势。肠道菌群由于可产生多种代谢产物，其中含有可作为黏膜内多种细胞类型信号分子的结构成分，因此可通过调节肠道内分泌细胞合成和/或释放多种激素(胆囊收缩素、胰高血糖素样肽1、5-羟色胺及胃饥饿素等)调节胰岛素敏感性、脂肪储存和食欲等[27]。此外，与肠道菌群密切相关的机体低度炎症状态也与糖脂代谢紊乱相关[28]。低度炎症和肠菌组成改变是T2DM的显著特征，有充分证据显示，肠道菌群和饮食之间相互作用所促进的慢性低度炎症是促进T2DM发生的一个重要因素[29]。肠道细菌和细菌内毒素可通过破坏肠壁屏障导致细菌毒素甚至活菌侵入机体，可能是影响T2DM发展的另一个重要因素[30]。
在诸多菌群中Akk表现出较强的抗代谢紊乱功能。从高脂模型小鼠中选出胰岛素抵抗(insulin resistance，IR)小鼠进行16S rRNA基因测序发现，与对照组相比，IR小鼠肠道Akk菌丰度明显下降，说明高脂诱导下IR组小鼠糖脂代谢更加明显，可能与小鼠肠道内Akk菌丰度呈负相关[31]。与动物实验结果类似，在超重和肥胖的个体中Akk菌丰度也出现降低[32]。Shin等最初的研究发现，给高脂饮食的模型小鼠口服Akk可明显改善其葡萄糖耐量，提示Akk在T2DM中具有潜在的保护作用[33]。Depommier等证实，给超重/肥胖志愿者口服3个月Akk，不仅安全性和耐受性良好，受试者的胰岛素敏感性也得到大幅改善，并且血浆总胆固醇、肝功能障碍和炎症相关标志物水平及受试者体重降低，但受试者的肠道菌群组成无明显变化[34]，提示Akk可能通过直接作用改善机体代谢。与上述发现一致，在临床肥胖症和2型糖尿病患者粪便中，Akk的丰度降低，补充益生元可使Akk的丰度逆转，并与代谢状况改善一致[35]。Everard等在肥胖和T2DM小鼠模型中得到了同样的结果，同时发现高热灭活处理的Akk并未改善代谢或黏液层厚度的作用，但当给予有活性的Akk治疗时不仅可逆转高脂肪饮食引起的代谢紊乱，包括脂肪量增加、代谢性内毒素血症和胰岛素抵抗，而且提高了控制肠道炎症、修复肠道屏障和肠道肽分泌的内源性大麻素水平[36]。对肥胖和超重人群进行进一步临床热量限制试验，结果表明Akk丰度与空腹血糖、皮下脂肪细胞直径和腰臀比呈负相关[37]。Akk丰度较高的个体表现出较好的代谢特征，包括改善的胰岛素敏感性等，这表明Akk菌在帮助身体应对胰岛素抵抗方面起着保护作用[38]。有研究进一步发现，IR是由活化的先天4-1BBL+B1a细胞(也称为4BL细胞)诱导的，这些细胞随着衰老过程中肠道共生菌的变化和有益代谢物(如丁酸盐)的减少而积累；其中，共生菌Akk的丧失会损害肠道完整性，导致内毒素等细菌产物的泄漏，当丁酸盐减少时内毒素会激活CCR2+单核细胞；在渗入网膜后，CCR2+单核细胞将B1a细胞转化为4BL细胞，进而通过表达4-1BBL诱导IR，可能会触发4-1BBL受体信号传导，引起如肥胖诱导的代谢紊乱[39]。
在机制研究方面，Lukovac等使用一种新的小鼠回肠器官体外模型研究微生物对宿主上皮的影响，他们观察到Akk及其代谢物丙酸酯可通过影响上皮细胞内多种代谢调节因子如Fiaf、Gpr43、HDACs和Pparγ的表达参与细胞的脂代谢[40]。高脂饮食小鼠模型研究还发现，Akk分泌的胞外囊泡可诱导附睾脂肪组织中PPAR-α和PPAR-γ mRNA的表达增加，影响脂肪酸氧化和能量代谢[41]。Akk还可调节TLR2和紧密连接相关蛋白的表达，提升肠道屏障功能[41]；其释放的胞外囊泡降低了高脂饮食诱导的结肠炎小鼠的肠道通透性，缓解了动物的肥胖症状[42]。值得注意的是，Akk的补充减轻了高脂饮食诱导的棕色脂肪白色化，促进了循环血液中游离脂肪酸和葡萄糖的利用，游离脂肪酸和葡萄糖可作为维持棕色脂肪组织产热的底物，确保棕色脂肪细胞的形态和功能[43]。此外，Akk产生的大多数蛋白质都与该菌的碳水化合物及氨基酸的运输和代谢有关[44]，这种代谢特点可能对肠道内环境及肠代谢功能产生有利影响。最近的研究还发现，巴斯德灭活的Akk可能有更好的代谢改善功能，而高温灭活的Akk则无此作用，提示Akk提供的“良性”作用可能是通过热敏感因子如蛋白质等发挥的[45]。进一步研究证实，分离得到的Akk外膜脂蛋白Amuc_1100具有代谢改善的活性，其可能通过TLR2信号通路发挥作用[46]。我们在前期研究中发现，葛根素在改善宿主肥胖和胰岛素抵抗病理的过程中存在明显的Akk富集和肠道屏障功能改善，提示葛根素可能通过影响肠道Akk丰度发挥其代谢调节功能[47]。
肠道菌群的组成变化与非酒精性脂肪肝疾病的发生、发展也有着密切的联系，其机制不明。有研究显示，肠道菌群与肝病之间有很强的联系，肠道菌群是Toll样受体(Toll like receptor，TLR)配体的重要来源，其组成变化可改变TLR信号通路的平衡[48]。后者可刺激肝细胞和局部巨噬细胞等产生促炎细胞因子(IL-1β、TNFα、IFN-γ等)增加肝损伤[49]。已知非酒精性脂肪性肝炎的发病机制与多个TLR信号通路相关，包括TLR2、TLR4、TLR5和TLR9，它们分别识别脂多糖(lipopolysaccharide，LPS)、肽聚糖、鞭毛蛋白和细菌DNA[50-51]。事实上，在酒精性脂肪性肝炎患者和实验性酒精性肝病小鼠模型的粪便中均发现Akk丰度降低；而Akk灌胃后可增加实验性酒精性肝病小鼠的黏液层厚度和紧密连接蛋白表达，促进肠屏障修复[52]。有文献报道小檗碱能通过介导IL-6/STAT3信号通路激活并上调血液和肝脏中具有免疫抑制功能的G-MDSC样细胞，同时改变整体肠道微生物群落，主要是增加Akk的丰度，从而减轻急性-慢性酒精性肝损伤[53]。基于Akk菌在肝损伤中具有抑制炎症、增强免疫及恢复肠道菌群多样性的功能，表明其在维持肠道稳态内环境平衡中发挥作用。上述证据表明，补充Akk菌可能是预防和治疗肝损伤的一个新方法[54]。
3 Akk具有抗衰老功能年龄的增加会引起一系列生理改变，如胃动力障碍、肠神经系统功能退化等，对肠道菌群的多样性、组成和功能都有重要的影响，主要表现为肠道菌群多样性减少、核心种属丰度(双歧杆菌、柔嫩梭菌、厚壁菌与拟杆菌比值等)降低及次优势种属丰度升高(如变形菌门等增加)[55-56]。值得注意的是，对于长寿老人(百岁老人)而言，其菌群改变表现出某些特殊性，虽然他们的菌群多样性更低(双歧杆菌、厚壁菌门、肠杆菌等丰度降低)；但其乳杆菌属、拟杆菌属、梭状芽孢杆菌特别是Akk的丰度增加[57-58]。相反地，在4个月的LmnaG609G/G609G早衰小鼠中，Akk丰度明显减少[59]。通过口服方式给LmnaG609G/ G609G小鼠补充Akk，小鼠获得了适度的寿命延长(P=0.016)，表明Akk可能具有减缓衰老的作用[59]。进一步对小鼠进行代谢组学研究发现，补充Akk其一级胆汁酸经过肠道微生物代谢后的二级胆汁酸水平增加，与老龄症状改善一致，这也与此前发现的早衰小鼠中二级胆汁酸水平减少的结果相符合[59]。
在上述实验中，研究者还发现，补充Akk后在回肠上皮中诱导了Reg3g和Tf3等蛋白的表达，这些蛋白可以促进细胞增殖，抑制炎症，有利于肠黏膜层受损后的修复愈合[60]。这些研究表明，衰老过程存在肠道Akk丰度减少，而在长寿老人中Akk水平的不减反增，可能是这类个体“逃逸”或“对抗”老化病理的原因之一。事实上，Akk可能通过产生粘液和脂质代谢产物如短链脂肪酸等维持肠道屏障的完整性，控制病原的扩散。相反地，Akk等益生菌的缺失可致慢性炎症和免疫失衡，增加老年相关疾病的病理性放大因素。有研究甚至发现，上述益生菌的减少和缺失损害对突变和衰老细胞的清除，进一步降低器官功能，增加癌症等风险[61]。
4 Akk参与神经性疾病的可能机制近年来的研究将中枢神经系统、自主神经系统(肠神经系统)、消化道及肠道菌群视为一个整体，提出了“脑-肠-菌轴”的概念，提示肠道菌群与神经系统功能密切相关[62-63]。文献表明，肠道菌群与中枢神经系统存在双向调节作用，一方面，肠道菌群通过代谢分子直接或间接地影响中枢；另一方面，中枢下行信号也通过控制肠道分泌、运动、免疫和内分泌等影响肠菌生态。例如上行迷走神经本身即表达胆囊收缩素、胰高血糖素样肽1及5-羟色胺等肠肽受体，将肠内信息传入大脑，而肠菌可调节这些肠肽的表达[64-66]。这些改变引起了多种神经性疾病的发生和发展。
阿尔兹海默症(Alzheimer’s disease，AD)是老年人群中一种常见的神经退行性疾病，可致严重的认知障碍和大脑皮层的明显病理变化，包括淀粉样β蛋白的沉积和Tau蛋白的过度磷酸化等[67]。早在2016年已有研究发现，抗生素诱导的肠道菌群改变会影响AD小鼠模型的神经炎症和淀粉样变性[68]。Kumar等的研究结果也证实了这一点，在5XFAD转基因小鼠胃肠道菌群的定殖加速了大脑β-淀粉样蛋白的沉积[69]。在APP/PS1 AD小鼠模型露天试验中，研究者发现Akk减轻了小鼠对自身和环境关注减少的现象[70]。Y-迷宫测试显示，高脂饮食会加重APP/PS1小鼠的学习和空间记忆能力的损害，Akk可以明显改善上述症状，提示Akk可能通过改善肠屏障功能等，减轻大脑炎症和Aβ的沉积[70]。16S rRNA基因测序结果显示，与对照小鼠相比，肠道菌群组成存在显著差异，主要表现为Rikenellaceae和Akk的减少[70]。事实上，肥胖和T2DM存在Akk丰度降低现象，而这2种疾病已知是AD发展的危险因素。
癫痫是最常见的脑部慢性非传染性疾病，主要由脑部神经元突发异常放电导致短暂的脑功能障碍。如今，全球癫痫病人高达7 000万人[71]，暂无有效的治疗手段。有研究发现，生酮饮食可以用来治疗难治性癫痫，可能与生酮饮食改变癫痫小鼠的肠道菌群组成和丰度、降低其α多样性、提高Akk和Parabacteroides丰度有关[72]。在无菌小鼠中，生酮饮食不能发挥其抗癫痫作用，当同时给予Parabecteroides和Akk时可恢复生酮饮食的抗癫痫功能[72]。进一步研究发现，Akk和Parabacteroides可致循环γ-谷氨酰化氨基酸减少及海马GABA/谷氨酸水平升高，降低了γ-谷氨酰转肽酶的活性，从而抑制γ-谷氨酰化，进而对癫痫发作起抑制作用[72]。在Kcna1−/−小鼠中，大剂量抗生素治疗致微生物群耗竭，会增加癫痫的发生率[72]。然而，肠道细菌的重新定殖消除了抗生素治疗的这些作用[72]。相反地，临床脑性瘫痪和癫痫症儿童(n=25)与健康儿童(n=21)的粪便16S rRNA基因测序发现，前者的肠道微生物多样性明显高于健康组(P < 0.001)，并且他们的双歧杆菌、链球菌和Akk显著富集而拟杆菌、费氏杆菌等减少，提示肠菌与癫痫等疾病的关系存在复杂的平衡，确切的机制目前还不清楚，不排除与Akk丰度过高有关[73]。
自闭症谱系障碍(autism spectrum disorder，ASD)是一种先天神经障碍，常与胃肠道营养关联[74-75]。Xu等通过对254名ASD儿童的肠道微生物研究发现，与对照组相比，ASD儿童的Akk、拟杆菌、双歧杆菌和副杆菌在检测到的总微生物群中的占比较低，而粪杆菌的占比较高，表明ASD与微生物群组成的改变之间存在关联[76]。ASD患者肠道菌群紊乱可能通过破坏肠黏膜屏障、增加肠道通透性促进疾病的发生和发展。自闭症儿童肠道中Akk的相对丰度较低，导致黏液屏障发生变化，不仅如此，自闭症患者肠道通透性异常的比例很高[77]。一项研究表明，生酮饮食可以提高ASD小鼠的社交能力，同时其也可以逆转ASD小鼠体内Akk丰度的下降，这与对照组相似；总体而言，肠道微生物群及其代谢物起着关键作用，通过“脑肠轴”在神经精神疾病的发生发展中发挥作用[78]。总之，ASD与肠道菌群的确切关系有待深入研究。
5 Akk在肿瘤免疫治疗中发挥作用在癌症治疗中，目前使用最广泛的免疫抑制剂是针对程序性死亡受体-1 (programmed death-ligand 1，PD-1)及其配体L1的单克隆抗体。PD-1阻断对晚期黑色素瘤、非小细胞肺癌和肾癌的治疗有效[79]。最新研究发现，肠道细菌影响癌症免疫治疗的有效性[80]。例如，在一项针对249名肺癌、肾癌等癌症患者进行的免疫抑制剂治疗中，69名接受广谱抗生素(broad- spectrum antibiotics，ATB)治疗的患者，其癌症复发率更高、存活时间更短[81]。在免疫反应较好的患者中，Akk的丰度与免疫检查点抑制剂(immune checkpoint inhibitor，ICI)显著相关[82]。将对ICI治疗有效小鼠的粪便移植给无菌小鼠，可致小鼠肿瘤生长延缓，肿瘤微环境中的CXCR3+ CD4+ T细胞积聚及脾脏中T细胞的PD-L1上调，明显改善了PD-1的疗效[83]。将对ICI不敏感的小鼠粪便移植给无菌小鼠，并比较不补充Akk和补充Akk这2种情况，发现补充Akk能恢复PD-1对ICI的反应，同时伴随CD4+ T细胞分泌的小肠相关趋化因子受体CCR9和Th1相关趋化因子受体CXCR3的积累[80, 83-84]。不仅如此，Akk的定殖与瘤内肉芽肿的形成和诱导树突细胞产生IL-12有关，而IL-12依赖性方式可在一定程度上恢复PD-1阻断的功效，提示Akk在癌症免疫治疗中发挥作用[85]。机制研究发现，在接受PD-1阻断治疗的癌症患者循环CD4+和CD8+ T细胞中，唯一与临床结果改善相关的免疫反应，是CD4+和CD8+ T细胞对Akk的反应，并且伴随更多干扰素的释放，而后者与延长患者生存期相关[86]。还有研究发现，在结肠炎和结直肠癌患者及相关疾病小鼠模型粪便中发现，Akk丰度明显降低[87]。通过口服巴氏灭活的Akk或其外膜蛋白Amuc_1100，可增加结肠和肠系膜淋巴结中细胞毒性T淋巴细胞(cytotoxic T lymphocyte，CTL)的数量，上调其TNF-α表达、抑制PD-1表达，进而对小鼠结肠炎和结直肠癌起抑制作用。在CTL-结肠癌细胞共培养实验中，Amuc_1100预处理可激活并增加脾脏来源的CTL，解释了Akk提高免疫疗效的可能机制[45]。不仅如此，Akk与其他抗癌药物如醋酸阿比特龙(abiraterone acetate，AA)——一种雄激素生物合成的抑制剂，其治疗效果也存在关联。例如，在前列腺癌治疗中发现，AA可致患者肠道Akk富集，在排除了免疫相关因素参与后，体外模拟实验中观察到AA同样诱导了Akk富集[88]。该实验结果显示，Akk可能介导了AA对去势抵抗性前列腺癌的治疗作用。预期未来粪便移植和特定菌分泌因子或蛋白的治疗可能成为癌症治疗的一种手段。
6 Akk影响免疫炎症过程炎症是一种先天免疫反应模式，在多数疾病的发展中至关重要。多项研究表明，Akk参与了这种免疫-炎症的调控过程。在细菌中的病原相关分子模式(microbe-associated molecular pattern，MAMP)是指一组生物大分子，如脂多糖、蛋白和核酸等，可被宿主的模式识别受体(pattern recognition receptor，PRR)所识别，并诱导免疫-炎症反应[89]。事实上，除了外源性病原外，体内组织损伤释放的损伤相关分子模式(damage-associated molecular pattern，DAMP)也会被PRR识别，从而引发非细菌性炎症[90]。TLR是最重要的PRR分子，存在于多种细胞类型中。在肠道中，TLR是最有代表性的PRR，其中TLR2/4/5等与细菌识别有关。在肥胖症和2型糖尿病研究中发现，Akk可以特异性激活TLR2受体，上调紧密连接蛋白Cldn3 (编码claudin 3)和Ocln (编码occludin)，但不激活TLR5/9或NOD2受体等[91]。进一步研究发现，Akk的外膜脂蛋白Amuc_1100可能是Akk激活TLR2受体的关键分子，可增强调节性T细胞和抗炎细胞因子的产生[46]。Ashrafian等的研究显示，在Caco-2细胞中，Akk激活TLR2和TLR4受体，同时上调其表达量[18] (图 1)。Ottman等在对HEK-Blue细胞的研究中也观察到了相同的结果[11]，提示Akk可能主要通过激活TLR2受体发挥作用。研究还发现Akk影响肠道免疫细胞组成，增加B细胞总数，同时减少T细胞和嗜中性粒细胞数量；降低树突状细胞激活标记MHCII的表达和B细胞CD86的表达[92]。
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| 图 1 Akk对部分组织器官功能影响的分子机制[18] Figure 1 Molecular mechanism of the effect of Akk on the function of some tissues and organs[18]. 食物进入肠腔后被肠菌发酵分解成碳水化合物和蛋白质等，形成短链脂肪酸等代谢物产物。同时，肠腔内存在大量菌群(包括Akk)，肠道菌群刺激肠上皮细胞激活TLR通路，可促使胰腺、肝脏组织分泌大量炎症因子。肠菌可产生γ-谷氨酰化氨基酸激活GABA/Glu通路释放出大量的神经递质如GABA和5-HT，进而调节神经免疫，影响神经内环境稳态 Food enters the intestinal lumen and is fermented and decomposed by intestinal bacteria into carbohydrates and proteins, forming metabolite products such as short-chain fatty acids. At the same time, a large number of flora (including Akk) exist in the intestinal lumen, and flora stimulate intestinal epithelial cells to activate TLR pathway, which can lead to the secretion of large amounts of inflammatory factors from pancreatic and liver tissues. Enterobacteriaceae can produce γ-glutamylated amino acids to activate the GABA /Glu pathway to release large amounts of neurotransmitters such as: GABA and 5-HT, which in turn regulate neuroimmunity and affect the homeostasis of the neuroendotropic environment. |
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此外，在Ⅰ型糖尿病小鼠模型中，使用万古霉素可改善疾病表型，测序发现Akk丰度显著增高，研究者提出Akk可能在自身免疫病中发挥重要作用[93]。2017年一项研究显示，在NOD.Cg- PrkdcscidIl2rgtm1Sug/JicCrl (NOD)小鼠中，Akk可以通过调控肠道菌群影响胰岛自身免疫，改善Ⅰ型糖尿病表型；在Ⅰ型糖尿病小鼠模型中，发病率较高的小鼠肠道内缺失Akk，并且移植后很难定殖于自身免疫亢进的NOD小鼠体内[94]，表明Akk的定殖与免疫环境、小鼠遗传背景有关。提高肠道Akk丰度的方法包括摄入有益菌、二甲双胍、某些抗生素和中药成分[95]，然而高脂饮食和过量饮酒等则降低肠道Akk丰度。
Akk虽然在修复黏膜上皮、缓解炎症和改善自身免疫中发挥治疗作用，但与健康人相比，发现Akk在帕金森患者和多发性硬化患者的肠道中丰度增高[96]。在临床试验中发现帕金森患者肠道中Ⅰ型Akk的丰度与血清尿酸水平呈正相关，而二者水平与帕金森患者病程呈负相关[97]。因此，肠道中低丰度的Akk和低水平的血清尿酸为早期的帕金森诊断提供了新的检测标志物。此外，卒中诱导的胃肠道黏膜菌群改变主要表现为Akk及梭菌的丰度增加，其意义不明[98]。这些研究表明，Akk在特定条件下也可能存在致病作用，提示肠道微生物中Akk平衡值得关注。例如，研究发现硫酸软骨素可促进硫酸酯酶分泌菌和硫酸盐还原菌的生长，当硫酸酯酶分泌菌和硫酸盐还原菌的含量与Akk相差过大时，硫酸软骨素加重骨关节炎，而在菌群平衡的条件下硫酸软骨素改善关节炎[99]。
7 结论Akk作为一种与宿主的代谢和免疫功能存在明确相互作用的重要共生菌，必然对宿主的多种组织器官功能发生影响，因此也与多种疾病的发展关联，在临床疾病的预防、诊断监测和干预治疗中具有很大的转化潜力，包括有望成为代谢性疾病、神经性疾病和癌症免疫治疗的辅助调节靶标。动物实验和人体干预表明，口服Akk或其外膜脂蛋白Amuc_1100有很好的安全性和有效性，但也存在不一致的结果，表明我们目前关于Akk的作用和机制的认识还存在缺陷，其应用于临床疾病干预仍需更多的研究验证。
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