微生物学通报  2019, Vol. 46 Issue (7): 1712−1722

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文章信息

李荣, 冯朋雅, 叶泽, 陈潇, 李祥锴, 刘璞
LI Rong, FENG Peng-Ya, YE Ze, CHEN Xiao, LI Xiang-Kai, LIU Pu
肠道修复:一种利用益生菌减少重金属积累的新思路
Gut remediation: a new approach to reduce the accumulation of heavy metals by using probiotics
微生物学通报, 2019, 46(7): 1712-1722
Microbiology China, 2019, 46(7): 1712-1722
DOI: 10.13344/j.microbiol.china.180691

文章历史

收稿日期: 2018-09-05
接受日期: 2019-01-22
网络首发日期: 2019-02-28
肠道修复:一种利用益生菌减少重金属积累的新思路
李荣 , 冯朋雅 , 叶泽 , 陈潇 , 李祥锴 , 刘璞     
细胞活动与逆境适应教育部重点实验室 兰州大学    甘肃  兰州    730000
摘要: 近年来受到重金属工业废水的排放及人类日常活动的影响,我国大面积土壤中重金属含量急剧增高。不同重金属可能通过食物链进入人体,给人类健康带来隐患。因此,减少重金属在动物体肠道中的积累是降低重金属危害的一个重要课题。研究显示,一些益生菌能够在体内外环境中有效地结合重金属,但人们对益生菌结合重金属的能力,及其对重金属的肠道修复机理了解较少。本文针对目前镉、铅、铬等重金属对环境与动物体健康造成严重危害的现状,分析了各类重金属的污染来源,概括了益生菌在环境与动物体肠道中对各种重金属的修复情况及作用机理,重点考察了益生菌在动物体肠道环境中与重金属相互作用的机理研究,同时对未来利用益生菌制剂直接减少人体肠道内重金属积累进行了展望。
关键词: 重金属毒性    益生菌    肠道修复    
Gut remediation: a new approach to reduce the accumulation of heavy metals by using probiotics
LI Rong , FENG Peng-Ya , YE Ze , CHEN Xiao , LI Xiang-Kai , LIU Pu     
MOE Key Laboratory of Cell Activities and Stress Adaptation, Lanzhou University, Lanzhou, Gansu 730000, China
Abstract: In recent years, heavy metal contamination in China has greatly increased due to the discharge of industrial wastewater and daily human activities. People living in polluted areas suffer from serious health problems as a result of long-term ingestion of contaminated crops. Therefore, it is of utmost importance to repair heavy metal pollution in developing countries. Recent studies have mainly focused on the probiotics effectively combine with heavy metals in vitro and in vivo, and different mechanisms have been proposed to explain the functions of probiotics in heavy metals' remediation. In view of the current situation, heavy metals such as cadmium, lead, and chromium have serious impacts on the environment and animal health, this review analyzes the sources of heavy metals pollution and the control of various heavy metals in the environment and animal intestines. Meanwhile, the mechanisms of heavy metal remediation processes by probiotics are summarized, and the utilization of probiotics in alleviating heavy metals' toxicity on human and the environment in the future.
Keywords: Heavy metal toxicity    Probiotics    Gut remediation    

近年来,随着工业废水的排放、采矿活动和污水灌溉的影响,土壤重金属污染日益成为一个全球性问题。据报道,仅欧洲就有多达250万个可能受到重金属污染的场所[1],例如在比利时的肯彭兰地区大约有700 km2的地域已经被大气中沉降的镉(Ⅱ)、锌(Ⅱ)、铅(Ⅱ)等重金属污染[2]。在中国,总共有2.88×106 hm2土地被用于重金属开采,每年大约有46 700 hm2的土地受到重金属的污染[3]。受土壤重金属污染的影响,种植在这些污染地区的水稻、大米、土豆等农作物同样也受到了重金属的污染。研究表明,在沈阳张士灌区,灌溉污水中的镉、汞、锌、铅等重金属大量沉积在土壤中,导致该地区种植的稻米中重金属含量增高[4]。Liu等[5]在对甘肃白银东大沟采矿区的土壤重金属污染情况的调查中发现,该地区种植的春小麦、玉米等农作物中的镉、铅、锌和铬(Ⅵ)等重金属的平均含量均超过我国食品安全标准。长期摄食被重金属污染的农作物会对人体健康构成威胁,一个典型的例子是日本“痛痛病”,这是一种由于人类食用镉污染地区种植的大米而导致骨质疏松、关节疼痛、肾功能衰竭的疾病,给人们带来了巨大的痛苦[6]

传统的物理和化学修复法能够有效地缓解土壤重金属污染,但它们同时存在对环境造成二次污染和使用成本高等问题[7]。相对而言,生物修复法因其成本低、效能高以及对环境造成污染较小而更易被应用[8]。然而,生物修复补救的土壤总面积远小于土壤重金属污染的总面积,同时这种修复无法在短期内直接使人体受益。针对重金属对人体造成的危害,传统的治疗策略是通过螯合疗法促进重金属排泄,如用于螯合汞、铅和砷(Ⅲ)等重金属的乙二胺四乙酸、二巯基丁二酸和二巯基丙磺酸钠等金属螯合剂已在临床上被广泛使用[9]。但金属螯合剂会造成机体肾脏等其它器官的损伤,同时还会将机体必需金属排出体外[10-11]。因此,寻找一种有效、环保而且快速解决人体重金属超标的方法十分必要。近年来,越来越多的研究试图寻找安全有效的膳食补充剂来对抗重金属毒性。一些植物提取物如柚皮素、胡黄连素以及黄酮素等被发现具有良好的抗氧化特性,能够减少肝脏等组织中的镉含量并缓解其诱导的氧化应激效应[12-14],但这些天然化合物依然存在着纯化成本高以及修复时效性短等问题无法有效解决人体重金属超标的现状。

益生菌是一类定殖于人体肠道内并且对机体有益的活性微生物的总称,主要包括乳酸杆菌、双歧杆菌、链球菌等,它具有抗菌作用,可以增强肠道屏障功能,参与人体免疫调节[15]。益生菌作为一种膳食补充剂已被用于许多疾病如抗生素相关性腹泻、免疫功能失调以及动脉粥样硬化等的预防及治疗[16-18]。一些乳杆菌,如鼠李糖乳杆菌、植物乳杆菌和短乳杆菌可以在体外结合镉、铅和铜(Ⅱ)等金属离子[19-20]。这些发现为减少重金属在体内的积累提供了新思路。进一步的体内研究表明,一些益生菌如肠系膜明串珠菌和植物乳杆菌可以有效减少小鼠、罗非鱼等动物体内重金属的积累,从而达到缓解组织损伤和氧化应激的目的[21-23]

肠道是人体吸收重金属的主要器官[24]。来源于农作物中的重金属通过食物链进入人体的消化道,首先在肠道中积累,人体的肠道中至少存在1 000种不同类型的微生物,菌落总数达到1×1014个,是人体细胞总数的10倍,其编码基因数是人类基因组编码基因数的150多倍[25-26]。肠道微生物影响着宿主的营养物质加工、能量平衡、免疫功能、胃肠道发育及其他多种重要生理活动[27]。许多研究表明,重金属与宿主及其肠道菌群三者之间存在密切的相互作用,重金属的摄入会造成动物和人体肠道菌群结构发生特异改变[28-31];反之,肠道菌群及其代谢产物又为宿主抵御重金属进入机体提供了“屏障”功能[32]。鉴于重金属污染的广泛性及其对人体健康造成的危害,探究益生菌与重金属以及宿主肠道菌群之间的相互作用机理对未来利用益生菌减少体内重金属积累的应用具有重要意义。本文旨在综述益生菌对重金属的体外结合与体内肠道修复机制,并介绍益生菌与不同重金属在体内外环境中作用机理的研究现状。

1 益生菌与环境及动物体内重金属的作用机制 1.1 益生菌在体外环境中吸附重金属

1.1.1 益生菌细胞壁的作用

重金属生物表面吸附是一个被动的非代谢过程,主要包括螯合、络合、金属吸附、离子交换及微量沉淀等途径[33]。多数益生菌属于革兰氏阳性细菌,其细胞壁由厚的带负电荷的肽聚糖和磷壁酸层组成,这是益生菌与重金属体外相互作用的重要基础。如鼠李糖乳杆菌和一些长双歧杆菌细胞壁上的肽聚糖和磷壁酸聚合物具有很强的吸附金属阳离子的能力[34-35]。Teemu等[36]发现Lactobacillus fermentum ME3和Bifidobacterium longum 46细胞壁磷壁酸的羧基等基团在经过甲基化修饰之后吸附镉和铅的效率明显降低。益生菌在体外吸附重金属时,还受到pH、温度等因素的影响[37]。益生菌体外吸附重金属的研究结果归纳见表 1

表 1 益生菌对不同重金属的体外吸附 Table 1 The adsorb of heavy metals and hazardous metals by different probiotics in vitro
重金属
Heavy metals
益生菌
Probiotics
重金属结合效率
Heavy metal-binding rate (%)
最适pH值
Optimum pH
最佳反应时间
Optimum reaction time (h)
参考文献
References
Cadmium B. lactis Bb12 73.0 6.0 1.0 [37]
L. fermentum ME3 65.0 6.0 1.0
L. rhamnosus GG 60.0 6.0 1.0
L. fermentum ME3 92.0 5.0 0.5
Lead B. longum 46 80.0 5.0 0.5 [36-37]
B. lactis Bb12 98.0 6.0 1.0
L. acidophilus MTCC447 100.0 5.5 6.0
Chromium L. rhamnosus MTCC1408 100.0 5.8 8.0 [38]
L. casei MTCC1423 100.0 6.0 10.0
L. plantarum CCFM639 64.5 4.5 2.0
Aluminum L. plantarum CCFM307 60.0 4.5 2.0 [39]
L. plantarum CCFM8661 55.0 4.5 2.0

1.1.2 胞外聚合物和S层蛋白的作用

胞外聚合物(Extracellular polymeric substances,EPS)是微生物在适宜温度及pH环境中产生的代谢产物,主要由多糖多肽组成,是一种潜在的金属生物吸附剂[40]。这类物质的表面常带有COO、HPO、OH等基团,这使得EPS能够在体外吸附金属阳离子[41]。Li等[42]通过对Lactobacillus helveticus MB2-1的完整基因组进行测序之后发现其EPS基因簇中含有21个EPS相关基因。此外,存在于许多乳酸杆菌表面的S层蛋白(S-layer),因拥有大量带负电荷的官能团如COO而能与重金属结合[43]。Åvall-Jääskeläinen等[44]发现乳酸菌的S层蛋白使细胞表面产生吸附镉的能力。最近的一项研究发现,当S层蛋白被固定在藻酸盐基质中时,其去除铬的能力达到了40%以上[45]。益生菌体外吸附重金属的机制如图 1所示。

图 1 益生菌体外吸附重金属的3种基本机制 Figure 1 Three basic mechanisms of heavy metal adsorption in vitro by probiotics 注:(1)肠道中益生菌表面的EPS结构与不同价态的重金属阳离子M(Ⅱ)和M(Ⅲ)结合,从而减少进入肠道的重金属离子;(2)益生菌细胞壁表面带负电基团的膜磷壁酸(M)与壁磷壁酸(W)结构分别吸附重金属阳离子;(3)益生菌细胞膜表面的S层蛋白可吸附少量肠道中的重金属阳离子. Note: (1) To reduce entrance of heavy metal ions, the EPS on the surface of probiotics can bind heavy metal cation M2+ and M3+; (2) The adsorb of heavy metal cations with membrane and wall phosphoric acid on the cell wall of probiotics; (3) The S-layer protein on the cell membrane of probiotics can also adsorb a small amount of heavy metal cations in the intestinal tract.
1.2 益生菌干预减少了重金属在动物体内的积累

基于益生菌在体外环境中具有良好的重金属吸附效率,研究者开始探究益生菌在体内结合重金属的能力和相关作用机制。综合目前的文献报道,益生菌主要通过肠道隔离、保护肠道屏障来减少小肠对重金属的吸收,同时益生菌具有潜在的抗氧化能力,能缓解重金属诱导的氧化应激。此外,益生菌还可能通过调节肠道菌群的结构和功能缓解重金属的毒性。这些发现为益生菌体内减少重金属的积累提供了重要的理论依据。益生菌在肠道内与重金属的作用机制如图 2所示。

图 2 益生菌在小鼠肠道内减少重金属积累的4种机制 Figure 2 Four mechanisms by which probiotics repair heavy metals in the intestinal tract of mice 注:(1)肠道隔离作用,即益生菌在肠道上皮细胞吸收重金属之前首先吸附部分重金属离子M(Ⅱ)和M(Ⅲ);(2)益生菌通过维持肠道屏障的完整性以及增强肠道屏障的功能来抑制肠道对重金属的吸收;(3)益生菌通过调节肠道菌群的结构以及维持肠道菌群的稳态来缓解重金属的毒性;(4)益生菌具有潜在的抗氧化能力. Note: (1) Intestinal sequestration: probiotics adsorb heavy metal ions M2+ and M3+ before intestinal epithelial cells binds them; (2) Probiotics inhibit intestinal absorption of heavy metals by maintaining the integrity and enhancing the function of intestinal barrier; (3) Probiotics can alleviate the toxicity of heavy metals by regulating the structure of intestinal flora and by maintaining their homeostasis; (4) The potential antioxidant capacity of probiotics.

1.2.1 益生菌在肠道隔离通路中的作用

小肠是机体吸收重金属的主要位点,重金属离子主要靠离子拟态,利用一些转运蛋白如DMT-1和钙通道进入肠上皮细胞[46]。肠道隔离作用指当重金属经由不同途径进入机体其他器官之前,益生菌首先在肠道中吸附大部分重金属,并且促使这些重金属离子随着粪便排出体外的过程[47]。在这一过程中,益生菌的作用主要有3个方面:(1)在小肠上皮细胞吸收重金属之前先吸收大部分重金属;(2)促进胃肠道蠕动增加重金属在粪便中的排泄[21];(3)益生菌通过参与调节肠道微生物的代谢活动而促进其它二价金属离子与重金属离子在小肠中形成竞争。研究表明,某些定殖在肠道中的益生菌如Lactobacillus reuteriLactobacillus rhamnosus HN001参与调节肠道菌群代谢,并增加短链脂肪酸等有机酸的产生[48-49]。这些有机酸有助于增加二价矿物元素如Ca(Ⅱ)、Mg(Ⅱ)、Fe(Ⅱ)的溶解性,使金属离子之间形成竞争关系,从而减少二价重金属离子在小肠中的吸收[50-51]。进入肠道的重金属在益生菌的隔离作用下,一部分会被有效地吸附,随着粪便排出体外[52],其余的重金属离子则会随着血液循环进入到机体的肝脏或肾脏组织中,诱导金属硫蛋白(Metallothionein,MT)的产生[53]。在哺乳动物中,MT半胱氨酸的巯基能结合二价金属阳离子如Zn(Ⅱ)、Cu(Ⅱ)、Cd(Ⅱ)和Hg(Ⅱ),从而减少重金属在机体其他组织中的积累[54]

1.2.2 益生菌在保护肠道屏障中的作用

单层肠道上皮细胞在肠道表面形成了一层能够选择性渗透各种物质的屏障结构,这种结构具有调控细胞表面营养素、电解质、水等物质的进出,防止肠道对腔内毒素、抗原等物质吸收的功能[55]。肠道上皮细胞主要通过两种方式进行选择性渗透:一是跨细胞选择性渗透,物质通过其转运蛋白以及水溶液的运动完成跨细胞渗透[56-58];二是细胞旁路选择性渗透,物质穿过连接上皮细胞间隙的特殊蛋白连接结构完成渗透作用[59]。在这两种途径中,紧密连接蛋白、粘连蛋白以及细胞桥粒被认为是判断肠道屏障渗透能力的指示剂[60]。重金属镉和铝会加速肠道上皮细胞HT-29的损伤和凋亡,导致肠道上皮细胞层发生泄漏,引起大量重金属离子进入体循环。此外,重金属会降低肠道上皮细胞之间紧密连接蛋白的表达,增加肠道通透性和诱导氧化应激及一系列炎症反应[61-62]。研究者在小鼠实验中还发现,在给予植物乳杆菌CCFM8610和CFM639治疗组中,HT-29细胞的凋亡率降低了13%以上,3种紧密连接蛋白ZO-1、Claudin-1和Occludin的表达水平均显著提高,且血清中用以表征肠道通透性的内毒素水平均显著降低。这些结果揭示了补充益生菌可以缓解重金属诱导的细胞毒性,减轻氧化应激和炎症反应,逆转紧密连接破坏,并降低肠上皮细胞的通透性,最终达到维持肠道屏障功能,缓解重金属在肠道内积累的目的[63-64]

1.2.3 益生菌调节肠道菌群的结构和功能

众多研究表明,重金属与宿主及其肠道菌群三者之间存在密切的相互作用。肠道屏障作为控制有毒金属进入机体的第一道防线,其功能的完整性取决于肠道微生物与宿主之间的相互作用[19, 65]。重金属的长期积累会造成一些动物如花背蟾蜍、小鼠、猪和人体肠道菌群的结构发生特异改变[28-31]。反之,肠道内的微生物会通过主动摄取或被动吸收直接与肠道中的金属接触,影响其生物有效度。Breton等[66]在长期摄入镉和铅的无菌鼠中发现,无菌鼠的血液及靶组织中的重金属含量明显高于对照普通小鼠,这一发现首次证实了肠道菌群具有固化、吸收某些重金属,从而减少重金属在机体组织中分布的功能。

益生菌作为一种膳食补充剂在调节人体肠道菌群结构和功能中具有重要作用[65-68]。目前,关于益生菌调节重金属诱导下肠道菌群的研究还不多。Wu等[52]通过对小鼠粪便菌群16S rRNA基因序列分析揭示,铬引起小鼠肠道微生物群落的整体结构发生特异改变,而植物乳杆菌TW1-1恢复了相对丰度发生改变的79个操作分类单元(OTU)中的49个,而且增强了肠道菌群对铬(Ⅵ)的还原能力。这一结果与益生菌用于肠道菌群紊乱所致代谢疾病的干预具有一致性。后续可结合宏基因组、宏转录组等技术分析菌群组成及功能变化,进一步阐明益生菌对肠道菌群的调节机制。

1.2.4 益生菌缓解重金属诱导的氧化应激

氧化应激是重金属毒性的重要机制,它包括增加脂质过氧化反应和降低抗氧化活性两个基本过程。氧化应激可损害细胞膜,导致肝细胞损伤或坏死[69]。一般认为丙二醛(MDA)是脂质过氧化过程的终产物和指示剂,而还原型谷胱甘肽(GSH)、过氧化氢酶(CAT)和超氧化物歧化酶(SOD)被认为在抗氧化防御系统中起着至关重要的作用。多种益生菌已被证实能够缓解小鼠体内由于各种毒性物质所致的氧化应激效应及对机体器官的毒性[70-71]。Zhang等[72]还发现Lactobacillus casei Zhang能够改善小鼠脂质代谢,并且增加其体内抗氧化酶活性,抑制脂质过氧化反应,从而缓解小鼠高脂血症。除此之外,一些乳杆菌具有完整的GSH系统,包括合成、转运、摄取和氧化还原循环,这个系统使它们很好地保护机体组织免受氧化应激反应的影响[73-74]。同样地,多种益生菌被证实可以减少由于重金属积累所致的组织损伤(表 2)。

表 2 益生菌缓解动物体内重金属积累所致的毒性 Table 2 The effect of probiotics against heavy metals toxicity in vivo
重金属
Heavy metals
益生菌
Probiotics
实验模型
Models
组织氧化应激的响应
Oxidative stress parameters
组织病理学变化
Histopathological alterations
参考文献
References
Cadmium L. plantarum CCFM8610 Kunming mice CAT, SOD, GSH and MDA Alleviated chromatin condensation, cytoplasmic vacuolization, and nuclear pyknosis in liver cells [21]
Chromium L. plantarum TW1-1 Kunming mice CAT, SOD, GSH and MDA Alleviated chromatin condensation, cytoplasmic vacuolization, and nuclear pyknosis in liver cells [52]
Lead L. plantarum CCFM8661 Kunming mice ALAD, SOD, GSH and MDA Alleviated chromatin condensation, cytoplasmic vacuolization, and nuclear pyknosis in liver cells [75]
Aluminum L. plantarum CCFM639 Tilapia CAT, SOD, T-AOC and MDA Alleviated chromatin condensation, cytoplasmic vacuolization in liver cells [22]
2 益生菌在环境与动物体肠道中与不同重金属的作用机理研究 2.1 益生菌对镉的去除

在自然界中镉通常不以单一元素的形式存在,而是与铅、锌、铜矿石等形成复合氧化物存在于环境中[76]。镉通过不同途径,如岩石风化和火山活动等释放到自然环境中[77],成为一种环境污染物。镉的大气沉降、采矿活动和农田中含镉化肥的施用都可能导致土壤的镉污染,以及农产品和牲畜对镉吸收的增加[78]。饮食是人类接触环境镉的主要来源之一,镉会在人体组织内积累,特别是在肾脏中具有很长的半衰期[79]

研究者首先将重点放在了益生菌与镉的体外吸附能力上。研究表明,鼠李糖乳杆菌和一些长双歧杆菌的胞外多糖所带的负电基团,包括羧基、羟基和磷酸能与镉结合[35, 80]。研究者还分别利用电子显微镜和傅里叶变换红外光谱法观察到Lactobacillus kefir CIDCA8348和JCM5818与镉结合之后其细胞膜上S层蛋白质二级结构的变化情况[81]。近年来,研究者开始探究益生菌体内结合镉的机制。Zhai等[21]Lactobacillus plantarum CCFM8610缓解小鼠急慢性镉中毒的试验中发现,CCFM8610可以通过肠道隔离作用增加粪便中镉的排泄,减少组织中镉的积累和脂质过氧化作用,提升抗氧化防御系统的能力,这是第一个对乳酸杆菌在体内去除镉的机制研究。近期的一项研究中他们还发现该菌株可以通过保护肠道屏障进一步减轻镉诱导的细胞毒性,缓解氧化应激和炎症反应,逆转对肠道上皮细胞紧密连接的破坏,降低肠上皮细胞的通透性[63]。这项研究表明,除了肠道内对镉的隔离作用,益生菌还可以通过保护肠道屏障来抑制镉的吸收。

2.2 益生菌对铬的去除

铬是毒性最大的重金属之一,由于冶金耐火材料、化工和制革工业以及农业实践的发展使其在环境中的水平显著提高,它已经成为水生和陆地生态系统中含量最多的污染物之一[82]。铬(Ⅵ)和铬(Ⅲ)是自然界两种稳定的氧化态。作为硫酸盐的类似物,铬酸盐可以通过硫酸盐转运系统进入细菌和哺乳动物细胞,对细胞和组织造成损伤[83]。铬(Ⅲ)与铬(Ⅵ)相比毒性较小且溶解性较差,在自然条件下通过各种氧化过程容易转化为铬(Ⅵ),被氧化的铬(Ⅵ)对生物体具有致癌性和致突变性,进而诱导肝、肾等组织发生病变[84]

在益生菌与铬的作用机理方面,研究者着重分析了益生菌对铬(Ⅵ)的还原能力。Mishra等[38]研究发现,铬酸盐抗性的乳酸杆菌具有在机体胃肠道及被污染的环境中结合铬(Ⅵ)的潜力。在小鼠中,肠道菌群可以将高毒性的铬(Ⅵ)转化为毒性较低的铬(Ⅲ),从而为机体提供了第一道防线[85]。Wu等[52]在最近的研究中发现,Lactobacillus plantarum TW1-1在给肠道微生物群落的结构带来有益影响的同时,整个肠道菌群还原铬(Ⅵ)的能力也随即增强,这暗示了益生菌可能通过改变肠道微生物群落的结构和功能而协同降低重金属的毒性。

2.3 益生菌对铅的去除

随着工业的发展,含铅烟尘的排放以及食品罐头、涂料和化妆品中含铅化合物的使用,使得铅成为一种对人类和动物健康造成不利影响的重金属[86]。铅进入机体后在血液和骨骼中有一定的生物累积能力,血液中铅的半衰期约为30 d,但可以留在骨骼系统多年[87-88]。长期的铅积累会导致动物及人体神经系统和血液系统功能障碍,肾脏和肝脏损害,以及人体生殖系统损害等不良反应[89-90]。因此铅中毒是一个长期积累的过程。

离子交换机制可能是目前益生菌在体外环境中吸附铅的主要机制[91]。Tian等[75]在以小鼠为模型的铅积累研究中发现,Lactobacillus plantarum CCFM8661能有效维持小鼠肝脏组织中ROS、GSH和MDA水平,进而减轻小鼠体内积累的铅毒性,这表明抗氧化能力是Lactobacillus plantarum CCFM8661缓解铅毒性的主要机制之一,其它可能的机理仍待进一步证实。

2.4 益生菌对汞的去除

汞是有毒重金属之一,在自然界中主要以无机和有机两种形式存在。联合国环境规划署提到,环境中汞污染的来源主要是一些手工制造业和小型金矿的开采[92]。无机汞通常用于黄金开采中的融合过程,由于缺乏适当的废物管理制度,过量的汞通常直接流入土壤、地下水甚至海洋[93]。研究者发现,在一些可食用的牛肝菌和野蘑菇中有大量的汞积累,对人类的健康存在威胁[94]。持续的汞积累可能会造成机体神经、免疫、血液系统以及肾脏等组织发生病变[95]

益生菌去除汞的研究目前处于起步阶段。Kinoshita等[96]在体外试验中发现,W. viridescens MYU205细胞表面存在许多汞结合蛋白,为益生菌细胞结合汞提供了可能。一些从人体及动物体内筛选出来的益生菌如Lactobacillus plantarum 299V、Lactobacillus rhamnosus ATCC9595等也被证实具有体外吸附汞的能力[97]。在最近的一项研究中还提出少数乳酸菌除了具有表面结合甲基汞的能力之外,自身可能存在编码甲基汞裂解酶的基因,因此自身的酶促反应可能是其结合甲基汞的机制之一,同时肠道菌群在人体甲基汞的代谢过程中可能起到重要作用[93]。目前益生菌结合汞的研究仅停留在体外实验阶段,动物体内的实验仍有待开展。

2.5 益生菌对铝的去除

铝是地壳中含量最丰富的金属,在日常生活中被广泛使用[98],铝制厨具的使用使膳食吸收成为人体内铝累积的主要途径。欧洲食品安全局规定的人体正常铝摄入量为1 mg/(kg·bw·week),而欧洲成年人通过膳食摄取的铝含量达到1.3 mg/(kg·bw·week)中国儿童摄取的铝含量达到3.3 mg/(kg·bw·week),均超过了规定的铝摄入值[99-100]。过量的铝会积累在脑、肝、肾、脾和骨骼中,可能进一步导致阿尔茨海默症、透析性脑病、小红细胞性贫血和骨软化等疾病的产生[101-103]

近年来,研究者发现Lactobacillus plantarum CCFM639含有较高的羟自由基清除和还原能力,能够在肠道吸收铝之前先结合铝,进而刺激肠道蠕动,最终使得铝随粪便排出体外[39]。近期的研究还发现,CCFM639可以调节肠粘膜免疫功能,恢复紧密连接蛋白的完整性并且维护肠道通透性的稳定。这些结果表明,除了肠道隔离机制之外,Lactobacillus plantarum CCFM639还可以通过维护肠道的屏障功能进一步减轻铝诱导的氧化应激和炎症反应[64]。Tian等[104]在C57BL/6小鼠的研究中发现,CCFM639可以缓解由于铝长期积累而造成的小鼠脑组织中的氧化应激反应,同时减少β-淀粉样肽在脑组织中的积累,进而增加了小鼠的记忆功能。因此,Lactobacillus plantarum CCFM639具有缓解铝毒性的潜力。

3 结论与展望

现阶段土壤及农田重金属污染问题依然严重,利用益生菌减少环境和动物体中重金属积累的研究仍处于起步阶段。许多益生菌如植物乳杆菌、鼠李糖乳杆菌等具有吸附和隔离重金属的能力,并且益生菌在食品工业方面具有安全良好的应用基础,因此,使用乳酸杆菌等益生菌作为膳食补充剂有望成为缓解人体重金属超标的一种有效方式。

目前关于益生菌在体内去除重金属的研究还不多,且局限于小鼠、大鼠等哺乳动物模型,具体的分子机理尚未完全明确。未来的研究还需要围绕以下几个方面开展:(1)益生菌与重金属的分子作用机理探究:现有关于益生菌在动物体内与重金属的作用机理报道主要包括肠道隔离、增强肠道屏障和缓解机体氧化应激等方面,因此在未来研究中还需要深入研究其分子机制,尤其是益生菌与宿主及其肠道微生物菌群之间的相互作用。尽管粪便菌群的16S rRNA基因序列分析已被广泛用来分析肠道微生物群落的结构组成,但这种测序技术并不能揭示肠道内活性微生物的转录和代谢活动。未来可通过宏基因组学、宏转录组学及宏代谢组学等技术进一步分析肠道微生物群落在重金属胁迫和益生菌干预下的分子应答,进而揭示益生菌与宿主及其肠道微生物三者之间的相互作用机理,为益生菌在机体内减少重金属毒性提供重要的分子机制基础。(2)益生菌在肠道中的定殖情况分析:目前多篇文献报道益生菌在动物体内的定殖具有个体特异性差异,受到宿主自身菌群等多种因素的影响。另外,关于肠道菌群的研究大部分是基于小鼠粪便样品进行的16S rRNA基因序列分析,然而粪便微生物并不能准确反映机体肠道内微生物群落。因此,未来的研究还需要关注益生菌在肠道中的定殖情况,同时还需在肠道内的不同区段取样,从而准确地解释分析修复效果,并且还可针对不同的群体研发制定出个性化的益生菌治疗方案。(3)菌株的筛选:由于同一种益生菌菌株并非对所有重金属都具有结合能力,因此要针对不同种类的重金属筛选出具有不同抗性的益生菌菌株。此外,通过合成生物学的方法构建工程化的益生菌应用于肠道修复中,也是未来研究的一个趋势。(4)菌剂在人体中的研究与应用:本文中论述的益生菌在体内对重金属的去除效果均基于动物模型,因此益生菌在人体内减少重金属积累的工作亟待开展。同时,在后续菌剂生产过程中,需要依照生产、生活需求,生产出对人体无害且可以直接服用的益生菌菌剂,并进行一系列的临床研究与工业化生产实践。

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