药学学报, 2019, 54(5): 768-777
引用本文:
彭典, 胡卓伟, 张晓伟. 肠道益生菌A.muciniphila抗代谢性疾病的治疗学展望[J]. 药学学报, 2019, 54(5): 768-777.
PENG Dian, HU Zhuo-wei, ZHANG Xiao-wei. Therapeutic perspectives of intestinal probiotics A. muciniphila in metabolic disorders[J]. Acta Pharmaceutica Sinica, 2019, 54(5): 768-777.

肠道益生菌A.muciniphila抗代谢性疾病的治疗学展望
彭典, 胡卓伟, 张晓伟
中国医学科学院、北京协和医学院药物研究所, 北京 100050
摘要:
Akkermansia muciniphilaA. muciniphila)是2004年从人类粪便样品中分离得到的一种肠道细菌,其降解黏蛋白的特性使其成为维持肠道黏膜屏障的关键微生物。A. muciniphila作为疣微菌门唯一能被培养的肠道菌代表,在宏基因组分析中相对容易被检测到。尽管它被鉴定出来的时间不久,但近年来由于其肠道定殖与多种代谢性疾病的发生发展密切相关,迅速引起了研究者们的关注,并成为目前国内外的研究热点。大量证据表明其在肠道中的定殖与宿主的健康息息相关,本文介绍了A. muciniphila的生物学特性及其定殖环境,并对A. muciniphila与宿主健康和疾病的关系进行综述,尤其着重于该菌与宿主代谢性疾病的关系以及其作用机制,同时本文总结了影响该菌在宿主内定殖的因素,以期为以A. muciniphila为靶点的药物研发提供依据和线索。
关键词:    Akkermansia muciniphila      肠道微生物      代谢疾病      肠道黏液     
Therapeutic perspectives of intestinal probiotics A. muciniphila in metabolic disorders
PENG Dian, HU Zhuo-wei, ZHANG Xiao-wei
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050
Abstract:
Akkermansia muciniphila (A. muciniphila) is an intestinal bacterium that was isolated from human feces in 2004. Its specialization in mucin degradation makes it a key organism that maintains the intestinal mucosal barrier function. A. muciniphila, which is the only representative of the Verrucomicrobia that can be cultured, is relatively easy to be detected in metagenomic analysis. For the past few years, A. muciniphila has quickly attracted the attention of researchers and become a medical and biological hotspot due to the close correlation between its intestinal colonization and the development and progression of various metabolic diseases. This review introduces the biological characteristics and colonization environment of A. muciniphila, and reviews its relationship with host health and disease, especially focusing on the metabolic disease and related mechanism, as well as the factors affecting its colonization in the host, expecting to provide evidence and clues for drug development targeting A. muciniphila.
Key words:    Akkermansia muciniphila    gut microbiota    metabolic disease    intestinal mucus   
收稿日期: 2018-12-13
DOI: 10.16438/j.0513-4870.2018-1113
基金项目: 国家自然科学基金资助项目(81773781,81773800);中国医学科学院医学与健康科技创新工程重大协同创新项目(2016-I2M-1-010).
通讯作者: 张晓伟,Tel:86-10-83161187,E-mail:zhxw@imm.ac.cn
Email: zhxw@imm.ac.cn
相关功能
PDF(468KB) Free
打印本文
0
作者相关文章
彭典  在本刊中的所有文章
胡卓伟  在本刊中的所有文章
张晓伟  在本刊中的所有文章

参考文献:
[1] Qin JJ, Li RQ, Raes J, et al. A human gut microbial gene cata logue established by metagenomic sequencing[J]. Nature, 2010, 464:59-65.
[2] Belzer C, de Vos WM. Microbes inside——from diversity to func tion:the case of Akkermansia[J]. ISME J, 2012, 6:1449-1458.
[3] Sears CL. A dynamic partnership:celebrating our gut flora[J]. Anaerobe, 2005, 11:247-251.
[4] Wostmann BS, Larkin C, Moriarty A, et al. Dietary intake, energy metabolism, and excretory losses of adult male germfree Wistar rats[J]. Lab Anim Sci, 1983, 33:46-50.
[5] Bäckhed F, Ley RE, Sonnenburg JL, et al. Host-bacterial mutualism in the human intestine[J]. Science, 2005, 307:1915-1920.
[6] Hooper LV, Wong MH, Thelin A, et al. Molecular analysis of commensal host-microbial relationships in the intestine[J]. Science, 2001, 291:881-884.
[7] Cone RA. Barrier properties of mucus[J]. Adv Drug Delivery Rev, 2009, 61:75-85.
[8] Hamer HM, Jonkers DM, Loof A, et al. Analyses of human colonic mucus obtained by an in vivo sampling technique[J]. Dig Liver Dis, 2009, 41:559-564.
[9] Clamp JR, Ene D. The gastric mucosal barrier[J]. Methods Find Exp Clin Pharmacol, 1989, 11 Suppl 1:19-25.
[10] Johansson MEV, Phillipson M, Petersson J, et al. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria[J]. Proc Natl Acad Sci U S A, 2008, 105:15064-15069.
[11] Derrien M, Collado MC, Ben-Amor K, et al. The Mucin degrader Akkermansia muciniphila is an abundant resident of the human intestinal tract[J]. Appl Environ Microbiol, 2008, 74:1646-1648.
[12] Derrien M, Vaughan EE, Plugge CM, et al. Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucindegrading bacterium[J]. Int J Syst Evol Microbiol, 2004, 54:1469-1476.
[13] Gómez-Gallego C, Pohl S, Salminen S, et al. Akkermansia muciniphila:a novel functional microbe with probiotic properties[J]. Benef Microbes, 2016, 7:571-584.
[14] Rajilić-Stojanović M, de Vos WM. The first 1000 cultured species of the human gastrointestinal microbiota[J]. FEMS Microbiol Rev, 2014, 38:996-1047.
[15] van Passel MW, Kant R, Zoetendal EG, et al. The genome of Akkermansia muciniphila, a dedicated intestinal mucin degrader, and its use in exploring intestinal metagenomes[J]. PLoS One, 2011, 6:e16876.
[16] Guo XF, Li SH, Zhang JC, et al. Genome sequencing of 39 Akkermansia muciniphila isolates reveals its population structure, genomic and functional diverisity, and global distribution in mammalian gut microbiotas[J]. BMC Genomics, 2017, 18:800.
[17] Ouwerkerk JP, van der Ark KCH, Davids M, et al. Adaptation of Akkermansia muciniphila to the oxic-anoxic interface of the mucus layer[J]. Appl Environ Microbiol, 2016, 82:6983-6993.
[18] Reunanen J, Kainulainen V, Huuskonen L, et al. Akkermansia muciniphila adheres to enterocytes and strengthens the integrity of the epithelial cell layer[J]. Appl Environ Microbiol, 2015, 81:3655-3662.
[19] Collado MC, Derrien M, Isolauri E, et al. Intestinal integrity and Akkermansia muciniphila, a mucin-degrading member of the intestinal microbiota present in infants, adults, and the elderly[J]. Appl Environ Microbiol, 2007, 73:7767-7770.
[20] Sonoyama K, Ogasawara T, Goto H, et al. Comparison of gut microbiota and allergic reactions in BALB/c mice fed different cultivars of rice[J]. Br J Nutr, 2010, 103:218-226.
[21] Sonoyama K, Fujiwara R, Takemura N, et al. Response of gut microbiota to fasting and hibernation in Syrian hamsters[J]. Appl Environ Microbiol, 2009, 75:6451-6456.
[22] Carey HV, Walters WA, Knight R. Seasonal restructuring of the ground squirrel gut microbiota over the annual hibernation cycle[J]. Am J Physiol Regul Integr Comp Physiol, 2013, 304:R33-R42.
[23] Hildebrand F, Ebersbach T, Nielsen HB, et al. A comparative analysis of the intestinal metagenomes present in guinea pigs (Cavia porcellus) and humans (Homo sapiens)[J]. BMC Genomics, 2012, 13:514.
[24] Zeng B, Han SS, Wang P, et al. The bacterial communities as sociated with fecal types and body weight of rex rabbits[J]. Sci Rep, 2015, 5:9342.
[25] Liu XF, Fan HL, Ding XB, et al. Analysis of the gut microbiota by high-throughput sequencing of the V5-V6 regions of the 16S rRNA gene in donkey[J]. Curr Microbiol, 2014, 68:657-662.
[26] Costello EK,Gordon JI, Secor SM, et al. Postprandial remodeling of the gut microbiota in Burmese pythons[J]. ISME J, 2010, 4:1375-1385.
[27] Roeselers G, Mittge EK, Stephens WZ, et al. Evidence for a core gut microbiota in the zebrafish[J]. ISME J, 2011, 5:1595-1608.
[28] Neef A, Sanz Y. Future for probiotic science in functional food and dietary supplement development[J]. Curr Opin Clin Nutr Metab Care, 2013, 16:679-687.
[29] Everard A, Belzer C, Geurts L, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls dietinduced obesity[J]. Proc Natl Acad Sci U S A, 2013, 110:9066-9071.
[30] Everard A, Lazarevic V, Gaïa N, et al. Microbiome of prebiotictreated mice reveals novel targets involved in host response during obesity[J]. ISME J, 2014, 8:2116-2130.
[31] Everard A, Lazarevic V, Derrien M, et al. Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice[J]. Diabetes, 2011, 60:2775-2786.
[32] Plovier H, Everard A, Druart C, et al. A purified membrane pro tein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice[J]. Nat Med, 2017, 23:107-113.
[33] Ottman N. Host Immunostimulation and Substrate Utilization of The Gut Symbiont Akkermansia muciniphila[D]. Wageningen:Wageningen University, 2015.
[34] Ottman N, Reunanen J, Meijerink M, et al. Pili-like proteins of Akkermansia muciniphila modulate host immune responses and gut barrier function[J]. PLoS One, 2017, 12:e0173004.
[35] Lukovac S, Belzer C, Pellis L, et al. Differential modulation by Akkermansia muciniphila and Faecalibacterium prausnitzii of host peripheral lipid metabolism and histone acetylation in mouse gut organoids[J]. mBio, 2014, 5:e01438-14.
[36] Greer RL, Dong XX, Carolina A, et al. Akkermansia muciniphila mediates negative effects of IFNγ on glucose metabolism[J]. Nat Commun, 2016, 7:13329.
[37] Teixeira TFS, Grześkowiak ŁM, Salminen S, et al. Faecal levels of Bifidobacterium and Clostridium coccoides but not plasma lipopolysaccharide are inversely related to insulin and HOMA index in women[J]. Clin Nutr, 2013, 32:1017-1022.
[38] Karlsson CLJ, Önnerfalt J, Xu J, et al. The microbiota of the gut in preschool children with normal and excessive body weight[J]. Obesity, 2012, 20:2257-2261.
[39] Remely M, Tesar I, Hippe B, et al. Gut microbiota composition correlates with changes in body fat content due to weight loss[J]. Benef Microbes, 2015, 6:431-439.
[40] Le Chatelier E, Nielsen T, Qin JJ, et al. Richness of human gut microbiome correlates with metabolic markers[J]. Nature, 2013, 500:541-546.
[41] Dao MC, Everard A, Aron-Wisnewsky J, et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity:relationship with gut microbiome richness and ecology[J]. Gut, 2016, 65:426-436.
[42] Piening BD, Zhou WY, Contrepois K, et al. Integrative personal omics profiles during periods of weight gain and loss[J]. Cell Syst, 2018, 6:157-170.e8.
[43] Hänninen A, Toivonen R, Pöysti S, et al. Akkermansia muciniphila induces gut microbiota remodelling and controls islet autoim munity in NOD mice[J]. Gut, 2018, 67:1445-1453.
[44] Qin JJ, Li YR, Cai ZM, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes[J]. Nature, 2012, 490:55-60.
[45] Chelakkot C, Choi Y, Kim DK, et al. Akkermansia muciniphiladerived extracellular vesicles influence gut permeability through the regulation of tight junctions[J]. Exp Mol Med, 2018, 50:e450.
[46] Grander C, Adolph TE, Wieser V, et al. Recovery of ethanolinduced Akkermansia muciniphila depletion ameliorates alcoholic liver disease[J]. Gut, 2017, 67:891-901.
[47] Li J, Lin SQ, Vanhoutte PM, et al. Akkermansia muciniphila protects against atherosclerosis by preventing metabolic endo toxemia-induced inflammation in Apoe-/-mice[J]. Circulation, 2016, 133:2434-2446.
[48] James SL, Christophersen CT, Bird AR, et al. Abnormal fibre usage in UC in remission[J]. Gut, 2015, 64:562-570.
[49] Vigsnæs LK, Brynskov J, Steenholdt C, et al. Gram-negative bacteria account for main differences between faecal microbiota from patients with ulcerative colitis and healthy controls[J]. Benef Microbes, 2012, 3:287-297.
[50] Png CW, Lindén SK, Gilshenan KS, et al. Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utili zation of mucin by other bacteria[J]. Am J Gastroenterol, 2010, 105:2420-2428.
[51] Kang CS, Ban M, Choi EJ, et al. Extracellular vesicles derived from gut microbiota, especially Akkermansia muciniphila, protect the progression of dextran sulfate sodium-induced colitis[J]. PLoS One, 2013, 8:e76520.
[52] Swidsinski A, Dörffel Y, Loening-Baucke V, et al. Acute appendi citis is characterised by local invasion with Fusobacterium nucleatum/necrophorum[J]. Gut, 2011, 60:34-40.
[53] Bachmann R, Leonard D, Delzenne N, et al. Novel insight into the role of microbiota in colorectal surgery[J]. Gut, 2017, 66:738-749.
[54] Zhang HS, DiBaise JK, Zuccolo A, et al. Human gut microbiota in obesity and after gastric bypass[J]. Proc Natl Acad Sci U S A, 2009, 106:2365-2370.
[55] Choiniere J, Wang L. Exposure to inorganic arsenic can lead to gut microbe perturbations and hepatocellular carcinoma[J]. Acta Pharm Sin B, 2016, 6:426-429.
[56] Dingemanse C, Belzer C, van Hijum SA, et al. Akkermansia muciniphila and Helicobacter typhlonius modulate intestinal tumor development in mice[J]. Carcinogenesis, 2015, 36:1388-1396.
[57] Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influ ences efficacy of PD-1-based immunotherapy against epithelial tumors[J]. Science, 2018, 359:91-97.
[58] Wang L, Christophersen CT, Sorich MJ, et al. Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. in feces of children with autism[J]. Appl Environ Microbiol, 2011, 77:6718-6721.
[59] Candela M, Rampelli S, Turroni S, et al. Unbalance of intestinal microbiota in atopic children[J]. BMC Microbiol, 2012, 12:95.
[60] Olson CA, Vuong HE, Yano JM, et al. The gut microbiota mediates the anti-seizure effects of the ketogenic diet[J]. Cell, 2018, 173:1728-1741.e13.
[61] Wang Q, Huang SQ, Li CQ, et al. Akkermansia muciniphila may determine chondroitin sulfate ameliorating or aggravating osteoarthritis[J]. Front Microbiol, 2017, 8:1955.
[62] Hansen CH, Krych L, Nielsen DS, et al. Early life treatment with vancomycin propagates Akkermansia muciniphila and reduces diabetes incidence in the NOD mouse[J]. Diabetologia, 2012, 55:2285-2294.
[63] Dubourg G, Lagier JC, Armougom F, et al. High-level colonisa tion of the human gut by Verrucomicrobia following broad-spec trum antibiotic treatment[J]. Int J Antimicrob Agents, 2013, 41:149-155.
[64] Nobel YR, Cox LM, Kirigin FF, et al. Metabolic and metage nomic outcomes from early-life pulsed antibiotic treatment[J]. Nat Commun, 2015, 6:7486.
[65] Ferrer M, Martins dos Santos VA, Ott SJ, et al. Gut microbiota disturbance during antibiotic therapy:a multi-omic approach[J]. Gut Microbes, 2014, 5:64-70.
[66] Anhê FF, Roy D, Pilon G, et al. A polyphenol-rich cranberry extract protects from diet-induced obesity, insulin resistance and intestinal inflammation in association with increased Akkermansia spp. population in the gut microbiota of mice[J]. Gut, 2015, 64:872-883.
[67] Chaplin A, Parra P, Serra F, et al. Conjugated linoleic acid supplementation under a high-fat diet modulates stomach protein expression and intestinal microbiota in adult mice[J]. PLoS One, 2015, 10:e0125091.
[68] Andersson KE, Axling U, Xu J, et al. Diverse effects of oats on cholesterol metabolism in C57BL/6 mice correlate with expression of hepatic bile acid-producing enzymes[J]. Eur J Nutr, 2013, 52:1755-1769.
[69] Halmos EP, Christophersen CT, Bird AR, et al. Diets that differ in their FODMAP content alter the colonic luminal microenvi ronment[J]. Gut, 2015, 64:93-100.
[70] Zhong YD, Nyman M, Fåk F. Modulation of gut microbiota in rats fed high-fat diets by processing whole-grain barley to barley malt[J]. Mol Nutr Food Res, 2015, 59:2066-2076.
[71] Gómez-Gallego C, Collado MC, Ilo T, et al. Infant formula supplemented with polyamines alters the intestinal microbiota in neonatal BALB/cOlaHsd mice[J]. J Nutr Biochem, 2012, 23:1508-1513.
[72] Song HZ, Chu Q, Yan FJ, et al. Red pitaya betacyanins protects from diet-induced obesity, liver steatosis and insulin resistance in association with modulation of gut microbiota in mice[J]. J Gastroenterol Hepatol, 2016, 31:1462-1469.
[73] Alard J, Lehrter V, Rhimi M, et al. Beneficial metabolic effects of selected probiotics on diet-induced obesity and insulin resis tance in mice are associated with improvement of dysbiotic gut microbiota[J]. Environ Microbiol, 2016, 18:1484-1497.
[74] Yang JY, Bindels LB, Segura Munoz RR, et al. Disparate metabolic responses in mice fed a high-fat diet supplemented with maize-derived non-digestible feruloylated oligo-and poly saccharides are linked to changes in the gut microbiota[J]. PLoS One, 2016, 11:e0146144.
[75] Suez J, Korem T, Zeevi D, et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota[J]. Nature, 2014, 514:181-186.
[76] Shin NR, Lee JC, Lee HY, et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice[J]. Gut, 2014, 63:727-735.
[77] Wang JH, Bose S, Kim GC, et al. Flos Lonicera ameliorates obesity and associated endotoxemia in rats through modulation of gut permeability and intestinal microbiota[J]. PLoS One, 2014, 9:e86117.
[78] Wang JH, Bose S, Kim HG, et al. Fermented Rhizoma Atractylodis Macrocephalae alleviates high fat diet-induced obesity in associ ation with regulation of intestinal permeability and microbiota in rats[J]. Sci Rep, 2015, 5:8391.
[79] Kemperman RA, Gross G, Mondot S, et al. Impact of poly-phenols from black tea and red wine/grape juice on a gut model microbiome[J]. Food Res Int, 2013, 53:659-669.
[80] Axling U, Olsson C, Xu J, et al. Green tea powder and Lactoba-cillus plantarum affect gut microbiota, lipid metabolism and inflammation in high-fat fed C57BL/6J mice[J]. Nutr Metab, 2012, 9:105.
[81] Roopchand DE, Carmody RN, Kuhn P, et al. Dietary polyphenols promote growth of the gut bacterium Akkermansia muciniphila and attenuate high-fat diet-induced metabolic syndrome[J]. Diabetes, 2015, 64:2847-2858.
[82] Reid DT, Eller LK, Nettleton JE, et al. Postnatal prebiotic fibre intake mitigates some detrimental metabolic outcomes of early overnutrition in rats[J]. Eur J Nutr, 2016, 55:2399-2409.
[83] Desai MS, Seekatz AM, Koropatkin NM, et al. A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility[J]. Cell, 2016, 167:1339-1353.e21.
[84] Lee H, Ko GP. Effect of metformin on metabolic improvement and gut microbiota[J]. Appl Environ Microbiol, 2014, 80:5935-5943.
[85] Chang CJ, Lin CS, Lu CC, et al. Ganoderma lucidum reduces obesity in mice by modulating the composition of the gut micro-biota[J]. Nat Commun, 2015, 6:7489.
[86] Marcial-Coba MS, Cieplak T, Cahú TB, et al. Viability of microencapsulated Akkermansia muciniphila and Lactobacillus plantarum during freeze-drying, storage and in vitro simulated upper gastrointestinal tract passage[J]. Food Funct, 2018, 9:5868-5879.
[87] Marcial-Coba MS, Saaby L, Knøchel S, et al. Dark chocolate as a stable carrier of microencapsulated Akkermansia muciniphila and Lactobacillus casei[J]. FEMS Microbiol Lett, 2019. DOI:10.1093/femsle/fny290.