胃肠道黏液层中Akkermansia muciniphila的定殖研究及其与宿主的相互作用

中国农业科学 2016,49(8):1577-1584

Scientia Agricultura Sinica doi: 10.3864/j.issn.0578-1752.2016.08.015 胃肠道黏液层中Akkermansia muciniphila的定殖

及其与宿主的相互作用

冯泽猛1，包显颖1,2，印遇龙1

（1中国科学院亚热带农业生态研究所畜禽健康养殖研究中心/中国科学院亚热带农业生态过程重点实验室/湖南省畜禽健康养殖工程技术研究中心，

长沙 410125；2湖南农业大学动物科技学院，长沙，410128）

摘要：动物胃肠道中定殖着数量巨大的肠道微生物，影响宿主动物的代谢和发育。肠道微生物在营养物质交换、信息传递和抵抗病原微生物入侵方面均发挥着重要的作用。依据定殖部位，可以分成黏液层微生物和肠腔内微生物，Akkermansia muciniphila偏好地定殖于肠道黏液层，对机体活动影响广泛。在肠道中，Akkermansia muciniphila可以特异地降解黏蛋白和低聚糖，分别产生短链脂肪酸和丙酸，在为宿主提供能量的同时也促进了自身的定殖。而与此同时，机体黏蛋白的降解会促使宿主补偿产生更多的黏蛋白，进而降低宿主蛋白的沉积。

Akkermansia muciniphila的定殖还可减缓脂肪沉积，延缓糖尿病。在肠道微生态系统中，该菌群并没有严重的致病性，适宜丰度的Akkermansia muciniphila定殖可以促进宿主免疫系统的发育，进而促进肠道健康。随着更多科学研究的展开，胃肠道微生物在机体中的重要性得到呈现。作为目前国内外的研究热点，Akkermansia muciniphila在机体肠道内的作用机制尚未完全明确。本文从Akkermansia muciniphila的定殖环境、生理特性、对机体营养代谢的影响、与代谢性疾病及机体免疫相互作用等方面进行了综述，Akkermansia muciniphila为很有潜力的生物标记，应用于营养状态、代谢性疾病、免疫甚至癌症的评估和检测。

关键词：黏液层；黏蛋白；Akkermansia muciniphila；肠道微生物

The Interaction of Colonization of Akkermansia muciniphila in

Gastrointestinal Tract and Its Host

FENG Ze-meng1, BAO Xian-ying1,2, YIN Yu-long1

(1Institute of Subtropical Agriculture, Chinese Academy of Sciences, Research Center of Healthy Breeding Livestock & Poultry/Hunan Engineering& Research Center of Animal & Poultry Science, Key Lab Agro-ecology Processing Subtropical Region, Scientific

Observational and experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture,

Changsha 410125; 2College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128)

Abstract: The gastrointestinal tract is a big harbour for viarous microbes, which have a great influence on the metabolism and development of the host. These intestinal microbiota can be divided into microbiota in inner lumen and in mucus layer, and both have important roles in nutrients delivery and prevention against pathogenic microorganism invasion. Akkermansia muciniphila, a kind of gram-negative bacteria, specially degrades mucin, has a growth preference in animal mucus and has a broad effect on the host. In the gastrointestinal tract, the flora of Akkermansia muciniphila degrade mucin and oligosaccharides, produce short chain fatty acid and propionic acid, respectively, which provide energy to the host and also promote their colonization. At the same time, the degradation of mucin will lead to more mucin secretion, thereby lowering the host protein deposition. The colonization of Akkermansia

收稿日期：2014-09-23；接受日期：2016-01-20

基金项目：农业部“948”项目（2015Z74）、中国科学院STS项目（KFJ-SW-STS-173）

联系方式：冯泽猛，Tel：0731-********；Fax：0731-********；E-mail：zemengfeng2006@https://www.wendangku.net/doc/c69284490.html,。通信作者印遇龙，Tel：0731-********；Fax：0731-********；E-mail：yinyulong@https://www.wendangku.net/doc/c69284490.html,

1578 中国农业科学49卷

muciniphila reduce fat deposition, delay the formation of diabetes. Akkermansia muciniphila have no serious pathogenicity, and suitable abundance will promote the development of the host immune system and intestinal health. With the development of more scientific research, the importance of intestinal microbiota will be the hot topic. However, the mechanism of the action of Akkermansia muciniphila to the host is still unclear. The colonized environment, physiological characteristics, host nutrition metabolism disturbance, relation with metabolic diseases, and host immune regulation of Akkermansia muciniphila were summarized in the present paper. Akkermansia muciniphila is a good potential biomarker, and can be applied in nutritional status, metabolic diseases, immunity and even cancer detection, and worth to be further studied.

Key words: mucus; mucin; Akkermansia muciniphila; intestinal microbiota

作为一个内腔，动物胃肠道内部环境对于机体来讲也是一种外部环境。在进化过程中，动物在体表形成了毛皮表层，作为机体与自然环境之间的屏障；而在胃肠道内，则形成了一道黏液层，将胃肠道内的营养物质、异生质、宿主分泌产物（如酶，胆汁酸等）、肠道微生物及其代谢物等与肠道上皮细胞隔离开来[1]。该黏液层主要由胶状的黏蛋白组成。黏蛋白是分布在上皮组织中的杯状细胞分泌的一种可形成聚合结构的多糖-蛋白质复合物，具有特定的结构：中间含有两个富含脯氨酸、苏氨酸和丝氨酸的结构域，作为O连接聚糖的结合位点[2]；糖基化黏蛋白的C端在内质网通过二硫键相互连接形成二聚结构；在高尔基体运输过程中，黏蛋白的N端三聚体化，形成庞大的网状聚合物[3]。黏液层可分成紧密结合肠道上皮细胞且缺乏微生物定殖的粘液内层（50—200 μm）[1,4]和易洗脱的粘液外层（150—70 μm）[5]。粘液外层不断脱落和被降解，而杯状细胞不断地分泌黏蛋白进行更新充实粘液内层，使得黏液层处在持续的动态平衡中。黏液层在胃肠道内的分布并不均一，其中胃和结肠的厚度最大。肠道各部位黏液层的黏蛋白组成也有所差别，胃主要为MUC5A，肠道内主要为MUC2。动物胃肠道内的黏蛋白分泌并不恒定，受多种因素影响，包括饥饿[6]、益生素[7]、糖类[8]、维生素A[9]、GABA[10]、鲁比前列素[11]等。甚至在不同的生长阶段的奶牛肠道中黏蛋白的表达也有较大区别[12]。

1.6亿年来，哺乳动物与定殖在其胃肠道内的微生物共同进化，这些肠道微生物数量巨大，有约1014以上的个体，分属500—1 000个种属，其宏基因组大小约为宿主自身基因组的100倍[13]。依据其空间分布，肠道微生物可分成黏液层微生物和肠腔内微生物，两类微生物菌群组成有较大不同，但在营养物质交换、信息交流、免疫系统发育和抵抗病原微生物入侵等方面均有重要作用。肠道微生物可参与到黏蛋白部分翻译后修饰[14-15]，通过产生脂多糖、短链脂肪酸等物质刺激黏蛋白的分泌，进而通过调节黏液层的厚度与强度[16-18]来影响肠道屏障功能。在哺乳动物胃肠道内定殖的微生物主要分属于厚壁菌门、拟杆菌门、放线菌门、变形菌门和疣微菌门等[19]。相较肠腔内，疣微菌门在黏液层有着更为丰富的定殖 [20]。Akkermansia 是疣微菌门中的优势菌群，约占83%，普遍存在于动物肠道内，尤其是豚鼠[21-22]。至少有8种不同的Akkermansia定殖在人类肠道内[23-24]，其中Akkermansia muciniphilia （A. muciniphila）更具普遍性。在婴儿出生后1年内，该菌群的定殖就可达到成年人的水平，约占总肠道微生物的1%—4%[25-26]。A. muciniphila在肠道内的定殖并不均一，即便在结肠部位，在上升结肠较少分布，但在横向和下行结肠定殖丰富[27]，可能是因为远端肠道葡萄糖醛酸酶的活性较高[28]。有关肠道微生物的研究是近年来的研究热点，多数研究关注在肠腔内微生物，而对黏液层微生物较少研究。A. muciniphila在机体肠道内的作用机制尚未完全明确。本文将从定殖环境、生理特性、对机体营养代谢作用、与代谢性疾病及机体免疫等的影响方面对现有的有关A. muciniphila的研究进行了综述梳理。

1 A. muciniphila的生理特性及其定

殖对宿主营养代谢的作用

A. muciniphila 是一种椭圆形革兰氏阴性菌，最初通过以黏蛋白为唯一碳源和氮源的培养基从人类肠道中分离得到[26，29]。该菌优先利用黏蛋白，偏好定殖在黏蛋白含量丰富的肠道黏液层[28]。A. muciniphila的定殖特性与该种群的生理特性密切相关。该菌群所属的疣微菌门虽属于原核生物，但其细分的6个分类中至少有3个具有超微结构，区别于典型的没有原子核的原核生物[29]。A. muciniphila可以产生60多种具与黏蛋白降解相关的蛋白，如糖苷酶、硫酸酯酶以及唾液酸苷酶等[23, 30]，均是可以和粘液结合的胞外蛋白，以适应黏液层中富含黏蛋白和脱落上皮细胞的内源性糖蛋白的生存环境。黏蛋白被降解后，微生物通过多种

8期冯泽猛等：胃肠道黏液层中Akkermansia muciniphila的定殖及其与宿主的相互作用 1579

策略利用多糖，包括革兰氏阴性菌中的淀粉利用系统相似系统以及革兰氏阳性菌中的糖类吸收的ABC转运载体系统[31]，至于A. muciniphila通过何种途径利用黏蛋白降解产物，尚未见相关报道。

A. muciniphila主要的生长代谢基质为黏蛋白，由宿主胃肠道组织中杯状细胞持续分泌，所以该菌群的定殖并不严格依赖饮食，具有其独特的生存优势。

A. muciniphila可在多种动物胃肠道中定殖，且对胃肠道部位（前肠和后肠）、饮食（食肉、食草和杂食）以及黏蛋白类型（相当多的多糖）没有要求。A. muciniphila的定殖主要受黏液层成分影响[27]，随黏液层的发育变化而变化。在老年人肠道内该种群细菌的定殖明显降低[25]。

A. muciniphila的定殖影响宿主营养物质的代谢吸收。A. muciniphila以黏蛋白为碳源和氮源，产生短链脂肪酸[26]，为宿主提供能量[32]；降解海藻糖化的人乳低聚糖，产生丙酸，在促进自身定殖的同时也有益于宿主动物[33]。同时，A. muciniphila也是宿主体内的重要蛋白抢夺者[34]，该菌群定殖的增加使得黏蛋白的分解加快，使得宿主补偿产生更多的黏蛋白，消耗蛋白合成需要的氨基酸，进而降低宿主蛋白的沉积。如何调控A. muciniphila的定殖，使其处在一个相对平衡的状态，在不影响其对肠道屏障功能贡献的同时，降低其对黏蛋白的耗费，进而提高宿主对饮食蛋白质的利用率是值得思考的研究方向。

2 A. muciniphila和宿主代谢性疾病

现有有关A. muciniphila的研究多与肥胖相关。Akkermansia在肠道内的定殖与腰围、体重及体质指数呈负相关，与整体脂肪含量、卵巢周围脂肪及循环中的瘦素浓度呈负相关，说明Akkermansia的定殖可减缓脂肪沉积，有利于体重降低[35-36]，并且已有试验证实[37]。体重超标或者肥胖的个体肠道中A. muciniphila 的定殖较低[38-42]。饮食干预肥胖的研究表明，随着肥胖症状的缓解，A. muciniphila 的定殖有所回升。因此，A. muciniphila可作为潜在的肥胖判定指标。

Akkermansia与Ⅱ型糖尿病的几项生化指标也呈现负相关[35]。前驱糖尿病患者比正常葡萄糖耐受的个体A. muciniphila定殖更低[43]。随着葡萄糖耐受的进一步恶化，A. muciniphila在肠道内消失[44]。胰岛素缺乏和高脂日粮均可降低A. muciniphila在小鼠肠道内的定殖。日粮添加菌后，空腹血糖、胰岛素抵抗、体重以及内毒素症都能恢复正常[37]。疣微菌门也可以作为Ⅱ型糖尿病的生物标记[43, 45]。

3 A. muciniphila与宿主机体免疫

A. muciniphila在动物胃肠道内的定殖影响宿主的免疫反应，至于效果，难说有益或有害。一方面，A. muciniphila偏好以黏蛋白为基质，降解黏蛋白，可以削弱黏液屏障的厚度，进而间接影响机体的天然和获得性免疫[46-49]。这一点可由A. muciniphila因干扰宿主粘膜平衡而加剧鼠伤寒沙门氏菌诱发的肠道炎症证明[50]。溃疡性结肠炎患者的黏液层也比正常人薄[51]。另一方面，A. muciniphila在肠道的定殖可促进宿主天然和获得性免疫系统的发育[52]，诱导肠道免疫调控、限制肠道上皮细胞NKG2D配体的表达，从而促进肠道健康[53]。A. muciniphila产生的胞外小泡可缓解葡聚糖硫酸钠诱导的结肠炎 [54]。Akkermansia类细菌与阑尾炎负相关[55]。遗传性过敏症儿童肠道中A. muciniphila 的定殖明显下降[56-58]。小鼠上的研究表明，高丰度的Akkermansia定殖与过敏性腹泻相关，低丰度定殖则和饮食、低症状过敏以及禁食相关[59-60]。给高脂日粮饲喂的小鼠灌胃A. muciniphila可激活调节T细胞，降低炎症反应[61]，使得因高脂肪低表达的Reg3g回归正常表达水平[37]。母乳和婴儿的肠道中均有A. muciniphila的分布[25]，其存在与促炎症信号相关，这类细菌的定殖与初乳中高浓度的TNF-α和IFN-γ，以及哺乳过程中低浓度的IL10和IL4相关[62]。体重超标的母体肠道内A. muciniphila的定殖与初乳中的IL6含量相关[62]。

4 展望

随着研究的深入，胃肠道内共生的肠道微生物的重要性也日益凸显[63]。虽然已经开展了多物种、多部位、多处理下的不同肠道微生物区系的研究，但是对偏好定殖于黏液层的微生物种群的研究才刚刚开始。虽然还有其他微生物种群也能定殖于胃肠道黏液层[64-67]，但占据主体地位的还是A. muciniphila。Akkermansia类细菌在多种肠道微生态系统中的频繁出现，表明此类细菌没有严重的致病性，并可能在微生态的平衡保持方面有积极作用。

Akkermansia特异分解利用黏蛋白，可影响胃肠道黏液层的厚度[68]，可作为一种方便的肠道通透性标记[69]。因为肠道黏蛋白的分泌也受饮食营养方面的影响，可以推断A. muciniphila受动物肠道营养状态的影响，因此，A. muciniphila也有可能作为一种肠道

1580 中国农业科学49卷

营养尤其是氨基酸营养状态的生物标示物。因 A. muciniphila在健康肠道粘膜层的分布，以及其分布与一些包括炎性肠病[70]、糖尿病[55]、肥胖[39, 41, 71]和阑尾炎在内的肠道紊乱[72]负相关。A. muciniphila在克罗恩病病人、溃疡性结肠炎患者和老人肠道的定殖较少[25, 70, 73]，表明此类菌对动物肠道健康有积极作用。该菌群在胃肠道内的定殖可用来作为宿主健康的生物标记[21]。在评价癌症的形成方面，A. muciniphila的定殖也有一定的参考价值。在结肠直肠癌患者中，A. muciniphila的定殖量提升约4倍[74-75]。特异的生理结构赋予了A. muciniphila独特的生存能力。万古霉素是多数微生物，包括耐药菌的终极杀手，但万古霉素反而能促进A. muciniphila在胃肠道黏液层中的定殖[53]。

A. muciniphila偏好降解黏蛋白，参与宿主体内的蛋白代谢，豚鼠肠道内分布有比人类更多的黏蛋白降解菌Akkermansia[22]，说明黏蛋白的高周转效率。Akkermansia参与宿主葡萄糖代谢调节，给饲喂高脂日粮的小鼠灌喂A. muciniphila可增加其葡萄糖耐受[61。此外，A. muciniphila还通过调节多种转录因子参与到宿主的脂质代谢[76]。A. muciniphila是有潜力的用于营养状态、疾病等相关的生物标记，值得多方面、深层次的具体研究。通过对肠道微生物区系调控，促使机体健康向有益的方向转变，是将来营养学研究中的重要方向[77]。鉴于A. muciniphila在动物机体代谢的作用，研究发掘调控措施，调控A. muciniphila在胃肠道中的定殖，进而对营养物质的吸收转运以及肥胖、糖尿病、肠道疾病等产生有益作用也是一很有意义的研究方向。

调控A. muciniphila在胃肠道中的定殖的意义已经明了，对于如何调控，现已有多项研究。动物的行为及采食影响A. muciniphila的定殖，禁食促进人和动物肠道中A. muciniphila的定殖[59,78-80]。二甲双胍可促进肠道上皮杯状细胞对黏蛋白的分泌，增加肠道内A. muciniphila 定殖量[61]。高纤维日粮可降低小鼠肠道内A. Muciniphila的定殖[60, 81]。益生菌增加小鼠肠道内的A. muciniphila的定殖[82]。菊粉和阿糖基木聚糖可以降低盲肠中Akkermansia的定殖，但在结肠却有促进作用[33]。共轭亚油酸[83]，低聚果糖[84]，多胺[85]可以促进盲肠中Akkermansia的定殖。

总体来讲，A. muciniphila作为一种偏好性地在胃肠道黏液层定殖的微生物，具有特有的生理特性来适应其生存的环境，与宿主的肠道屏障[86]、营养物质代谢、免疫、疾病等有着密切的关系，可作为很有潜力的生物标记，应用于营养状态、代谢性疾病、免疫甚至癌症的评估和检测，值得深入研究。

References

[1] Johansson M E, Phillipson M, Petersson J, Velcich A, Holm L,

Hansson G C. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proceedings of the National Academy of Sciences U S A, 2008, 105(39):15064-15069.

[2] Moran A P, Gupta A, Joshi L. Sweet-talk: role of host glycosylation in

bacterial pathogenesis of the gastrointestinal tract. Gut, 2011, 60(10):1412-1425.

[3] Hansson G C. Role of mucus layers in gut infection and inflammation.

Current Opinion in Microbiology, 2012, 15(1):57-62.

[4] Johansson M E, Larsson J M, Hansson G C. The two mucus layers of

colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host-microbial interactions. Proceedings of the National Academy of Sciences U S A, 2011, 108(Suppl. 1):4659-4665.

[5] Atuma C, Strugala V, Allen A, Holm L. The adherent gastrointestinal

mucus gel layer: thickness and physical state in vivo. American Journal of Physiology, 2001, 280(5):G922-G929.

[6] Smirnov A, Sklan D, Uni Z. Mucin dynamics in the chick small

intestine are altered by starvation. Journal of Nutrition, 2004, 134(4): 736-742.

[7] Smirnov A, Perez R, Amit-Romach E, Sklan D, Uni Z. Mucin

dynamics and microbial populations in chicken small intestine are changed by dietary probiotic and antibiotic growth promoter supplementation. Journal of Nutrition, 2005, 135(2):187-192.

[8] Smirnov A, Tako E, Ferket P R, Uni Z. Mucin gene expression and

mucin content in the chicken intestinal goblet cells are affected by in ovo feeding of carbohydrates. Poultry Science, 2006, 85(4):669-673.

[9] Fan X, Liu S, Liu G, Zhao J, Jiao H, Wang X, Song Z, Lin H. Vitamin

a deficiency impairs mucin expression and suppresses the mucosal

immune function of the respiratory tract in chicks. PLoS One, 2015, 10(9):e0139131.

[10] Braun H S, Sponder G, Pieper R, Aschenbach J R, Deiner C. GABA

selectively increases mucin-1 expression in isolated pig jejunum.

Genes and Nutrition, 2015, 10(6):47.

[11] De Lisle R C. Lubiprostone stimulates small intestinal mucin release.

BMC Gastroenterology, 2012, 12:156.

[12] Kasimanickam R, Kasimanickam V, Kastelic JP. Mucin 1 and

cytokines mRNA in endometrium of dairy cows with postpartum uterine disease or repeat breeding. Theriogenology, 2014, 1(7): 952-958.e2.

8期冯泽猛等：胃肠道黏液层中Akkermansia muciniphila的定殖及其与宿主的相互作用 1581

[13] Xu J, Gordon J I. Honor thy symbionts. Proceedings of the National

Academy of Sciences U S A, 2003, 100:10452-10459.

[14] Makivuokko H, Lahtinen S J, Wacklin P, Tuovinen E, Tenkanen H,

Nikkil? J, Bj?rklund M, Aranko K, Ouwehand A C, M?tt? J.

Association between the ABO blood group and the human intestinal microbiota composition. BMC Microbiology, 2012, 12:94.

[15] Wacklin P, M?kivuokko H, Alakulppi N, Nikkil? J, Tenkanen H,

R?bin? J, Partanen J, Aranko K, M?tt? J. Secretor genotype (FUT2 gene) is strongly associated with the composition of Bifidobacteria in the human intestine. PLoS ONE, 2011, 6(5):e20113.

[16] Barcelo A, Claustre J, Moro F, Chayvialle J A, Cuber J C, Plaisancie P.

Mucin secretion is modulated by luminal factors in the isolated vascularly perfused rat colon. Gut, 2000, 46(2):218-224.

[17] Smirnova M G, Guo L, Birchall J P, Pearson J P. LPS up-regulates

mucin and cytokine mRNA expression and stimulates mucin and cytokine secretion in goblet cells. Cellular Immunology, 2003, 221(1): 42-49.

[18] Willemsen L E, Koetsier M A, van Deventer S J, van Tol E A. Short

chain fatty acids stimulate epithelial mucin 2 expression through differential effects on prostaglandin E(1) and E(2) production by intestinal myofibroblasts. Gut, 2003, 52(10): 1442-1447.

[19] Scott K P, Gratz S W, Sheridan P O, Flint H J, Duncan S H.

The influence of diet on the gut microbiota. Pharmacological Research, 2013, 69(1):52-60.

[20] Eckburg P B, Bik E M, Bernstein C N, Purdom E, Dethlefsen L,

Sargent M, Gill S R, Nelson K E, Relman D A. Diversity of the human intestinal microbial flora. Science, 2005, 308(5728): 1635-1638.

[21] Belzer C, de V os W M. Microbes inside - from diversity to function:

the case of Akkermansia. ISME Journal, 2012，6(8): 1449-1458. [22] Hildebrand F, Ebersbach T, Nielsen H B, Li X, Sonne S B, Bertalan M,

Dimitrov P, Madsen L, Qin J, Wang J, Raes J, Kristiansen K, Licht T R. A comparative analysis of the intestinal metagenomes present in guinea pigs (Cavia porcellus) and humans (Homo sapiens). BMC Genomics, 2012, 13:514.

[23] van Passel M W, Kant R, Zoetendal E G, Plugge C M, Derrien M,

Malfatti S A, Chain P S, Woyke T, Palva A, de V os W M, Smidt H.

The genome of Akkermansia muciniphila, a dedicated intestinal mucin degrader, and its use in exploring intestinal metagenomes. PLoS One, 2011, 6(3):e16876.

[24] Derrien M, Vaughan E E, Plugge C M, de V os W M. Akkermansia

muciniphila gen. nov., sp nov., a human intestinal mucin-degrading bacterium. International Journal of Systematic and Evolutionary

Microbiology, 2004, 54:1469-1476.

[25] Collado M C, Derrien M, Isolauri E, de V os W M, Salminen S.

Intestinal integrity and Akkermansia muciniphila, a mucin degrading member of the intestinal microbiota present in infants, adults, and the elderly. Applied and Environmental Microbiology, 2007, 73(23): 7767-7770.

[26] Derrien M, Collado M C, Ben-Amor K, Salminen S, de V os W M. The

mucin degrader Akkermansia muciniphila is an abundant resident of the human intestinal tract. Applied and Environmental Microbiology, 2008, 74:1646-1648.

[27] Van den Abbeele P, Grootaert C, Marzorati M, Possemiers S,

Verstraete W, Gérard P, Rabot S, Bruneau A, El Aidy S, Derrien M, Zoetendal E, Kleerebezem M, Smidt H, Van de Wiele T. Microbial community development in a dynamic gut model is reproducible, colon region specific, and selective for Bacteroidetes and Clostridium cluster IX. Applied and Environmental Microbiology, 2010, 76(15): 5237-5246.

[28] Derrien, M.Mucin utilisation and host interactions of the novel

intestinal microbe Akkermansia muciniphila[D]. Wageningen: Wageningen University, 2007.

[29] Georgiades K, Merhej V, Raoult D. The influence of rickettsiologists

on post-modern microbiology. Frontiers in Cellular and Infection Microbiology, 2011(1): 8.

[30] Huang K, Wang M M, Kulinich A, Yao H L, Ma H Y, Martínez J E,

Duan X C, Chen H, Cai Z P, Flitsch S L, Liu L, V oglmeir J.

Biochemical characterisation of the neuraminidase pool of the human gut symbiont Akkermansia muciniphila. Carbohydrate Research, 2015, 415:60-65.

[31] Koropatkin N M, Cameron E A, Martens E C. How glycan

metabolism shapes the human gut microbiota. Nature Reviews Microbiology, 2012, 10(5):323-335.

[32] Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, Mende D

R, Fernandes G R, Tap J, Bruls T, Batto J M, Bertalan M, Borruel N, Casellas F, Fernandez L, Gautier L, Hansen T, Hattori M, Hayashi T, Kleerebezem M, Kurokawa K, Leclerc M, Levenez F, Manichanh C, Nielsen HB, Nielsen T, Pons N, Poulain J, Qin J, Sicheritz-Ponten T, Tims S,Torrents D, Ugarte E, Zoetendal E G, Wang J, Guarner F, Pedersen O, de V os W M, Brunak S, Doré J; MetaHIT Consortium, Antolín M, Artiguenave F, Blottiere H M, Almeida M, Brechot C, Cara C, Chervaux C, Cultrone A, Delorme C, Denariaz G, Dervyn R, Foerstner KU, Friss C, van de Guchte M, Guedon E, Haimet F, Huber W, van Hylckama-Vlieg J, Jamet A, Juste C, Kaci G, Knol J, Lakhdari O, Layec S, Le Roux K, Maguin E, Mérieux A, Melo Minardi R,

1582 中国农业科学49卷

M'rini C,Muller J, Oozeer R, Parkhill J, Renault P, Rescigno M, Sanchez N, Sunagawa S, Torrejon A, Turner K,Vandemeulebrouck G, Varela E, Winogradsky Y, Zeller G, Weissenbach J, Ehrlich S D, Bork P. Enterotypes of the human gut microbiome. Nature, 2011, 473: 174-180.

[33] Van den Abbeele P, Gérard P, Rabot S, Bruneau A, Aidy S E,

Derrien M, Kleerebezem M, Zoetendal E G, Smidt H, Verstraete W, Van de Wiele T, Possemiers S. Arabinoxylans and inulin differentially modulate the mucosal and luminal gut microbiota and mucin- degradation in humanized rats. Environmental Microbiology, 2011, 13(10):2667-2680.

[34] Berry D, Stecher B, Schintlmeister A, Reichert J, Brugiroux S, Wild B,

Wanek W, Richter A, Rauch I, Decker T, Loy A, Wagner M.

Host-compound foraging by intestinal microbiota revealed by single-cell stable isotope probing. Proceedings of the National Academy of Sciences U S A, 2013, 110(12):4720-4725.

[35] Axling U, Olsson C, Xu J, Fernandez C, Larsson S, Str?m K, Ahrné S,

Holm C, Molin G, Berger K. Green tea powder and Lactobacillus plantarum affect gut microbiota, lipid metabolism and inflammation in high-fat fed C57BL/6J mice. Nutrition & Metabolism, 2012, 9(1):105.

[36] Kim B S, Song M Y, Kim H. The anti-obesity effect of Ephedra sinica

through modulation of gut microbiota in obese Korean women.

Journal of Ethnopharmacology, 2014, 152(3):532-539.

[37] Everard A, Belzer C, Geurts L, Ouwerkerk J P, Druart C, Bindels L B,

Guiot Y, Derrien M, Muccioli G G, Delzenne N M, de V os W M, Cani P D. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proceedings of the National Academy of Sciences U S A, 2013, 110(22):9066-9071.

[38] Karlsson C L, Onnerf?lt J, Xu J, Molin G, Ahrné S, Thorngren-Jerneck

K. The microbiota of the gut in preschool children with normal and excessive body weight. Obesity (Silver Spring), 2012, 20(11): 2257-2261.

[39] Santacruz A, Collado M C, García-Valdés L, Segura M T,

Martín-Lagos J A, Anjos T, Martí-Romero M, Lopez RM, Florido J, Campoy C, Sanz Y. Gut microbiota composition is associated with body weight, weight gain and biochemical parameters in pregnant women. British Journal of Nutrition, 2010, 104(1):83-92.

[40] Collado MC, Isolauri E, Laitinen K, Salminen S. Effect of mother's

weight on infant's microbiota acquisition, composition, and activity during early infancy: a prospective follow-up study initiated in early pregnancy. American Journal of Clinical Nutrition, 2010, 92(5): 1023-1030.

[41] Zhang H, DiBaise J K, Zuccolo A, Kudrna D, Braidotti M, Yu Y,

Parameswaran P, Crowell M D, Wing R, Rittmann B E, Krajmalnik-Brown R: Human gut microbiota in obesity and after gastric bypass. Proceedings of the National Academy of Sciences U S A, 2009, 106:2365-2370.

[42] Teixeira T, Grze?kowiak LM, Salminen S, Laitinen K, Bressan J,

Gouveia Peluzio Mdo C. Faecal levels of Bifidobacterium and Clostridium coccoides but not plasma lipopolysaccharide are inversely related to insulin and HOMA index in women. Clinical Nutrition, 2013, 32(6):1017-1022.

[43] Zhang X, Shen D, Fang Z, Jie Z, Qiu X, Zhang C, Chen Y, Ji L.

Human Gut Microbiota Changes Reveal the Progression of Glucose Intolerance. PLoS One, 2013, 8(8):e71108.

[44] Ellekilde M, Krych L, Hansen C H, Hufeldt M R, Dahl K, Hansen L H,

S?rensen S J, V ogensen F K, Nielsen D S, Hansen A K.

Characterization of the gut microbiota in leptin deficient obese mice - Correlation to inflammatory and diabetic parameters. Research in Veterinary Science, 2014, 96(2):241-250.

[45] Tilg H, Moschen A R. Microbiota and diabetes: an evolving

relationship. Gut, 2014, 63(9):1513-1521.

[46] McGuckin M A, Linden S K, Sutton P, Florin TH. Mucin dynamics

and enteric pathogens. Nature Reviews Microbiology, 2011, 9:265-278.

[47] Bergstrom K S B, Kissoon-Singh V, Gibson D L, Ma C, Montero M,

Sham H P, Ryz N, Huang T, Velcich A, Finlay B B, Chadee K, Vallance B A. Muc2 protects against lethal infectious colitis by disassociating pathogenic and commensal bacteria from the colonic mucosa. Plos Pathogens, 2010, 6:e1000902.

[48] Hasnain S Z, Wang H, Ghia JE, Haq N, Deng Y, Velcich A, Grencis R

K, Thornton D J, Khan W I. Mucin gene deficiency in mice impairs host resistance to an enteric parasitic infection. Gastroenterology, 2010, 138(5):1763-1771.

[49] Derrien M, van Passel M W, van de Bovenkamp J H, Schipper R G, de

V os W M, Dekker J. Mucin-bacterial interactions in the human oral cavity and digestive tract. Gut Microbes, 2010, 1(4):254-268.

[50] Ganesh B P, Klopfleisch R, Loh G, Blaut M. Commensal akkermansia

muciniphila exacerbates Gut inflammation in salmonella typhimurium- infected gnotobiotic mice. PLoS One, 2013, 8(9): e74963.

[51] Corazziari E S. Intestinal mucus barrier in normal and inflamed colon.

Journal of Pediatric Gastroenterology and Nutrition, 2009, 48: S54-S55.

[52] Harmsen H J, Wildeboer-Veloo A C, Raangs G C, Wagendorp A A,

Klijn N, Bindels J G, Wagendorp A A, Klijn N, Welling G W. Analysis of intestinal flora development in breast-fed and formula-fed infants

8期冯泽猛等：胃肠道黏液层中Akkermansia muciniphila的定殖及其与宿主的相互作用 1583

by using molecular identification and detection methods. Journal of Pediatric Gastroenterology and Nutrition, 2000, 30(1):61-67.

[53] Hansen C H, Holm T L, Krych ?, Andresen L, Nielsen D S, Rune I,

Hansen A K, Skov S. Gut microbiota regulates NKG2D ligand expression on intestinal epithelial cells. European Journal of Immunology, 2013, 43(2):447-457.

[54] Kang C S, Ban M, Choi EJ, Moon H G, Jeon J S, Kim D K, Park S K,

Jeon S G, Roh T Y, Myung S J, Gho Y S, Kim J G, Kim Y K.

Extracellular vesicles derived from Gut microbiota, especially akkermansia muciniphila, protect the progression of dextran sulfate sodium-induced colitis. PLoS ONE, 2013, 8(10): e76520.

[55] Swidsinski A, D?rffel Y, Loening-Baucke V, Theissig F, Rückert J C,

Ismail M, Rau W A, Gaschler D, Weizenegger M, Kühn S, Schilling J, D?rffel W V. Acute appendicitis is characterised by local invasion with Fusobacterium nucleatum/ necrophorum. Gut, 2011, 60(1):34-40.

[56] Campieri M, Gionchetti P. Bacteria as the cause of ulcerative colitis.

Gut, 2001, 48(1):132-135.

[57] Shih D Q, Targan S R. Immunopathogenesis of inflammatory bowel

disease. World Journal of Gastroenterology, 2008, 14(3):390-400. [58] Candela M, Rampelli S, Turroni S, Severgnini M, Consolandi C, De

Bellis G, Masetti R, Ricci G, Pession A, Brigidi P. Unbalance of intestinal microbiota in atopic children. BMC Microbiology, 2012, 12:95.

[59] Sonoyama K, Fujiwara R, Takemura N, Watanabe J, Ito H, Morita T.

Response of gut microbiota to fasting and hibernation in Syrian hamsters. Applied and Environmental Microbiology, 2009, 75(20): 6451-6456.

[60] Sonoyama K, Ogasawara T, Goto H, Yoshida T, Takemura N,

Fujiwara R, Watanabe J, Ito H, Morita T, Tokunaga Y, Yanagihara T.

Comparison of gut microbiota and allergic reactions in BALB/c mice fed different cultivars of rice. British Journal of Nutrition, 2010, 103(2):218-226.

[61] Shin N R, Lee J C, Lee H Y, Kim M S, Whon T W, Lee M S, Bae J W.

An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice.

Gut, 2013, 63:727-735.

[62] Collado M C, Laitinen K, Salminen S, Isolauri E. Maternal weight and

excessive weight gain during pregnancy modify the immunomodulatory potential of breast milk. Pediatric Research, 2012, 72(1):77-85. [63] Joyce S A, Gahan C G. The gut microbiota and the metabolic health of

the host. Current Opinion in Gastroenterology, 2014, 30(2):120-127. [64] Benjdia A, Martens E C, Gordon J I, Berteau O. Sulfatases and a

radical S-adenosyl-L-methionine (AdoMet) enzyme are key for

mucosal foraging and fitness of the prominent human gut symbiont, Bacteroides thetaiotaomicron. Journal of Biological Chemistry, 2011, 286(29):25973-25982.

[65] Turroni F, Bottacini F, Foroni E, Mulder I, Kim J H, Zomer A,

Sánchez B, Bidossi A, Ferrarini A, Giubellini V, Delledonne M, Henrissat B, Coutinho P, Oggioni M, Fitzgerald G F, Mills D, Margolles A, Kelly D, van Sinderen D, Ventura M. Genome analysis of Bifidobacterium bifidum PRL2010 reveals metabolic pathways for host-derived glycan foraging. Proceedings of the National Academy of Sciences U S A, 2010, 107(45):19514-19519.

[66] Huang J Y, Lee S M, Mazmanian S K. The human commensal

Bacteroides fragilis binds intestinal mucin. Anaerobe, 2011, 17(4): 137-41.

[67] Crost E H, Tailford L E, Le Gall G, Fons M, Henrissat B, Juge N.

Utilisation of mucin glycans by the human gut symbiont Ruminococcus gnavus is strain-dependent. PLoS One, 2013, 8(10): e76341.

[68] Louis P, Flint H J. Development of a semiquantitative degenerate

real-time pcr-based assay for estimation of numbers of butyryl- coenzyme A (CoA) CoA transferase genes in complex bacterial samples. Applied and Environmental Microbiology, 2007, 73: 2009-2012.

[69] Hippe B, Remely M, Bartosiewicz N, Riedel M, Nichterl C, Schatz L,

Pummer S, Haslberger A. Abundance and diversity of GI microbiota ratherthan IgG4 levels correlate with abdominal inconvenience and gut permeability in consumers claiming food intolerances. Endocrine Metabolic & Immune Disorders-Drug Targets, 2014, 14(1): 67-75. [70] Png C W, Lindén S K, Gilshenan K S, Zoetendal E G, McSweeney C

S, Sly L I, McGuckin M A, Florin T H. Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria. American Journal of Gastroenterology, 2010, 105(11):2420-2428.

[71] Brahe L K, Le Chatelier E, Prifti E, Pons N, Kennedy S, Hansen T,

Pedersen O, Astrup A, Ehrlich S D, Larsen L H. Specific gut microbiota features and metabolic markers in postmenopausal women with obesity. Nutrition & Diabetes, 2015, 5:e159.

[72] Wang L, Christophersen C T, Sorich M J, Gerber J P, Angley M T,

Conlon M A. Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. in feces of children with autism. Applied and Environmental Microbiology, 2011, 77(18):6718-6721.

[73] Miller R S, Hoskins L C. Mucin degradation in human colon

ecosystems. Fecal population densities of mucin-degrading bacteria

1584 中国农业科学49卷

estimated by a “most probable number” method. Gastroenterology, 1981, 81:759-765.

[74] Weir T L, Manter D K, Sheflin A M, Barnett B A, Heuberger A L,

Ryan E P. Stool microbiome and metabolome differences between colorectal cancer patients and healthy adults. PLoS One, 2013, 8(8):e70803.

[75] Zackular J P, Baxter N T, Iverson K D, Sadler W D, Petrosino J F,

Chen G Y, Schloss P D. The gut microbiome modulates colon tumorigenesis. MBio, 2013, 4(6):e00692-13.

[76] Lukovac S, Belzer C, Pellis L, Keijser BJ, de V os WM, Montijn R C,

Roeselers G. Differential modulation by Akkermansia muciniphila and Faecalibacterium prausnitzii of host peripheral lipid metabolism and histone acetylation in mouse gut organoids. MBio, 2014, pii: e01438-14.

[77] Walsh C J, Guinane C M, O'Toole P W, Cotter P D. Beneficial

modulation of the gut microbiota. FEBS Letters, 2014, pii: S0014-5793(14)00254-3.

[78] Carey H V, Walters W A, Knight R. Seasonal restructuring of the

ground squirrel gut microbiota over the annual hibernation cycle.

American Journal of Physiology, 2013, 304(1):R33-R42.

[79] Costello E K, Gordon J I, Secor S M, Knight R. Postprandial

remodeling of the gut microbiota in Burmese pythons. ISME Journal, 2010, 4(11):1375-1385.

[80] Preidis G A, Ajami N J, Wong M C, Bessard B C, Conner M E,

Petrosino J F. Composition and function of the undernourished neonatal mouse intestinal microbiome. Journal of Nutritional Biochemistry, 2015, 26(10):1050-1057.

[81] Jakobsdottir G, Xu J, Molin G, Ahrn? S, Nyman M. High-fat diet

reduces the formation of butyrate, but increases succinate, inflammation, liver fat and cholesterol in rats, while dietary fibre counteracts these effects. PLoS One, 2013, 8(11): e80476.

[82] Everard A, Lazarevic V, Derrien M, Girard M, Muccioli G G,

Neyrinck A M, Possemiers S, Van Holle A, Fran?ois P, de V os W M, Delzenne N M, Schrenzel J, Cani P D. Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet induced leptin-resistant mice. Diabetes, 2011, 60:2775-2786. [83] Chaplin A, Parra P, Serra F, Palou A. Conjugated Linoleic Acid

supplementation under a high-fat diet modulates stomach protein expression and intestinal microbiota in adult mice. PLoS One, 2015, 10(4):e0125091.

[84] Reid D T, Eller L K, Nettleton J E, Reimer R A. Postnatal prebiotic

fibre intake mitigates some detrimental metabolic outcomes of early overnutrition in rats. European Journal of Nutrition, 2015. [Epub ahead of print]

[85] Gómez-Gallego C, Collado M C, Ilo T, Jaakkola U M, Bernal M J,

Periago M J, Salminen S, Ros G, Frias R. Infant formula supplemented with polyamines alters the intestinal microbiota in neonatal BALB/ cOlaHsd mice. Journal of Nutritional Biochemistry, 2012, 23(11): 1508-1513.

[86] Reunanen J, Kainulainen V, Huuskonen L, Ottman N, Belzer C,

Huhtinen H, de V os W M, Satokari R. Akkermansia muciniphila adheres to enterocytes and strengthens the integrity of the epithelial cell layer. Applied and Environmental Microbiology, 2015, 81(11): 3655-3662.

（责任编辑林鉴非）