宿主遗传因素对肠道菌群的影响
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摘要
随着高通量测序技术的发展,人们逐渐认识到肠道菌群与人类的健康和疾病密切相关,并发现肠道菌群受很多因素的影响。除了研究传统饮食和药物对肠道菌群的改变外,近年来,科学家也开始注重遗传因素在塑造肠道菌群中的作用。遗传因素可决定宿主的饮食偏好、肠道的生理结构、肠道屏障功能和免疫功能等,而这些都直接与肠道菌群相互作用,参与肠道微生态平衡的构建和稳定。因此,在研究肠道菌群与疾病发生相关性的过程中也需要考虑遗传因素的重要性。随着基因敲除、无菌小鼠和菌群移植等实验技术的革新,以及主成分分析、数量性状基因座和全基因组关联性分析等大数据分析手段的提高,科学家能够深入研究宿主遗传基因与肠道菌群之间的关联性,从而证明宿主遗传基因在塑造肠道微生态的过程中具有重要作用。本文将首先简述肠道菌群与疾病发生之间可能存在的联系,然后从多方面综述遗传因素对肠道菌群的影响及主要的研究进展,从而为今后该领域的深入研究提供重要的指导,也为今后预防和治疗疾病提供新思路和新方法。
With the development of high-throughput sequencing technologies, researches have gradually realized that gut microbiota is closely related to human health and diseases. They also have found that gut microbiota is affected by many factors. In addition to the effects of traditional diet and drugs on gut microbiota, in recent years scientists have begun to focus on the role of genetic factors in shaping gut microbiota. Genetic factors can determine the dietary preferences of the host, the physiological structure of the intestine, gut barrier function and immune function. These factors interact directly with the gut microbiota and participate in the establishment and stabilization of the microecological balance in gut. Therefore, genetic factors also need to be considered in the study on the relationship between gut microbiota and disease occurrence. With the advancement of experimental techniques such as gene knock-outs, germ-free mice, microbial colony transplantation, and with the development of big data analysis including principal component analysis, quantitative trait loci, and genome-wide association analysis, scientists can conduct in-depth studies on the association of host genetics with gut microbiota, thus demonstrating that host genetics play an important role in shaping gut microbiota. This article briefly described the possible links between gut microbiota and disease occurrence, then reviewed the effects of genetic factors on gut microbiota and major advances in the research in many aspects to provide important guidance for further research in this area, as well as new ideas and methods for future research on the prevention and treatment of diseases.
With the development of high-throughput sequencing technologies, researches have gradually realized that gut microbiota is closely related to human health and diseases. They also have found that gut microbiota is affected by many factors. In addition to the effects of traditional diet and drugs on gut microbiota, in recent years scientists have begun to focus on the role of genetic factors in shaping gut microbiota. Genetic factors can determine the dietary preferences of the host, the physiological structure of the intestine, gut barrier function and immune function. These factors interact directly with the gut microbiota and participate in the establishment and stabilization of the microecological balance in gut. Therefore, genetic factors also need to be considered in the study on the relationship between gut microbiota and disease occurrence. With the advancement of experimental techniques such as gene knock-outs, germ-free mice, microbial colony transplantation, and with the development of big data analysis including principal component analysis, quantitative trait loci, and genome-wide association analysis, scientists can conduct in-depth studies on the association of host genetics with gut microbiota, thus demonstrating that host genetics play an important role in shaping gut microbiota. This article briefly described the possible links between gut microbiota and disease occurrence, then reviewed the effects of genetic factors on gut microbiota and major advances in the research in many aspects to provide important guidance for further research in this area, as well as new ideas and methods for future research on the prevention and treatment of diseases.
引文
[1] Zhao L.The gut microbiota and obesity:From correlation to causality[J].Nat Rev Microbiol,2013,11(9):639-47.
[2] Carmody RN,Gerber GK,Luevano JM,et al.Diet dominates host genotype in shaping the murine gut microbiota[J].Cell Host Microbe,2015,17(1):72-84.
[3] Benson AK,Kelly SA,Legge R,et al.Individuality in gut microbiota composition is a complex polygenic trait shaped by multiple environmental and host genetic factors[J].Proc Natl Acad Sci U S A,2010,107(44):18933-18938.
[4] Goodrich JK,Waters JL,Poole AC,et al.Human genetics shape the gut microbiome[J].Cell,2014,159(4):789-799.
[5] Goodrich J,Davenport E,Beaumont M,et al.Genetic determinants of the gut microbiome in UK twins[J].Cell Host Microbe,2016,19(5):731-743.
[6] Ley RE,Hamady M,Lozupone C,et al.Evolution of mammals and their gut microbes[J].Science,2008,320(5883):1647-1651.
[7] Sender R,Fuchs S,Milo R.Are we really vastly outnumbered?Revisiting the ratio of bacterial to host cells in humans[J].Cell,2016,164(3):337-340.
[8] Zhao L.Genomics:The tale of our other genome[J].Nature,2010,465(7300):879-880.
[9] O′Hara AM,Shanahan F.The gut flora as a forgotten organ[J].EMBO Rep,2006,7(7):688-693.
[10] Sommer F,B?ckhed F.The gut microbiota--masters of host development and physiology[J].Nat Rev Microbiol,2013,11(4):227-238.
[11] Kurilshikov A,Wijmenga C,Fu J,et al.Host genetics and gut microbiome:Challenges and perspectives[J].Trends in Immunol,2017,38(9):633-647.
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[13] Schulz MD,Atay ?,Heringer J,et al.High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity[J].Nature,2014,514(7523):508-512.
[14] Chang CJ,Lin CS,Lu CC,et al.Ganoderma lucidum reduces obesity in mice by modulating the composition of the gut microbiota[J].Nat Commun,2015,6:7489.
[15] Zoetendal EG,Akkermans AD,Akkermans-van Vliet WM,et al.The host genotype affects the bacterial community in the human gastronintestinal tract,microbial ecology in health and disease,informa healthcare[J].Microb Ecol Health Dis,2001,13:129-134.
[16] Yatsunenko T,Rey FE,Manary MJ,et al.Human gut microbiome viewed across age and geography[J].Nature,2012,486(7402):222-227.
[17] Wang J,Kalyan S,Steck N,et al.Analysis of intestinal microbiota in hybrid house mice reveals evolutionary divergence in a vertebrate hologenome[J].Nat Commun,2015,6:6440.
[18] Leamy LJ,Kelly SA,Nietfeldt J,et al.Host genetics and diet,but not immunoglobulin A expression,converge to shape compositional features of the gut microbiome in an advanced intercross population of mice[J].Genome Biol,2014,15(12):552.
[19] McKnite AM,Perez-Munoz ME,Lu L,et al.Murine gut microbiota is defined by host genetics and modulates variation of metabolic traits[J].PLoS One,2012,7(6):e39191.
[20] Org E,Parks BW,Joo JW,et al.Genetic and environmental control of host-gut microbiota interactions[J].Genome Res,2015,25(10):1558-1569.
[21] Blekhman R,Goodrich JK,Huang K,et al.Host genetic variation impacts microbiome composition across human body sites[J].Genome Biol,2015,16:191.
[22] Wang J,Thingholm LB,Skieceviien J,et al.Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota[J].Nat Genet,2016,48(11):1396-1406.
[23] Jin D,Wu S,Zhang YG,et al.Lack of vitamin D receptor causes dysbiosis and changes the functions of the murine intestinal microbiome[J].Clin Ther,2015,37(5):996-1009.
[24] Bonder MJ,Kurilshikov A,Tigchelaar EF,et al.The effect of host genetics on the gut microbiome[J].Nat Genet,2016,48(11):1407-1412.
[25] Goodrich JK,Davenport ER,Clark AG,et al.The relationship between the human genome and microbiome comes into view[J].Annu Rev Genet,2017,51:413-433.
[26] Davenport ER,Cusanovich DA,Michelini K,et al.Genome-wide association studies of the human gut microbiota[J].PLoS One,2015,10(11):e0140301.
[27] Turpin W,Espin-Garcia O,Xu W,et al.Association of host genome with intestinal microbial composition in a large healthy cohort[J].Nat Genet,2016,48(11):1413-1417.
[28] Igartua C,Davenport ER,Gilad Y,et al.Host genetic variation in mucosal immunity pathways influences the upper airway microbiome[J].Microbiome,2017,5(1):16.
[29] Ley RE,B?ckhed F,Turnbaugh P,et al.Obesity alters gut microbial ecology[J].Proc Natl Acad Sci U S A,2005,102(31):11070-11075.
[30] Geurts L,Everard A,Van Hul M,et al.Adipose tissue NAPE-PLD controls fat mass development by altering the browning process and gut microbiota[J].Nat Commun,2015,6:6495.
[31] Bidu C,Escoula Q,Bellenger S,et al.The transplantation of omega3 PUFA-altered gut microbiota of fat-1 mice to wild-type littermates prevents obesity and associated metabolic disorders[J].Diabetes,2018,67(8):1512-1523.
[32] Ruan JW,Statt S,Huang CT,et al.Dual-specificity phosphatase 6 deficiency regulates gut microbiome and transcriptome response against diet-induced obesity in mice[J].Nat Microbiol,2016,2:16220.
[33] Vijay-Kumar M,Aitken JD,Carvalho FA,et al.Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5[J].Science,2010,328(5975):228-231.
[34] Rodriguez-Nunez I,Caluag T,Kirby K,et al.Nod2 and Nod2-regulated microbiota protect BALB/c mice from diet-induced obesity and metabolic dysfunction[J].Sci Rep,2017,7(1):548.
[35] AI Nabhani Z,Dietrich G,Hugot JP,et al.Nod2:The intestinal gate keeper[J].PLoS Pathog,2017,13(3):e1006177.
[36] Lamas B,Richard ML,Leducq V,et al.CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands[J].Nat Med,2016,22(6):598-605.
[37] Rausch P,Künzel S,Suwandi A,et al.Multigenerational influences of the Fut2 gene on the dynamics of the gut microbiota in mice[J].Front Microbiol,2017,8:991.
[38] Larsson E,Tremaroli V,Lee YS,et al.Analysis of gut microbial regulation of host gene expression along the length of the gut and regulation of gut microbial ecology through MyD88[J].Gut,2012,61(8):1124-1131.
[39] Sovran B,Loonen LM,Lu P,et al.IL-22-STAT3 pathway plays a key role in the maintenance of ileal homeostasis in mice lacking secreted mucus barrier[J].Inflamm Bowel Dis,2015,21(3):531-542.
[40] Van der Sluis M,De Koning BA,De Bruijn AC,et al.Muc2-deficient mice spontaneously develop colitis,indicating that MUC2 is critical for colonic protection[J].Gastroenterology,2006,131(1):117-129.
[41] Wang L,Fouts DE,St?rkel P,et al.Intestinal REG3 lectins protect against alcoholic steatohepatitis by reducing mucosa-associated microbiota and preventing bacterial translocation[J].Cell Host Microbe,2016,19(2):227-239.
[42] Everard A,Belzer C,Geurts L,et al.Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity[J].Proc Natl Acad Sci U S A,2013,110(22):9066-9071.
[43] Williams M,Stedtfeld RD,Tiedje JM,et al.MicroRNAs-based inter-domain communication between the host and members of the gut microbiome[J].Front Microbiol,2017,8:1896.
[44] Wang J,Chen L,Zhao N,et al.Of genes and microbes:Solving the intricacies in host genomes[J].Protein Cell,2018,9(5):446-461.
[2] Carmody RN,Gerber GK,Luevano JM,et al.Diet dominates host genotype in shaping the murine gut microbiota[J].Cell Host Microbe,2015,17(1):72-84.
[3] Benson AK,Kelly SA,Legge R,et al.Individuality in gut microbiota composition is a complex polygenic trait shaped by multiple environmental and host genetic factors[J].Proc Natl Acad Sci U S A,2010,107(44):18933-18938.
[4] Goodrich JK,Waters JL,Poole AC,et al.Human genetics shape the gut microbiome[J].Cell,2014,159(4):789-799.
[5] Goodrich J,Davenport E,Beaumont M,et al.Genetic determinants of the gut microbiome in UK twins[J].Cell Host Microbe,2016,19(5):731-743.
[6] Ley RE,Hamady M,Lozupone C,et al.Evolution of mammals and their gut microbes[J].Science,2008,320(5883):1647-1651.
[7] Sender R,Fuchs S,Milo R.Are we really vastly outnumbered?Revisiting the ratio of bacterial to host cells in humans[J].Cell,2016,164(3):337-340.
[8] Zhao L.Genomics:The tale of our other genome[J].Nature,2010,465(7300):879-880.
[9] O′Hara AM,Shanahan F.The gut flora as a forgotten organ[J].EMBO Rep,2006,7(7):688-693.
[10] Sommer F,B?ckhed F.The gut microbiota--masters of host development and physiology[J].Nat Rev Microbiol,2013,11(4):227-238.
[11] Kurilshikov A,Wijmenga C,Fu J,et al.Host genetics and gut microbiome:Challenges and perspectives[J].Trends in Immunol,2017,38(9):633-647.
[12] Marchesi JR,Adams DH,Fava F,et al.The gut microbiota and host health:A new clinical frontier[J].Gut,2016,65(2):330-339.
[13] Schulz MD,Atay ?,Heringer J,et al.High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity[J].Nature,2014,514(7523):508-512.
[14] Chang CJ,Lin CS,Lu CC,et al.Ganoderma lucidum reduces obesity in mice by modulating the composition of the gut microbiota[J].Nat Commun,2015,6:7489.
[15] Zoetendal EG,Akkermans AD,Akkermans-van Vliet WM,et al.The host genotype affects the bacterial community in the human gastronintestinal tract,microbial ecology in health and disease,informa healthcare[J].Microb Ecol Health Dis,2001,13:129-134.
[16] Yatsunenko T,Rey FE,Manary MJ,et al.Human gut microbiome viewed across age and geography[J].Nature,2012,486(7402):222-227.
[17] Wang J,Kalyan S,Steck N,et al.Analysis of intestinal microbiota in hybrid house mice reveals evolutionary divergence in a vertebrate hologenome[J].Nat Commun,2015,6:6440.
[18] Leamy LJ,Kelly SA,Nietfeldt J,et al.Host genetics and diet,but not immunoglobulin A expression,converge to shape compositional features of the gut microbiome in an advanced intercross population of mice[J].Genome Biol,2014,15(12):552.
[19] McKnite AM,Perez-Munoz ME,Lu L,et al.Murine gut microbiota is defined by host genetics and modulates variation of metabolic traits[J].PLoS One,2012,7(6):e39191.
[20] Org E,Parks BW,Joo JW,et al.Genetic and environmental control of host-gut microbiota interactions[J].Genome Res,2015,25(10):1558-1569.
[21] Blekhman R,Goodrich JK,Huang K,et al.Host genetic variation impacts microbiome composition across human body sites[J].Genome Biol,2015,16:191.
[22] Wang J,Thingholm LB,Skieceviien J,et al.Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota[J].Nat Genet,2016,48(11):1396-1406.
[23] Jin D,Wu S,Zhang YG,et al.Lack of vitamin D receptor causes dysbiosis and changes the functions of the murine intestinal microbiome[J].Clin Ther,2015,37(5):996-1009.
[24] Bonder MJ,Kurilshikov A,Tigchelaar EF,et al.The effect of host genetics on the gut microbiome[J].Nat Genet,2016,48(11):1407-1412.
[25] Goodrich JK,Davenport ER,Clark AG,et al.The relationship between the human genome and microbiome comes into view[J].Annu Rev Genet,2017,51:413-433.
[26] Davenport ER,Cusanovich DA,Michelini K,et al.Genome-wide association studies of the human gut microbiota[J].PLoS One,2015,10(11):e0140301.
[27] Turpin W,Espin-Garcia O,Xu W,et al.Association of host genome with intestinal microbial composition in a large healthy cohort[J].Nat Genet,2016,48(11):1413-1417.
[28] Igartua C,Davenport ER,Gilad Y,et al.Host genetic variation in mucosal immunity pathways influences the upper airway microbiome[J].Microbiome,2017,5(1):16.
[29] Ley RE,B?ckhed F,Turnbaugh P,et al.Obesity alters gut microbial ecology[J].Proc Natl Acad Sci U S A,2005,102(31):11070-11075.
[30] Geurts L,Everard A,Van Hul M,et al.Adipose tissue NAPE-PLD controls fat mass development by altering the browning process and gut microbiota[J].Nat Commun,2015,6:6495.
[31] Bidu C,Escoula Q,Bellenger S,et al.The transplantation of omega3 PUFA-altered gut microbiota of fat-1 mice to wild-type littermates prevents obesity and associated metabolic disorders[J].Diabetes,2018,67(8):1512-1523.
[32] Ruan JW,Statt S,Huang CT,et al.Dual-specificity phosphatase 6 deficiency regulates gut microbiome and transcriptome response against diet-induced obesity in mice[J].Nat Microbiol,2016,2:16220.
[33] Vijay-Kumar M,Aitken JD,Carvalho FA,et al.Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5[J].Science,2010,328(5975):228-231.
[34] Rodriguez-Nunez I,Caluag T,Kirby K,et al.Nod2 and Nod2-regulated microbiota protect BALB/c mice from diet-induced obesity and metabolic dysfunction[J].Sci Rep,2017,7(1):548.
[35] AI Nabhani Z,Dietrich G,Hugot JP,et al.Nod2:The intestinal gate keeper[J].PLoS Pathog,2017,13(3):e1006177.
[36] Lamas B,Richard ML,Leducq V,et al.CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands[J].Nat Med,2016,22(6):598-605.
[37] Rausch P,Künzel S,Suwandi A,et al.Multigenerational influences of the Fut2 gene on the dynamics of the gut microbiota in mice[J].Front Microbiol,2017,8:991.
[38] Larsson E,Tremaroli V,Lee YS,et al.Analysis of gut microbial regulation of host gene expression along the length of the gut and regulation of gut microbial ecology through MyD88[J].Gut,2012,61(8):1124-1131.
[39] Sovran B,Loonen LM,Lu P,et al.IL-22-STAT3 pathway plays a key role in the maintenance of ileal homeostasis in mice lacking secreted mucus barrier[J].Inflamm Bowel Dis,2015,21(3):531-542.
[40] Van der Sluis M,De Koning BA,De Bruijn AC,et al.Muc2-deficient mice spontaneously develop colitis,indicating that MUC2 is critical for colonic protection[J].Gastroenterology,2006,131(1):117-129.
[41] Wang L,Fouts DE,St?rkel P,et al.Intestinal REG3 lectins protect against alcoholic steatohepatitis by reducing mucosa-associated microbiota and preventing bacterial translocation[J].Cell Host Microbe,2016,19(2):227-239.
[42] Everard A,Belzer C,Geurts L,et al.Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity[J].Proc Natl Acad Sci U S A,2013,110(22):9066-9071.
[43] Williams M,Stedtfeld RD,Tiedje JM,et al.MicroRNAs-based inter-domain communication between the host and members of the gut microbiome[J].Front Microbiol,2017,8:1896.
[44] Wang J,Chen L,Zhao N,et al.Of genes and microbes:Solving the intricacies in host genomes[J].Protein Cell,2018,9(5):446-461.