肠道菌群与人体疾病发病机制的研究进展-林璋

ActaPharmaceuticaSinica2016,51(6):843−8528431,2,3,1,2,2*,1,2*(1.,200240;2.,200433;3.,310014):2007(TheHumanMicrobiomeProject,HMP)()(MetagenomicsofTheHumanIntestinalTract,MetaHIT),90%,,,:;;;;;;:R378;R363:A:0513-4870(2016)06-0843-10ResearchprogressinmechanismofintestinalmicroorganismsinhumandiseasesLINZhang1,ZUXian-peng2,XIEHai-sheng3,JINHui-zi1,YANGNiao2,LIUXin-ru2*,ZHANGWei-dong1,2*(1.SchoolofPharmacy,ShanghaiJiaotongUniversity,Shanghai200240,China;2.SchoolofPharmacy,SecondMilitaryMed-icalUniversity,Shanghai200433,China;3.CollaborativeInnovationCenterofYangtzeRiverDeltaRegionGreenPharmaceuticals,ZhejiangUniversityofTechnology,Hangzhou310014,China)Abstract:TheinternationalcooperatedresearchprojectsoftheHumanMicrobiomeProject(HMP)andMetagenomicsofTheHumanIntestinalTract(MetaHIT)wereofficiallylaunchedin2007,whichindicatedtheeraofmetagenomicsresearchofmicroorganismsinhumangastrointestinaltracthadbeencoming.Eachhumanbodyisasuperorganismwhichiscomposedof90%commensalmicroorganisms,especiallytheintestinalmicroorganisms.Theintestinalmicroorganismsplayanimportantroleonhealthmaintenancesincetheyareinvolvedintheabsorptionandmetabolismofnutrientsinthehumanbodies.Herein,wereviewtheresearchprogressinthemechanismofintestinalmicroorganismsinhumandiseases.Ourpurposeistoprovidenovelideasonhumanhealthandtherapeutictargetsofdiseases.Keywords:gutmicrobiota;metagenomics;metabolicdisease;gastrointestinaldisease;behaviorandcognitivedisorder;cancer;autoimmunedisease:2015-09-14;:2015-11-17.:;(81230090,81520108030).*Tel/Fax:[phone],E-mail:[e-mail];Tel/Fax:[phone],E-mail:[e-mail]:10.16438/j.0513-4870.2015-08031,,,1014,10,··844ActaPharmaceuticaSinica2016,51(6):843−852,,,1012101450,(Firmicutes)(Bacter-oidetes)(Proteobacteria)(Actinobacteria)(Verrucomicrobia)(Fusobacteria),(98%)3:,;,;,,,,2,99.8%,,,DNA(1)16SrDNAPCR,(,metagenomics),3:;;16SrDNA[1]:16SrDNA16SrDNA,;DNA,,,13,,,,[2,3],,[4](2)2TG(triglyceride):;Angptl4(angiopoietin-like4):4;AMPK(adenosine5'-monophosphate-activatedproteinkinase):AMP;ZO-1(zonulaoccludens-1):;Occludin:;LPS(lipopolysaccharide):;GPCR41/43(G-protein-coupledreceptor41/43):G41/43;PYY(peptidetyrosine-tyrosine):;GLP-1(glu-cagon-likepeptide-1):1;PPARγ(peroxisomeproliferator-activatedreceptorγ):;TMA(trimethylamine):;TMAO(trimethylamineoxide):;FXR5(farnesoidXreceptor5):X;VDR(vitaminDreceptor):D;TGR5(Gprotein-coupledreceptorforbileacids):G:845,3.1(H2)(CO2)(CH4)(shortchainfattyacids,SCFAs),(triglyceride,TG),TG[5],(adenosine5'-monophosphate-activatedproteinkinase,AMPK),,[6],4(angiopoietin-like4,Angptl4)TG[6]Angptl4,TG,Angptl4TG,Angptl43.2[7](lipopoly-saccharide,LPS),,[8]LPS,1(zonulaoccludens-1,ZO-1)occludin[9,10],;1(cannabinoid1,Cb-1),[11],,LPS3.3SCFAsSCFAsSCFAs,,SCFAsG(G-protein-coupledreceptor41/43,GPCR-41/43)GPCR-41(peptidetyrosine-tyrosine,PYY),,[12]GPCR-43,,β-[13],L-1(glucagon-likepeptide-1,GLP-1),,[14],(peroxisomeproliferator-activatedreceptorγ,PPARγ)[15],SCFAs3.4,,,(trimethylamine,TMA),(flavin-containingmonooxygenase,FMO)(trimethylamineoxide,TMAO),TMAO,,[16]3.5,X(farnesoidXreceptor,FXR)D(vitaminDreceptor,VDR)G(Gprotein-coupledreceptorforbileacids,TGR5),FXR7α(cholesterol7-alphahydroxylase,CYP7A1)TGFXR5TGR5VDR,[17,18]3.6−,,−[19]99,−−[20]−(centralnervoussystem,CNS)(entericnervoussystem,ENS),;,,,;846ActaPharmaceuticaSinica2016,51(6):843−852,,[21],44.14.1.1(obesity),,,,2004,JerffGordon[22−24]:,,,/(Firmicutes/Bacteroidetes,F/B),2007,,[10,25]LPSLPS(lipopolysaccharidebindingprotein,LBP),LBPLPS(CD14TLR4)(TNF)(IL-1IL-6),[26,27]LPS,B29(germfree,GF),TG,LPS,LPS,[28](endoge-nouscannabinoids,eCB)eCB,eCBLPS,[11],B29(fasting-inducedadipocytefactor,Fiaf)[(acetyl-CoAcarboxylases-α,Acc1)(fattyacidsynthase,Fasn)][29]FiafB29,4.1.2121[30],,,/,,1[31],1,1[32]2,,2[33]1872,,DNA,Faecalibacteriumprausnitzii,,,,Trøseid[34],LPS,LPS[35],(Akkermansia,AKK)2,,24.1.3(non-alcoholicfattyliverdisease,NAFLD)NAFCD,,,NAFLD[36],Frasinariu[37],,LPSGpGDNA(toll-likereceptors,TLRs),TLRs:84788TRIFκB3,TNFαIL1,[38]TLR4NAFLDTLR4MyD2LPS,,NAFLD[39]4.1.4,Karlsson[40],,Chen[41]ATCC4356E(ApoE−/−),ATCC4356Koeth[16],(TMA)(TMAO),,,,4.24.2.1(inflammatoryboweldisease,IBD),(ulcerativecolitis,UC)(Crohn’sdisease,CD),,Clemente[42]Faecalibacteriumprasnitzii/EscherichiacoliIBDCDCDAIEC(adherent-invasiveE.coli)AIEC,IFN-γTNF-α,[43][44],UCUC,,T,,miRNA[45]GF,8miRNA,,ATPAbcc3mRNA,miRNA-665,miRNA-665Abcc33'Abcc3,miRNA-665Abcc3,Abcc3[46]Xue[47]IL-12/IL-23p40,miRNA-10a,miRNA-10aIL-12/IL-23p404.2.2(irritablebowelsyndrome,IBS),IBS,IBS(smallintestinalbacterialovergrowth,SIBO)[48]16SrRNA,IBS,IBS[49],IBS,[50]4.34.3.1,−−(5-),Yano[51],GF,GF60%,GF,,90%,,,,,DePalma[52]:,848ActaPharmaceuticaSinica2016,51(6):843−8523h321,,;,,,,;,,,4.3.2(Alzheimer’sdisease,AD),,AD(β-N-methylamino-L-alanine,BMAA)NADA(N-methyl-D-asparticacidreceptor)AD[53][54][55,56],AD,,AD4.3.3Parracho[57],5891.4%,,,Adams[58],,,4.4,,[59,60][61][62],2013Science,,,,[63],,,,,,,,,,[64]4.5,,,,,,,Wang[65],,,Verhulst[66]3,1,,(rheumatoidarthritis,RA),,[67]RA,RA:849,100%,,DNA,RA,(Haemophilussp.)RA,RA(Lactoba