多糖利用位点研究进展及其在中药药理研究中的应用
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摘要
多糖利用位点(PULs)是与多糖分解代谢相关且位于特定区域的一组基因簇,包括淀粉利用系统(SusC),SusD,及编码外膜糖蛋白结合蛋白、编码碳水化合物活性酶等基因。多糖利用位点广泛存在于肠道拟杆菌中,这种能突出利用多糖的能力是拟杆菌适应肠道的生存策略之一。一方面,肠道拟杆菌的丰度高、种类繁多,是中药调节肠道菌群的最主要靶点菌群;另一方面,诸多中药化学成分中,中药多糖是重要有效成分且含量高,也可以作为肠道细菌的竞争性碳源;中药多糖如何基于碳源调节肠道拟杆菌是中药药理学研究的重要内容。本文结合最新的文献介绍了多糖利用位点的基因及蛋白构成、综述了多糖利用位点研究的最新进展,分析了多形拟杆菌和脆弱拟杆菌基因组中多糖利用位点多样性及其组成;同时,结合自己的中药多糖体外影响拟杆菌的碳源实验,对基于多糖利用位点研究中药微生态药理机制提出了展望,该方向的研究,不仅是细菌多糖利用位点研究的新内容,也是"人-药物-菌群"整体观及中医健脾研究的重要内容。
Polysaccharide utilization loci( PULs) are a group of gene clusters related to polysaccharides catabolism and located in specific areas,including starch utilization system( SusC),SusD,encoding outer membrane glycoprotein binding proteins, and carbohydrate active enzymes. The wide existence of PULs in Bacteroides,and the extraordinary ability of utilizing polysaccharide is its survival strategy to adapt to the intestinal tract. On one hand,Bacteroides feature a high abundance and variety,making it the most important bacterial target group regulated by traditional Chinese medicine( TCM). On the other hand,polysaccharide is an important effective constituent among TCM chemicals,with a high content,and can also be used as a competitive carbon source for intestinal bacteria. Therefore,what is the mechanism of regulating the intestinal flora based on the carbon source of polysaccharide is an important part of the pharmacological research of TCM. According to the latest literatures,this paper introduces the gene and protein composition of PULs,reviews the latest developments in PULs research, and analyzes the structure of PULs in the genomes of Bacteroides fragilis and Bacteroides thetaiotaomicron. Furthermore,we also put forward a prospect for the pharmacological micro-ecological mechanism of TCM based on PULs based on our carbon source experiments,which focuses the effects of Bacteroides by TCM polysaccharides in vitro. This research is not only the new content of bacterial PULs researches,but also the important part of researches of " human-drug-bacteria" holistic view and TCM spleen-tonifying concept.
Polysaccharide utilization loci( PULs) are a group of gene clusters related to polysaccharides catabolism and located in specific areas,including starch utilization system( SusC),SusD,encoding outer membrane glycoprotein binding proteins, and carbohydrate active enzymes. The wide existence of PULs in Bacteroides,and the extraordinary ability of utilizing polysaccharide is its survival strategy to adapt to the intestinal tract. On one hand,Bacteroides feature a high abundance and variety,making it the most important bacterial target group regulated by traditional Chinese medicine( TCM). On the other hand,polysaccharide is an important effective constituent among TCM chemicals,with a high content,and can also be used as a competitive carbon source for intestinal bacteria. Therefore,what is the mechanism of regulating the intestinal flora based on the carbon source of polysaccharide is an important part of the pharmacological research of TCM. According to the latest literatures,this paper introduces the gene and protein composition of PULs,reviews the latest developments in PULs research, and analyzes the structure of PULs in the genomes of Bacteroides fragilis and Bacteroides thetaiotaomicron. Furthermore,we also put forward a prospect for the pharmacological micro-ecological mechanism of TCM based on PULs based on our carbon source experiments,which focuses the effects of Bacteroides by TCM polysaccharides in vitro. This research is not only the new content of bacterial PULs researches,but also the important part of researches of " human-drug-bacteria" holistic view and TCM spleen-tonifying concept.
引文
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[34]张培,郑晓萍,马玉玲,等.党参多糖单糖组成与其对Hep G2细胞毒活性的相关分析[J].中草药,2016,47(15):2684-2692.
[35]李雨庭,李诗畅,牛雯颖,等.方剂药理研究的方法与思路[J].中国实验方剂学杂志,2017,23(21):229-234.
[36]安婉丽,李雪丽,孔冉,等.中医药治疗肠道菌群失调症的方剂用药规律分析[J].中国实验方剂学杂志,2018,24(12):210-215.
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[42]吴秀,周联,罗霞,等.四君子汤多糖对脾虚小鼠肠道菌群及免疫功能的影响[J].中药药理与临床,2014,30(2):12-14.
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[2] CHEN L,Brar M S,Leung F C C,et al. Triterpenoid herbal saponins enhance beneficial bacteria,decrease sulfate-reducing bacteria, modulate inflammatory intestinal microenvironment and exert cancer preventive effects in Apc Min/+mice[J]. Oncotarget,2016,7(21):31226-31242.
[3] D'Argenio,Valeria,Salvatore F. The role of the gut microbiome in the healthy adult status[J]. Clin Chi Acta,2015,451:97-102.
[4]孙冶,李新鸣,王蔺,等.益生菌对肠道健康的功效及其作用机制的研究进展[J].沈阳医学院学报,2018,20(4):347-360.
[5]王雨珊,李万丛,游颖,等.中药调节肠道菌群改善人体健康的研究进展[J].中草药,2018,49(9):2203-2209.
[6] XU J,CHEN H B,LI S L. Understanding the molecular mechanisms of the interplay between herbal medicines and gut microbiota[J]. Med Res Rev,2017,37(5):1140-1185.
[7]郑礼胜,邰文,兰新新,等.基于肠道菌群新靶点的中药防治糖尿病研究进展[J].药物评价研究,2017,40(8):1173-1181.
[8]刘骏,孙经梦,王辉.肠道菌群与疾病发生及中草药调节和治疗作用的研究概述[J].中国微生态学杂志,2013,25(7):855-860.
[9] Soest P J V. Nutritional ecology of the ruminant[J].Corn Uni P,1994,44(11):2552-2561.
[10] Martens E C,Chiang H C,Gordon J I. Mucosal glycan foraging enhances fitness and transmission of a saccharolytic human gut bact sym[J]. Cell Host Mic,2008,4(5):447-457.
[11] Consortium H M P. Structure,function and diversity of the healthy human microbiome[J]. Nature,2012,486(7402):207-214.
[12] Martens E C,Kelly A G,Tauzin A S,et al. The devil lies in the details:how variations in polysaccharide finestructure impact the physiology and evolution of gut microbes[J]. J Mole Bio,2014,426(23):3851-3865.
[13] Martens E C,Koropatkin N M,Smith T J,et al. Complex glycan catabolism by the human gut microbiota:the bacteroidetes sus-like paradigm[J]. J Bio Chem,2009,284(37):24673-24677.
[14] Mcnulty N P,WU M,Erickson A R,et al. Effects of diet on resource utilization by a model human gut microbiota containing Bacteroides cellulosilyticus WH2,a symbiont with an extensive glycobiome[J]. PLo S Bio,2013,11(8):e1001637.
[15] Glenwright A J,Pothula K R,Bhamidimarri S P,et al.Structural basis for nutrient acquisition by dominant members of the human gut microbiota[J]. Nature,2017,541(7637):407-411.
[16] Lombard V,Golaconda R H,Drula E,et al. The carbohydrate-active enzymes database(CAZy)in 2013[J]. Nuc Aci Res,2014,42(D1):D490-D495.
[17] CAO Y,FA珟rstner K U,Vogel J,et al. cis-Encoded Small RNAs,a conserved mechanism for repression of polysaccharide utilization in Bacteroides[J]. J Bac,2016,198(18):2410-2418.
[18] Ndeh D,Rogowski A,Cartmell A,et al. Complex pectin metabolism by gut bacteria reveals novel catalytic functions[J]. Nature,2017,544(7648):65-70.
[19] Cuskin F,Lowe E C,Temple M J,et al. Human gut Bacteroidetes can utilize yeast mannan through a selfish mechanism[J]. Nature,2015,517(7533):165-169.
[20] Schwalm N D,Groisman E A. Navigating the gut buffet control of polysaccharide utilization in Bacteroides spp[J]. Tren Mic,2017,25(12):1005-1015.
[21] Matthew H F,Darrell W C,Nicole M K. The Sus operon:a model system for starch uptake by the human gut Bacteroidetes[J]. Cell Mol Scie,2016,73(14):1-15.
[22] Cameron E A,Maynard M A,Smith C J,et al.Multidomain carbohydrate-binding proteins involved in Bacteroides thetaiotaomicron starch metabolism[J]. J Bio Chem,2012,287(41):34614-34625.
[23] Temple M J,Cuskin F,Baslé, Arnaud, et al. A Bacteroidetes locus dedicated to fungal 1,6-β-glucan degradation:unique substrate conformation drives specificity of the key endo-1,6-β-glucanase[J]. J Bio Chem,2017,292(25):10639-10650.
[24] Martens E C,Lowe E C,Chiang H,et al. Recognition and degradation of plant cell wall polysaccharides by two human gut symbionts[J]. PLo S Bio, 2011, 9(12):e1001221.
[25] Schwalm N D,Townsend G E,Groisman E A. Multiple signals govern utilization of a polysaccharide in the gut bacterium Bacteroides thetaiotaomicron[J]. MBio,2016,7(5):e01342-16.
[26] Ravcheev D A,Godzik A,Osterman A L,et al.Polysaccharides utilization in human gut bacterium Bacteroides thetaiotaomicron:comparative genomics reconstruction of metabolic and regulatory networks[J].BMC Gen,2013,14(1):873.
[27] Groisman E A. Feedback control of two-component regulatory systems[J]. Ann Rev Mic,2016,70(1):103-124.
[28] Lloydprice J,Abuali G,Huttenhower C. The healthy human microbiome[J]. Genome Medicine,2016,8(1):51.
[29] Rogowski A,Briggs J A,Mortimer J C,et al.Corrigendum:glycan complexity dictates microbial resource allocation in the large intestine[J]. Nat Commun,2016,doi:10. 1038/ncomms10705.
[30] Terrapon N,Lombard V,Gilbert H J,et al. Automatic prediction of polysaccharide utilization loci in Bacteroidetes species[J]. Bioinformatics,2015,31(5):647-655.
[31] CAO Y,Rocha E R,Smith C J. Efficient utilization of complex N-linked glycans is a selective advantage for Bacteroides fragilis in extraintestinal infections[J]. Proc Natl Acad Sci USA,2014,111(35):12901-12906.
[32]孟祥云,郭树明,杨丽霞.中药植物多糖对2型糖尿病胰岛素抵抗的作用机制研究进展[J].中国实验方剂学杂志,2017,23(8):220-225.
[33]钱增堃,崔凡,凌云熹,等.泽泻多糖对糖尿病大鼠肝脏糖脂代谢的影响[J].中国实验方剂学杂志,2018,24(11):117-125.
[34]张培,郑晓萍,马玉玲,等.党参多糖单糖组成与其对Hep G2细胞毒活性的相关分析[J].中草药,2016,47(15):2684-2692.
[35]李雨庭,李诗畅,牛雯颖,等.方剂药理研究的方法与思路[J].中国实验方剂学杂志,2017,23(21):229-234.
[36]安婉丽,李雪丽,孔冉,等.中医药治疗肠道菌群失调症的方剂用药规律分析[J].中国实验方剂学杂志,2018,24(12):210-215.
[37] Claire L B,Neves A L,Chilloux J,et al. Impact of the gut microbiota on inflammation,obesity,and metabolic disease[J]. Genome Med,2016, doi:10. 1186/s13073-016-0303-2.
[38]李艳,宋亚刚,白明,等.基于调控肠道菌群探讨中药防治脑卒中[J].中国实验方剂学杂志,2019,25(1):228-234.
[39] Roy S,Trinchieri G. Microbiota:a key orchestrator of cancer therapy[J]. Nat Rev Can,2017,17(5):271-285.
[40] TAI N,WONG F S,WEN L. The role of gut microbiota in the development of type 1,type 2 diabetes mellitus and obesity[J]. Rev End Met Dis,2015,16(1):55-65.
[41] Sonnenburg J L,Fredrik B. Diet-microbiota interactions as moderators of human metabolism[J]. Nature,2016,535(7610):56-64.
[42]吴秀,周联,罗霞,等.四君子汤多糖对脾虚小鼠肠道菌群及免疫功能的影响[J].中药药理与临床,2014,30(2):12-14.
[43]舒青龙,王萍,封勇,等.理中汤对抗生素相关性腹泻模型构建中肠道菌群变化的影响[J].中国实验方剂学杂志,2015,21(21):82-87.
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