
中国科学院微生物研究所,中国微生物学会
文章信息
- 黄桥深, 张永康, 汪水平, 谭支良, 刘勇. 2023
- HUANG Qiaoshen, ZHANG Yongkang, WANG Shuiping, TAN Zhiliang, LIU Yong.
- 嗜黏蛋白阿克曼氏菌治疗疾病的潜力与作用机制研究进展
- Potential and mechanism of Akkermansia muciniphila in disease treatment
- 微生物学报, 63(9): 3360-3373
- Acta Microbiologica Sinica, 63(9): 3360-3373
-
文章历史
- 收稿日期:2023-01-04
- 网络出版日期:2023-03-22
2. 中国科学院亚热带农业生态研究所 亚热带农业生态过程重点实验室, 湖南 长沙 410125
2. Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, Hunan, China
嗜黏蛋白阿克曼氏菌(Akkermansia muciniphila, AKK)是一种属于疣微菌门(Verrucomicrobiae)的肠道共生菌,具有多个遗传分支和表型多样性[1]。AKK以杯状细胞(goblet cells)分泌的黏蛋白作为主要碳源和氮源,通过自身分泌型代谢酶分解代谢生成短链脂肪酸(short-chain fatty acids, SCFAs)为其提供能源物质,同时,AKK可促进杯状细胞分泌黏蛋白,维持肠腔黏液黏蛋白的动态平衡,促进肠黏膜屏障功能。此外,AKK还可通过胆汁酸、代谢酶、膜脂和膜蛋白等功能成分调控肠、肝、脑和肾等实质器官的代谢功能,在治疗代谢紊乱和免疫炎症等疾病中发挥重要作用[2-4]。AKK对肠易激综合征[5](irritable bowel syndrome, IBS)和脂肪肝等消化系统疾病、机体代谢紊乱性疾病、神经退行症以及癌症等均有改善作用。本文系统概述了AKK的分布规律与生物学特性及其在消化系统疾病、神经系统疾病、机体代谢紊乱以及癌症等多种疾病中的治疗潜力及其作用分子机制,以期为AKK应用在疾病治疗中提供理论基础。
1 AKK的分布规律及生物学特性 1.1 AKK分布规律AKK最初是从健康成人粪便中分离出的一株黏液降解菌[6],约占健康个体肠道微生物区系的3%–5%[7],其模式菌株为AKK MucT[8]。AKK在哺乳动物的小肠(空肠和回肠)和大肠(盲肠和结肠)段均可定殖并以结肠段为主[9]。AKK在人类婴幼儿时期的肠道内就开始定殖并快速生长富集,一年内便可达到成人肠道AKK丰度水平,此后其丰度随着年龄的增加、疾病的发生而逐渐降低。有研究表明,在长寿老人体内AKK的丰度值会比普通老人(65岁以上)更高[10],小鼠试验也表明AKK单菌移植可通过恢复早衰症小鼠回肠中的次级胆汁酸含量进而改善早衰症小鼠的健康状况并延长寿命[11]。随着对AKK的研究的不断深入,在人体鼻咽、胆道系统、口腔甚至母乳中均有发现AKK定殖[9],其中,乳源AKK可能是婴幼儿肠道AKK早期定殖的主要来源。研究表明AKK通过分泌键聚糖降解酶(α-l-fucosidases、β-galactosidases和β-acetylhexosaminidases)利用人乳低聚糖(oligosaccharides)以帮助其在婴幼儿肠道中的早期存活与定殖[9]。除人体外,在鼠[12]、鸡[13]、兔[14]和驴[15]等动物胃肠道中也发现了AKK的定殖,并且研究发现增加小鼠乳汁中甜菜碱的含量可增加其后代幼鼠体内AKK的丰度[12]。
1.2 生物学特性AKK呈现椭圆形、不形成内生孢子、不运动以及严格厌氧的特性,在宿主体内单独或成对存在。有趣的是,严格厌氧的AKK暴露在空气中仍具有一定的生存能力,具有严格厌氧菌的氧耐受性功能[4, 6]。此外,AKK具有遗传多样性和表型多样性并且能够通过表达多种功能基因来发挥作用[1]。Kumar等[16]在人体中发现并分离了一种与模式菌株AKK MucT具有不同遗传结构的AKK菌株,其能编码表达精氨酸脱羧酶促进精氨酸转化为胍丁胺。研究者还通过高通量测序发现AKK可表达多种与黏蛋白降解有关的基因(约占总基因的14%),这些基因大约可编码78种黏蛋白降解酶,其中,唾液酸酶、岩藻糖苷酶、硫酸酯酶等60种存在于粪便中,这表明AKK可高效利用黏蛋白而不依赖于宿主饮食。体外培养试验也证实AKK可在以黏蛋白为单一碳源和氮源的培养基中生存,是体外利用黏蛋白最活跃的菌株[17-19]。除此之外,AKK还可合成分解糖苷键的糖苷酶,属于可分解寡聚糖的益生菌[6]。在AKK代谢模型中,发现N-乙酰氨基葡萄糖、岩藻糖和葡萄糖等均可促进AKK生长,但生长速率显著低于黏蛋白组,有趣的是,AKK表现出具有可以优先吸收葡萄糖的特性[8, 20]。
目前,AKK菌株不同亚型之间最显著的代谢差异是产生维生素B12 (vitamin B12, Vit B12)的能力,大约三分之一的AKK分离菌株能产生Vit B12用于合成丙酸盐。另外,多种结肠微生物产生的Vit B12可供AKK利用,例如,霍氏真杆菌(Eubacterium hallii)在共培养试验中可与AKK MucT形成微生物网络,促进产生丙酸盐和丁酸盐[21-22]。肠屏障功能稳态取决于肠黏液层的动态稳衡,因病原菌侵染导致肠黏膜屏障功能破坏将引发宿主肠道健康紊乱,而对于嗜黏微生物来说,宿主肠黏膜分泌的黏蛋白为其提供了持续的碳源、氮源和能量[17],同时嗜黏微生物,如AKK可促进黏蛋白的分泌,从而实现肠黏液层的动态平衡。
2 AKK在缓解疾病中具有重要作用 2.1 AKK具有改善消化系统疾病的作用 2.1.1 肠道疾病AKK主要定殖于肠道,以改善肠道免疫功能而闻名,对维持肠道正常功能十分重要。研究发现AKK对多种肠道疾病均有改善作用,在患有IBS[5]、炎症性肠病[23](inflammatory bowel disease, IBD)、阑尾炎[24]和过敏性腹泻[25]等肠道炎症性疾病小鼠中AKK的丰度显著减少,粪菌移植后AKK数量显著提升,并且症状明显得到改善。IBS最显著的特征是机体内源性大麻素水平降低,AKK可通过恢复内源性大麻素水平来增强宿主肠道免疫力并改善IBS[5]。口服AKK可减少IBD小鼠炎性细胞浸润,促进由肿瘤坏死因子-α (tumor necrosis factor-α, TNF-α)介导的白细胞介素-8 (interleukin-8, IL-8)以及由Toll样受体2 (Toll-like receptor 2, TLR2)介导的IL-10和TNF-α的表达,进而降低炎症指数[26-27]。AKK MucT、外膜菌毛样蛋白Amuc_1100以及AKK来源的细胞外囊泡(AKK-derived extracellular vesicles, AmEVs)都可改善由葡聚糖硫酸钠诱导(dextran sulfate sodium salt, DSS)的结肠炎[28]。活菌或巴氏灭活后AKK都可通过刺激TLR2增强AMP活化蛋白激酶(AMP-activated protein kinase, AMPK)的活性并抑制核转录因子(nuclear factor-κB, NF-κB)的激活,进而抑制脂多糖(lipopolysaccharide, LPS)诱导的肠炎[29]。有趣的是,来自AKK的LPS尚未发现有致病作用,以上研究进一步表明AKK可改善肠道炎症并且不具有毒性。
更有研究表明,AKK可通过增加宿主调节性T细胞的数量抑制宿主肠道肿瘤细胞的异常增殖。结直肠癌患者极易出现营养匮乏和癌症恶化症状,AKK具有依靠黏蛋白为能源,不依赖宿主膳食营养而优先增殖的特性,从而在癌症免疫治疗中发挥作用,AKK的相对丰度值在结直肠癌患者的粪便和肠黏膜中显著提高[30]。然而,当前对AKK改善肠道疾病的作用仍然存在学术争议。有研究发现,AKK在特定环境中会发挥相反作用,如与健康个体相比,在便秘型IBS患者中AKK的丰度更高且易导致肠道菌群平衡慢性失调[31]。在双敲除IL-10基因的小鼠中AKK的定殖会通过增加结肠重量与长度的比值、IL-6等因子的分泌促进自发性结肠肠炎发生[32]。
2.1.2 肝脏疾病肠-肝轴通过紧密联系肠道、微生物和肝脏参与调控宿主健康。例如,Kim等[33]发现,在高脂饮食(high-fat diet, HFD)诱导的脂肪肝小鼠中肠道通透性遭到破坏,肠道屏障功能失衡,且体内AKK的丰度下降,而通过口服AKK会恢复肠道AKK的丰度,同时,AKK可通过抑制IL-6表达、增加丙氨酸氨基转移酶水平和恢复肠道菌群多样性来减少肝损伤、增强肝免疫以及改善脂肪肝。另外,直接补充AKK或者饲喂大黄、低聚果糖和二甲双胍等间接提升AKK的丰度可通过降低HFD小鼠血清甘油三酯水平及其合成基因的表达,抑制IL-2、INF-γ和IL-12p40等因子表达,上调抗菌肽、增加丙氨酸氨基转移酶活性以及杯状细胞数量,平衡肠道菌群结构、改善肝损伤和肝脂质代谢功能,起到改善肝病的作用[33–35]。肠道IBD与原发性硬化性胆管炎常相互伴发[36],AKK在治疗IBD中表现出的积极效应进一步验证AKK作用于肠-肝轴调节健康。
2.2 AKK具有改善神经系统疾病的作用大量研究显示AKK可作用于人体神经系统,对多种神经系统疾病具有改善作用。例如,神经退行性疾病易导致神经元永久性死亡,对机体健康产生多种负面影响,研究发现,神经退行性疾病的发病与肠道菌群变化有关,给患有神经退行性疾病的小鼠移植AKK可显著改善小鼠的病情,降低小鼠的死亡率并延长寿命[37]。
此外,研究发现AKK丰度与帕金森病[38]、癫痫病[39]等神经系统疾病发病率呈负相关。Vallio等[40]研究发现在AKK作用下,在多发性硬化症患者的脑脊液中可测得相较于健康人群更高的IgG抗体水平且这种变化在血液中无法测出。在HFD诱导的阿尔茨海默病小鼠模型试验中,除了抗肥胖作用外,还发现AKK可提高小鼠认知测试水平,改善阿尔茨海默病[41]。值得注意的是,也有人[17]提出帕金森病患者的粪便中AKK的丰度检出较高并不意味着AKK与帕金森病有直接联系,因为还有许多混杂因素,比如慢性便秘、饮食习惯(禁食期)和药物治疗等多种环境因素都会影响AKK富集。
2.3 AKK在调控代谢性疾病中发挥重要作用代谢紊乱导致的肥胖诱因复杂且伴随着多种并发症,其中消化系统和神经系统功能紊乱均与肥胖密切相关。小肠是营养素吸收的主要器官,与肥胖具有直接的联系,肠道免疫和代谢失衡也会促进肥胖及诱发多种肥胖相关代谢性疾病[42-43]。目前,关于AKK在代谢紊乱性疾病中的研究主要集中在代谢失调性肥胖中,AKK在改善肥胖的同时对肥胖引起的一系列疾病,如糖尿病、高血压和高血糖等都有良好的改善作用[44-45]。与正常小鼠相比,肥胖小鼠中AKK的相对丰度显著降低,补充AKK可通过改善葡萄糖稳态、促进胰岛素分泌和减少白色脂肪细胞的大小等途径改善肥胖症状,也可改善HFD诱导的胰岛素抵抗、LPS血症以及逆转HFD诱导的代谢紊乱、肥胖和糖尿病[44, 46-47]。此外,补充AKK可通过调控慢性肾脏病、一氧化碳(nitric oxid, NO)途径、表观遗传和肾素-血管紧张素系统改善高血压,包括肾高血压[48-49]。然而,Arias等[50]发现,在雌性C3HeB/FeJ小鼠中,HFD处理后AKK的相对丰度显著增加。造成此种差异的原因可能是宿主基因型的不同。正如Carmody等[51]研究表明,饮食对AKK水平的影响在小鼠中具有遗传依赖性。
临床研究发现,在肥胖患者中AKK丰度比健康个体低,并且肥胖导致的AKK丰度减少会加重糖尿病等其他代谢性疾病的症状[42, 52]。同样,活菌、巴氏灭活菌及其各种功能活性成分都对肥胖起改善作用,口服AKK不会影响食物摄入,但可逆转HFD引起的肥胖[23, 47, 53-54],且不同形式的AKK在宿主体内都具有良好的安全性和耐受性[55]。AKK对不同糖尿病的作用具有差异性,如研究发现外源补充AKK MucT有利于改善宿主胰岛功能,降低I型糖尿病的发病率[56],而在患有II型糖尿病的中国人中发现AKK并没有改善病症的作用[57]。目前,还需要更多的研究来佐证AKK的作用及其分子机制。
2.4 AKK改善癌症除肠道肿瘤和肝癌外,AKK还表现出对多种癌症有治疗效果。Derosa等[58]发现AKK在体内与程序性死亡受体抑制剂含量呈正相关,可改善非小细胞肺癌的症状,AKK通过阻断宿主对免疫检查点的反应来恢复对癌细胞的抑制活性,有望借此通过免疫疗法靶向调控机体抗肿瘤活性。此外,AKK外膜囊泡(extracellular vesicle)可通过抑制癌细胞增殖、改变巨噬细胞极化治疗前列腺癌[59]。
3 AKK改善疾病的分子机制 3.1 改善消化系统功能 3.1.1 增强肠道屏障功能肠道屏障功能可有效保护宿主体内组织免受致病菌及各种毒素的侵入,对维持肠道健康和消化系统功能至关重要。AKK可增强肠道屏障功能。首先,AKK及其代谢产物、代谢酶和外膜蛋白等功能活性成分都可通过调节肠上皮细胞生长发育、增强紧密连接(tight junction, TJ)等来有效改善肠道物理屏障。例如,补充AKK可增加小鼠肠道杯状细胞数量,使内黏液层厚度正常化,并上调TJ蛋白的表达,改善肠道屏障完整性[54]。Reunanen等[60]发现AKK在体外可黏附肠上皮,改善肠上皮电阻、促进肠细胞增殖和保障上皮细胞完整性,并促进损伤部位黏膜修复。在溃疡性结肠炎(ulcerative colitis, UC)患者中,补充AKK可改善因杯状细胞分泌黏蛋白减少引起的肠道物理屏障功能失衡[4]。此外,AKK显著增加肠跨上皮电阻和下调大麻素1受体(cannabinoid 1 receptor, CB1 receptor)[27, 61],CB1受体的下调与肝脏和脂肪组织中LPS诱导的肠道完整性和脂质积累的改善有关[62]。AKK的代谢产物SCFAs可促进细胞更新、维持肠道屏障功能并为其他共生菌提供能量,乙酸和丁酸可促进肠道菌群的代谢活性,改善肠黏液层的厚度,有助于肠上皮细胞抵抗病原体和致病菌的入侵[63],其中,丁酸盐可为机体结肠细胞增殖和维持肠道屏障功能提供重要能量来源[64]。研究发现口服AKK会增加机体SCFAs的生成量,并且发现乙酸和丙酸可能是促进杯状细胞功能的关键因素,AKK借此通过Wnt信号转导促进肠道干细胞的增殖和肠上皮细胞更新[65]。外膜蛋白Amuc_1100能够直接增加小鼠TJ蛋白的表达量[66],在DSS诱导的小鼠中,AmEVs能够通过减少结肠壁炎症细胞的数量来改善炎症性肠病[67]。
另外,AKK可通过调节免疫细胞和免疫因子改善肠道免疫屏障。研究发现,在UC患者中,AKK可通过调节性T细胞限制CD4+ T细胞的转移来缓解免疫损伤[68];口服AKK可减少巨噬细胞数量、炎性浸润和炎症因子分泌[69]。AKK产生的代谢酶能够以间接(通过高效降解黏蛋白产生的SCFAs)和直接两种方式改善肠道免疫屏障。AKK代谢产生的SCFAs中的乙酸可通过白色脂肪组织中的脂肪酸受体G蛋白偶联受体-43 (G-protein-coupled receptor, GPR-43)促进抗脂解活性[63]。AKK MucT可通过天冬氨酸蛋白酶(aspartic protease)和β-N-乙酰氨基己糖苷酶(β-N-acetylhexosaminidases, EC.3.2.1.52)发挥有益作用,前者可通过肿瘤坏死因子相关细胞凋亡诱导配体介导的细胞凋亡途径上调肿瘤蛋白53的表达、增加人结直肠腺癌细胞中线粒体活性氧水平、抑制人结直肠腺癌细胞活力进而增强免疫力[70];EC.3.2.1.52则可抑制IL-6、IL-1β、NLRP3和TNF-α等分泌进而改善DSS诱导的小鼠结肠炎[71]。AmEVs可显著降低肥胖小鼠结肠组织中TLR-4的表达并诱导TLR-2的低表达[54]。在DSS诱导的小鼠中,AmEVs通过改善结肠上皮细胞IL-6的分泌来改善炎症性肠病[67]。然而,目前尚不清楚AmEVs的口服剂量以及AKK分泌的AmEVs与宿主生理水平之间的相关性,也不清楚AmEVs是否含有Amuc_1100或其他特殊成分。
最后,研究表明AKK还可改善肠道生物屏障。AKK以黏蛋白为唯一能源,对其他细菌具有竞争抑制作用[6],主要通过降解黏蛋白以抑制病原菌的生长,其代谢产物丁酸抑制编码诱导型一氧化氮合酶(inducible nitric oxidesynthase, iNOS)的基因表达,从而减少NO的产生,并最终降低腔内硝酸盐水平,减少致病性、兼性厌氧菌增殖所利用的特定能量来源。AKK产生的SCFAs等会提供并调控有益菌生长所需的能源,如在补充AKK的同时增加双歧杆菌(Bifidobacterium)的丰度可更有效通过改善肠黏膜生物屏障,抑制UC介导的肠道炎症[72],同时AKK的丰度也受其他共生菌的调控,如在UC中,戊糖乳杆菌(L. pentosus)可增加AKK丰度[73]。综上所述,AKK在改善肠道屏障功能和维持肠道稳态方面发挥重要作用。
3.1.2 调节肠-肝轴肠道吸收的营养素可以运送到肝脏以维持肝脏正常功能,肠源细菌、LPS和免疫因子等可少量进入肝脏并激活肝脏免疫系统。肝脏通过胆汁酸等介导肠-肝轴可以调节肠道菌群稳态和脂类营养素的消化吸收,体现出肠-肝轴在消化系统中起着重要作用[74]。胆汁酸与肝脏代谢、肠道损伤密切相关,在IBD患者和DSS诱导的结肠炎模型中发现肝脏、肠道和血清中均会发生胆汁酸代谢紊乱,胆酸盐异常积累会借助过氧化物酶体增殖物激活受体-α (peroxisome proliferator- activated receptor, PPARs)信号通路抑制脂肪酸氧化从而诱导肠上皮黏膜受损并减少肠细胞更新、增殖和再生[75]。外源补充AKK可增强肠道及肝脏胆汁酸的反流调节、从头合成和转运从而改善肥胖小鼠肠-肝轴胆汁酸代谢紊乱。在早衰症小鼠中也发现AKK水平与胆汁酸,特别是次级胆汁酸水平呈正相关[11]。
此外,AKK还可通过显著降低肝脏中二酰基甘油和甘油三酯的水平,抑制TNF-α、IL-6的分泌以及抑制脂肪酸合成酶相关基因的表达而有效改善肝损伤。更为重要的是,AKK通过促进肠道l-天冬氨酸转运以激活AMPK途径和肠-肝轴介导的脂质氧化进而调节机体能量消耗并改善与代谢相关的脂肪性肝病,同时,AKK可通过解偶联蛋白途径促进能量消耗改善肥胖症状,并可通过调节肝脏、回肠以及结肠部位葡萄糖和脂质的转运吸收进而改善肥胖患者伴发的糖脂代谢紊乱[23, 76-77]。
3.2 有助于维持神经系统功能机体神经系统功能的维持需要借助于以肠、肝等器官为媒介的营养素吸收、消化。丙酸能够通过增加血清中酪酪肽(peptide tyrosine tyrosine, PYY)水平提高机体能量吸收水平,改善神经系统功能,AKK可通过丙酸等SCFAs诱导肠内分泌系统激活位于肠上皮的GPR-43,从而诱导肠道L细胞产生肠激肽(enterokinin)和胰高血糖素样肽-1 (glucagon-like peptide-1, GLP-1),并协同其他产脂肪酸的细菌改善宿主代谢功能、维持神经系统功能(SCFAs提供能量,脑肠肽作为肠-脑轴双向调节的媒介)[6, 42, 78]。AKK还通过作用于机体前额叶皮层和海马体等脑部组织改善脑部代谢功能,如AKK可通过减少大脑中淀粉样β蛋白斑块的沉积、恢复神经元的发育以及突触可塑性,进而改善高脂高胆固醇和HFD诱导的小鼠认知障碍,逆转其受损的空间工作记忆能力[37, 41, 79]。
机体内色氨酸及其代谢物的浓度降低会加剧阿尔茨海默病,提高色氨酸浓度可减轻阿尔茨海默病中5-羟色胺能信号传递紊乱[80]。多种形式的AKK都可通过提高血清中吲哚丙烯酸(indole acrylic acid)的水平来改善结肠炎中色氨酸的代谢紊乱状况而恢复色氨酸水平[81],从而改善阿尔茨海默病。AKK可通过提高血液和脑脊液中烟酰胺的水平来改善小鼠运动神经元与线粒体的功能,从而治疗小鼠渐冻症[37]。AKK在生酮饮食作用下可与肠道细菌共同减少γ-谷氨酰胺基酸水平,提高海马体中γ-氨基丁酸与谷氨酸的比值,进而对宿主癫痫病症起到良好的改善作用[39]。同时,在实验性自身免疫性脑脊髓炎模型中发现,AKK可通过刺激调节性T细胞驱动细胞因子靶向脑组织,激活宿主体内免疫细胞的免疫交叉反应[82]。
3.3 其他方式Bae等[53]发现AKK中含有一种特有的磷脂酰乙醇胺(phosphatidyl ethanolamine, PE),其含量约占AKK膜脂质的50%,并将其命名为a15:0-i15:0 PE,a15:0-i15:0 PE通过TLR2受体上调IL-6和TNF-α的分泌水平来调节细胞免疫应答。AKK还可通过一种蛋白质(protein 9, P9)与ICAM-2结合和诱导IL-6基因表达两种途径增加胰高血糖素前体的表达促进GLP-1分泌[23],并且IL-6缺乏会下调ICAM-2的表达和阻断P9诱导的GLP-1分泌,P9直接结合ICAM-2可诱导棕色脂肪组织产热。Zhang等[83]研究表明AKK细胞外囊泡衍生的鸟氨酸脂质(ornithine lipids, OL)能够显著增加机体IL-10、IL-129等抗炎因子的分泌从而改善LPS诱导的肠炎,更重要的是,OL可上调激活转录因子3 (activating transcription factor 3, ATF3)基因的表达以负调控TLR4,并且上调该基因的表达可能会通过不同的途径调控宿主的先天免疫应答反应。
最后,研究发现AKK通过促进NO和肾素等分泌以减少促炎因子分泌,进而改善血管功能障碍引起的高血压以及慢性肾病[49],这表明AKK可作用于肠-肾轴。然而,该作用机制尚存在学术争议。
4 结论与展望AKK及其代谢产物SCFAs、代谢酶、膜脂a15:0-i15:0 PE和外膜蛋白Amuc_1100等可通过CB-1和TJ改善肠道通透性,通过增加免疫细胞因子的分泌和恢复肠道菌群的平衡来改善肠道的物理、免疫和生物屏障功能,从而改善消化道功能。在此基础上,AKK通过次级胆汁酸、γ-谷氨酰胺基酸和色氨酸代谢信号分子等与肝、脑等器官相联系并调节其功能,进一步发挥疾病改善作用,具体机制见图 1。
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图 1 AKK改善疾病的作用机制 Figure 1 Mechanisms of AKK in improving diseases. A: AKK enhances intestinal barrier function. B: AKK maintains nervous system function. C: Gut-liver axis, Vit B3 or nicotinamide. 5-HT: 5-hydroxytryptamine; Trp: Tryptophan; PYY: Peptide tyrosine tyrosine; GPR: G-protein-coupled receptor; Wnt: Wingless-type; LPS: Lipopolysaccharide; AMPK: AMP-activated protein kinase; TJ: Tight junction; P9: Protein 9; AmEVs: Akkermansia muciniphila-derived extracellular vesicles; TLR: Toll-like receptor; l-Asp: l-aspartate; NF-κB: Nuclear factor-κB; CB1: Cannabinoid 1 receptor; ICAM-2: Intercellular cell adhesion molecule-2; GLP-1: Glucagon-like peptide-1; Aβ: Amyloid-β; PE: Phosphatidyl ethanolamine. |
此外,巴氏灭活AKK在疾病中的改善作用也进一步说明AKK发挥功能可不依赖于其代谢产物,其可能机制是:增加肠上皮更新、增加粪便能量排泄和减少碳水化合物吸收[47];也可能是AKK灭活之后会丧失代谢黏蛋白的能力,但可刺激黏蛋白的再生;也可能是其特殊的功能活性成分(如Amuc_1100)起重要作用。
AKK因具有氧耐受性和嗜黏蛋白性而在肠道黏液外层(特别是结肠)定殖时具有明显优势。同时,AKK可有效改善肠道屏障功能,对多种疾病具有显著的改善作用,在临床中表现出巨大的治疗疾病的潜力。然而,不同个体体内黏蛋白的含量和生成能力有所差异,盲目外源直接补充AKK或间接提高体内AKK的丰度可能会适得其反。
综上所述,关于AKK治疗疾病的深入研究首先应聚焦于AKK发挥益生作用的菌株、宿主特异性,AKK外源补充剂量与宿主体内生理剂量之间的等效性及其临床副作用。比如,AKK通过肾素-血管紧张素系统改善高血压,但会促进慢性肾炎的发生。其次,探究AKK发挥益生作用的功能活性成分,以及更多有效提升宿主体内AKK丰度的方式(如AKK培养上清液可直接激活NF-κB信号通路,但该激活分子还不明确),为AKK产业化利用提供理论基础。
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