肠道菌群和胆道菌群多样性与胆石病的相关性研究
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摘要
背景：细菌与胆固醇结石发生的相关性一直存在争议；关于胆道菌群的组分、结构和起源,受限于研究的条件以及测序的高成本,检测出来的细菌的种类和数目极为有限,缺乏全面完整的概念；胆囊结石患者是否存在肠道菌群失调仍然未知；目前关于细菌与结石形成的相关性的研究,多局限在体外模拟实验及培养的条件下对生理生化上的研究,缺乏细菌功能基因的研究。
目的：本研究拟从肠道菌群和胆道菌群出发,借助新兴的二代测序技术,全面系统的揭示并比较胆结石患者的胆道(胆结石和胆汁)菌群、肠道菌群的结构和组分的变化规律；探讨胆结石患者是否存在肠道菌群失调,鉴定与结石病发生相关的胆道核心菌群,拟从细菌的功能角色层面(或功能基因层面)探讨与胆结石发生的相关性,为进一步研究胆固醇结石形成的细菌学机制提供重要的素材和前期工作基础,为临床上防治胆结石提供一定的参考。
方法：本研究中胆道菌群采用胆囊结石患者的胆结石及胆汁的菌群为代表,胆结石患者的肠道菌群采用其粪便菌群代表,肠道的正常菌群采用正常人的粪便菌群作为代表。我们收集了29例胆囊结石患者的结石、胆汁和粪便,并收集了38例正常人的粪便共120个样本。主要方法有：
1.采用酶CHOD-PAP法,测定胆囊结石的胆固醇含量并鉴定胆囊结石的类型；
2.于非培养条件下,采用物理破碎和化学裂解相结合的方法,提取样品的细菌DNA,采用酶链聚合反应(PCR)进行扩增。PCR扩增产物经过电泳分析、胶回收、纯化；
3.采用高通量的454焦磷酸测序技术对16S rRNA基因V1-V2可变区的PCR扩增子进行大规模的测序,获取序列数据,鉴定细菌OTU(相当于种的水平)；
4.结合生物信息学、网络分析和功能注释相似的物种的基因组的手段,与已公布的细菌基因库比对,并结合统计学的方法检查和分析从所有胆结石患者所获得的胆汁、胆石及粪便,以及正常人粪便的细菌组分、群落结构。
结果：
1.本研究中胆固醇结石所占比例为92.55%,代表了胆囊结石的主要类型。
2.所有类型的样本(包含纯胆固醇结石)均检测出细菌DNA,检出率为100%。
3.本研究从所有样总计获得299,217条高质量、可分类的细菌16SrRNA基因序列。其中,从胆结石患者的胆汁中获得81661条细菌基因系列、结石中获得76135条细菌基因系列、粪便中获得64360条细菌基因系列；从正常个体的粪便共获得77601条细菌基因系列。
4.共鉴定了4637个细菌OUT。其中,在患者的胆汁中鉴定了3696个细菌OTU、结石中鉴定了3456个细菌OTU、粪便中鉴定了1772个细菌OUT；正常个体粪便中鉴定了1497个细菌OUT；所鉴定的细菌OTU能够被划分为20种细菌门类群,胆结石中有20种,胆汁中有19种,在胆结石患者的粪便中有13种,在正常个体的粪便中有14种。最占优势的细菌类群为厚壁菌门。
5.胆道菌群比较(胆汁和结石)：胆汁与结石菌群无明显差异(P>0.05),
6.肠道菌群比较(正常人和胆囊结石患者)：(1)细菌门的水平：胆结石患者的肠道细菌中Proteobacteria(变形菌门)较正常人显著增高(P<0.001)；(2)细菌属的水平：三个肠道细菌属Faecalibacterium(柔嫩梭菌属),Lachnospira(毛螺菌属),Roseburia(氏菌属)较正常人显著减少(P<0.001)。
7.胆囊结石患者肠道菌群和胆道菌群比较：(1)细菌门的水平：最占优势的细菌门Firmicutes以及最为稀少的细菌门Fusobacteria,二者均无明显差异(P>0.05)；除了Bacteroidetes在胆道中的组成显著低于肠道外(P<0.001),其余的六个细菌门类Proteobacteria、Tenericutes、Actinobacteria、Cyanobacteria、TM7、Thermi在胆道中的组成均显著高于肠道(P<0.001)；(2)细菌属的水平：胆道的两个细菌属Bacteroides和Clostridium(L.)较肠道显著减少(P<0.001),而另外16个细菌属较肠道显著增加(P<0.001)；胆道菌群的多样性显著高于肠道菌群(P<0.001)。
8.胆汁和结石分享超过85%的细菌OTU；仅60%的肠道细菌OTU在病人和正常人之间分享；约有70%的病人肠道细菌OTU以及正常人40%的肠道细菌OTU在胆道中被发现。
9.鉴定并分析了胆囊结石患者胆道核心菌群(包括106个细菌OTUs),仅33.96%(36/106)能匹配到已知的细菌种类,而其中只有15种细菌具有已知的已公布的基因组。这15种胆道细菌至少包含了四个基因(MDR外排泵蛋白,BSH, bG和phL,被认为是促结石形成的四种细菌因子)中的一个。
结论：
1.本研究首次采用了高通量的二代测序的方法(454焦磷酸测序),通过大规模的分析胆道和肠道细菌的16SrRNA基因,首次从系统层面全面的揭示了胆道细菌群落多样性和结构组分的基本特征。
2.本研究所发现的结石和胆汁的细菌的种类和数量均远远超出以往的发现,极大的丰富和拓宽了胆道的细菌学谱,为后续研究提供了一定的基础。
3.本研究首次揭示了胆囊结石患者存在明显的肠道菌群失调,提示了胆结石患者存在潜在的胃肠道健康风险,另一方面也提示了肠道菌群失调也可能导致胆囊结石形成；胆道菌群至少部分源于肠道菌群的移位,且比肠道菌群更加复杂多变。
4.本研究揭示了胆道的核心菌群,并鉴定了核心菌群中与结石形成相关的四种细菌因子(MDR外排泵蛋白、bG和phL),胆道核心菌群与胆结石的形成密切相关。
5.胆结石形成的细菌学机制可能为细菌-细菌的综合多因素共同作用。
6.本研究对胆结石形成相关的细菌学机制作了较为全面的探讨,充分探讨了细菌及菌群失调与胆结石形成的关系,对理解胆囊结石形成的细菌学机制做了有益的补充,对临床上对胆结石,尤其是胆固醇结石的预防和治疗提供了一定的参考。
Objective:The aims of this study are:1) to reveal the variation of bacterial community and composition in both gut and biliary tract (gallstones and bile) in patients with gallstones;2) clarify whether there exist gut bacterial dysbiosis in patients with gallstones;3) to identify the biliary tract bacteria associated with the formation of cholesterol gallstones, as well as to elucidate the relationship between the biliary tract bacteria and cholesterol gallstones formation out of four potential bacterial factors contributing to cholesterol gallstones. The study will provide foundationalfindings for further studying bacteriological mechanism of the cholesterol stone formation, which will be helpful for both preventions and therapeutics for cholelithiasis.
Methods:We collected samples of stone, bile and feces from29patients with gallbladder stones, and also fecal samplesfrom38normalindividuals, and finally obtained a total of120samples. The content of cholesterol in gallstones was analyzed for the classification of gallstone disease. The bacterial16S rRNA gene was amplified by PCR methods using bacterial DNAs extracted from all120samples and was used to perform454-barcoded pyrosequencing. Bacterial16S rDNA sequences were filtered and used to identify bacterial OTUs (equal to bacterial species) according to97%sequence identity. Final OTUs were used to clarify thecommunity structure and composition of bacteria in both gut and biliary tractwith cholelithiasis. Based on these results, a series of analyses were further performed, including heat-map based abundance, network analysis, and functional annotation depending on similar species' genomes.
Results:
1. Cholesterol stone proportion is92.55%of all sampled stones, which represents the main type of gallstone disease.
2. Bacterial DNAs were detected from all samples.
3.We obtained a dataset consisting of299,217high-quality and classifiable16S rRNA gene sequences. From the dataset, we identified a total of4637operational taxonomic units (OTUs). These identified bacterial OTUs can be classified into20bacterial phyla.
4. Comparison of gutbacteria community (normal individuals and patients with gallbladder stone) was conducted. Within the gut, the relative abundance of the bacterial phylum Proteobacteria among patientswere significantly (P<0.001) higher than that in normal. The relative abundances of three bacterial genera (Faecalibacterium, Lachnospira,andRoseburia) in normal subjects were significantly (P<0.001) lower in those in patients.
5. Gut bacteria were compared with biliary bacteria in the gallstone patients.
(1) This study found that Bacteroidetes phylum in biliary tract was significantly lower than that in the gut (P<0.001).The abundances of six bacterial phyla in the biliary tract, includingProteobacteria, TM7, Tenericutes, Actinobacteria, Thermi,and Cyanobacteriawere significantly higher than those in the gut (P<0.001).
(2) This study also found that, in the biliarytract, there was a significant (P<0.001) decreasing of two bacterial genera and increasing of16otherbacterial genera (P<0.001). Bacteriadiversity in the biliary tract was significantly higher than that in the gut (P<0.001).
6. This study showed that over85%of bacterial OTUs were shared by both bile and gallstones, but only60%ofgut bacterial OTUs were shared by patients and healthysubjects. Around70%of gut bacterial OTUs from patients and40%OTUs from healthy subjects were found in the biliary tract, respectively.
7. Based on the dataset described above, this study identified biliary tract core microbiome out of gallstone patients, which includes106bacterial OTUs belonging to six bacterial phyla. Only33.96%(36/106) of the members of the biliary tract core microbiomecould be matched to known bacterial species. About15of the36-matched bacterial species havepublicly available genomes. Based on reference genomesof those15bacterial species, this studyfurther analyzed the presence or absence of four genes potentially associated withthe formation of gallstones, includingMDR, BSH, bG,andphL.The results found each of15speciesat least contained one of the four genes.
Conclusions:
1. This is the first study to use a454-basedpyrosequencing of bacterial16S rDNAs to clarify the structure and composition of bacteria in both gut and biliary tract with cholelithiasis.
2. To the best of our knowledge, this is the first study todiscover a potential association of the gut microbiotadysbiosis that is present among gallstone patients.Our results discovered significant changes of gut microbial components between gallstone patients andhealthy subjects. This raises a possibility that biliary tractmicrobiota could be partially originated from the gut. Furtherevidence is obviously needed to explore this possibility,but nonetheless it is an intriguing prospect.
3. This study supports mounting evidence that cultureindependent454-based16S rDNA sequencing is necessaryas a diagnostic tool in gallstone-associated bacterial infection, because it provides more detailed information thancurrently employed and sequence analysis of clonedmicrobial16S rDNA.
4. This study reveals the core of biliary tract bacteria and identified four types of bacteria associated with stone formation factors (MDR efflux pump protein, BSH, bG and PhL). The biliary core bacteria are closely related to the formation of gallstones.
5. These findings indicatedthat bacterial community assembly might be more important than single species in the formation of cholesterol gallstones.
6. This study makes a comprehensive discussion of the relationship between the bacteria community assembly and cholesterol stone formation. These findings have numerous medical implications for both prevention and therapeutics for cholelithiasis or other relative GIT healthy risks, warranting further follow-up studies that are needed to verify these findings and move forward. The most poignant implication of this study is that prevention and management of bacterial infections in the biliary tract may be a target for lowering the risks of cholesterol gallstones. The study also provides some clues for further exploringthe mechanism of bacteriology leading to the cholesterol stone formation.
目的：本研究拟从肠道菌群和胆道菌群出发,借助新兴的二代测序技术,全面系统的揭示并比较胆结石患者的胆道(胆结石和胆汁)菌群、肠道菌群的结构和组分的变化规律；探讨胆结石患者是否存在肠道菌群失调,鉴定与结石病发生相关的胆道核心菌群,拟从细菌的功能角色层面(或功能基因层面)探讨与胆结石发生的相关性,为进一步研究胆固醇结石形成的细菌学机制提供重要的素材和前期工作基础,为临床上防治胆结石提供一定的参考。
方法：本研究中胆道菌群采用胆囊结石患者的胆结石及胆汁的菌群为代表,胆结石患者的肠道菌群采用其粪便菌群代表,肠道的正常菌群采用正常人的粪便菌群作为代表。我们收集了29例胆囊结石患者的结石、胆汁和粪便,并收集了38例正常人的粪便共120个样本。主要方法有：
1.采用酶CHOD-PAP法,测定胆囊结石的胆固醇含量并鉴定胆囊结石的类型；
2.于非培养条件下,采用物理破碎和化学裂解相结合的方法,提取样品的细菌DNA,采用酶链聚合反应(PCR)进行扩增。PCR扩增产物经过电泳分析、胶回收、纯化；
3.采用高通量的454焦磷酸测序技术对16S rRNA基因V1-V2可变区的PCR扩增子进行大规模的测序,获取序列数据,鉴定细菌OTU(相当于种的水平)；
4.结合生物信息学、网络分析和功能注释相似的物种的基因组的手段,与已公布的细菌基因库比对,并结合统计学的方法检查和分析从所有胆结石患者所获得的胆汁、胆石及粪便,以及正常人粪便的细菌组分、群落结构。
结果：
1.本研究中胆固醇结石所占比例为92.55%,代表了胆囊结石的主要类型。
2.所有类型的样本(包含纯胆固醇结石)均检测出细菌DNA,检出率为100%。
3.本研究从所有样总计获得299,217条高质量、可分类的细菌16SrRNA基因序列。其中,从胆结石患者的胆汁中获得81661条细菌基因系列、结石中获得76135条细菌基因系列、粪便中获得64360条细菌基因系列；从正常个体的粪便共获得77601条细菌基因系列。
4.共鉴定了4637个细菌OUT。其中,在患者的胆汁中鉴定了3696个细菌OTU、结石中鉴定了3456个细菌OTU、粪便中鉴定了1772个细菌OUT；正常个体粪便中鉴定了1497个细菌OUT；所鉴定的细菌OTU能够被划分为20种细菌门类群,胆结石中有20种,胆汁中有19种,在胆结石患者的粪便中有13种,在正常个体的粪便中有14种。最占优势的细菌类群为厚壁菌门。
5.胆道菌群比较(胆汁和结石)：胆汁与结石菌群无明显差异(P>0.05),
6.肠道菌群比较(正常人和胆囊结石患者)：(1)细菌门的水平：胆结石患者的肠道细菌中Proteobacteria(变形菌门)较正常人显著增高(P<0.001)；(2)细菌属的水平：三个肠道细菌属Faecalibacterium(柔嫩梭菌属),Lachnospira(毛螺菌属),Roseburia(氏菌属)较正常人显著减少(P<0.001)。
7.胆囊结石患者肠道菌群和胆道菌群比较：(1)细菌门的水平：最占优势的细菌门Firmicutes以及最为稀少的细菌门Fusobacteria,二者均无明显差异(P>0.05)；除了Bacteroidetes在胆道中的组成显著低于肠道外(P<0.001),其余的六个细菌门类Proteobacteria、Tenericutes、Actinobacteria、Cyanobacteria、TM7、Thermi在胆道中的组成均显著高于肠道(P<0.001)；(2)细菌属的水平：胆道的两个细菌属Bacteroides和Clostridium(L.)较肠道显著减少(P<0.001),而另外16个细菌属较肠道显著增加(P<0.001)；胆道菌群的多样性显著高于肠道菌群(P<0.001)。
8.胆汁和结石分享超过85%的细菌OTU；仅60%的肠道细菌OTU在病人和正常人之间分享；约有70%的病人肠道细菌OTU以及正常人40%的肠道细菌OTU在胆道中被发现。
9.鉴定并分析了胆囊结石患者胆道核心菌群(包括106个细菌OTUs),仅33.96%(36/106)能匹配到已知的细菌种类,而其中只有15种细菌具有已知的已公布的基因组。这15种胆道细菌至少包含了四个基因(MDR外排泵蛋白,BSH, bG和phL,被认为是促结石形成的四种细菌因子)中的一个。
结论：
1.本研究首次采用了高通量的二代测序的方法(454焦磷酸测序),通过大规模的分析胆道和肠道细菌的16SrRNA基因,首次从系统层面全面的揭示了胆道细菌群落多样性和结构组分的基本特征。
2.本研究所发现的结石和胆汁的细菌的种类和数量均远远超出以往的发现,极大的丰富和拓宽了胆道的细菌学谱,为后续研究提供了一定的基础。
3.本研究首次揭示了胆囊结石患者存在明显的肠道菌群失调,提示了胆结石患者存在潜在的胃肠道健康风险,另一方面也提示了肠道菌群失调也可能导致胆囊结石形成；胆道菌群至少部分源于肠道菌群的移位,且比肠道菌群更加复杂多变。
4.本研究揭示了胆道的核心菌群,并鉴定了核心菌群中与结石形成相关的四种细菌因子(MDR外排泵蛋白、bG和phL),胆道核心菌群与胆结石的形成密切相关。
5.胆结石形成的细菌学机制可能为细菌-细菌的综合多因素共同作用。
6.本研究对胆结石形成相关的细菌学机制作了较为全面的探讨,充分探讨了细菌及菌群失调与胆结石形成的关系,对理解胆囊结石形成的细菌学机制做了有益的补充,对临床上对胆结石,尤其是胆固醇结石的预防和治疗提供了一定的参考。
Objective:The aims of this study are:1) to reveal the variation of bacterial community and composition in both gut and biliary tract (gallstones and bile) in patients with gallstones;2) clarify whether there exist gut bacterial dysbiosis in patients with gallstones;3) to identify the biliary tract bacteria associated with the formation of cholesterol gallstones, as well as to elucidate the relationship between the biliary tract bacteria and cholesterol gallstones formation out of four potential bacterial factors contributing to cholesterol gallstones. The study will provide foundationalfindings for further studying bacteriological mechanism of the cholesterol stone formation, which will be helpful for both preventions and therapeutics for cholelithiasis.
Methods:We collected samples of stone, bile and feces from29patients with gallbladder stones, and also fecal samplesfrom38normalindividuals, and finally obtained a total of120samples. The content of cholesterol in gallstones was analyzed for the classification of gallstone disease. The bacterial16S rRNA gene was amplified by PCR methods using bacterial DNAs extracted from all120samples and was used to perform454-barcoded pyrosequencing. Bacterial16S rDNA sequences were filtered and used to identify bacterial OTUs (equal to bacterial species) according to97%sequence identity. Final OTUs were used to clarify thecommunity structure and composition of bacteria in both gut and biliary tractwith cholelithiasis. Based on these results, a series of analyses were further performed, including heat-map based abundance, network analysis, and functional annotation depending on similar species' genomes.
Results:
1. Cholesterol stone proportion is92.55%of all sampled stones, which represents the main type of gallstone disease.
2. Bacterial DNAs were detected from all samples.
3.We obtained a dataset consisting of299,217high-quality and classifiable16S rRNA gene sequences. From the dataset, we identified a total of4637operational taxonomic units (OTUs). These identified bacterial OTUs can be classified into20bacterial phyla.
4. Comparison of gutbacteria community (normal individuals and patients with gallbladder stone) was conducted. Within the gut, the relative abundance of the bacterial phylum Proteobacteria among patientswere significantly (P<0.001) higher than that in normal. The relative abundances of three bacterial genera (Faecalibacterium, Lachnospira,andRoseburia) in normal subjects were significantly (P<0.001) lower in those in patients.
5. Gut bacteria were compared with biliary bacteria in the gallstone patients.
(1) This study found that Bacteroidetes phylum in biliary tract was significantly lower than that in the gut (P<0.001).The abundances of six bacterial phyla in the biliary tract, includingProteobacteria, TM7, Tenericutes, Actinobacteria, Thermi,and Cyanobacteriawere significantly higher than those in the gut (P<0.001).
(2) This study also found that, in the biliarytract, there was a significant (P<0.001) decreasing of two bacterial genera and increasing of16otherbacterial genera (P<0.001). Bacteriadiversity in the biliary tract was significantly higher than that in the gut (P<0.001).
6. This study showed that over85%of bacterial OTUs were shared by both bile and gallstones, but only60%ofgut bacterial OTUs were shared by patients and healthysubjects. Around70%of gut bacterial OTUs from patients and40%OTUs from healthy subjects were found in the biliary tract, respectively.
7. Based on the dataset described above, this study identified biliary tract core microbiome out of gallstone patients, which includes106bacterial OTUs belonging to six bacterial phyla. Only33.96%(36/106) of the members of the biliary tract core microbiomecould be matched to known bacterial species. About15of the36-matched bacterial species havepublicly available genomes. Based on reference genomesof those15bacterial species, this studyfurther analyzed the presence or absence of four genes potentially associated withthe formation of gallstones, includingMDR, BSH, bG,andphL.The results found each of15speciesat least contained one of the four genes.
Conclusions:
1. This is the first study to use a454-basedpyrosequencing of bacterial16S rDNAs to clarify the structure and composition of bacteria in both gut and biliary tract with cholelithiasis.
2. To the best of our knowledge, this is the first study todiscover a potential association of the gut microbiotadysbiosis that is present among gallstone patients.Our results discovered significant changes of gut microbial components between gallstone patients andhealthy subjects. This raises a possibility that biliary tractmicrobiota could be partially originated from the gut. Furtherevidence is obviously needed to explore this possibility,but nonetheless it is an intriguing prospect.
3. This study supports mounting evidence that cultureindependent454-based16S rDNA sequencing is necessaryas a diagnostic tool in gallstone-associated bacterial infection, because it provides more detailed information thancurrently employed and sequence analysis of clonedmicrobial16S rDNA.
4. This study reveals the core of biliary tract bacteria and identified four types of bacteria associated with stone formation factors (MDR efflux pump protein, BSH, bG and PhL). The biliary core bacteria are closely related to the formation of gallstones.
5. These findings indicatedthat bacterial community assembly might be more important than single species in the formation of cholesterol gallstones.
6. This study makes a comprehensive discussion of the relationship between the bacteria community assembly and cholesterol stone formation. These findings have numerous medical implications for both prevention and therapeutics for cholelithiasis or other relative GIT healthy risks, warranting further follow-up studies that are needed to verify these findings and move forward. The most poignant implication of this study is that prevention and management of bacterial infections in the biliary tract may be a target for lowering the risks of cholesterol gallstones. The study also provides some clues for further exploringthe mechanism of bacteriology leading to the cholesterol stone formation.
引文
1. Cariati A, Cetta F. Re:Kawai et al.[mdash]bacteria are not important in the formation of pure cholesterol stones. Am J Gastroenterol 2002;97(11):2921-2922.
2. Kaufman HS, Magnuson TH, Lillemoe KD, Frasca P, Pitt HA. The role of bacteria in gallbladder and common duct stone formation. Ann Surg 1989;209(5):584-91; discussion 591-2.
3. Alexander S, Wolfgang L, Hartmut P, Friedrich P. Molecular genetic evidence of bacterial colonization of cholesterol gallstones. Gastroenterology 1995;108(3):860-864.
4. Lee DK, Tarr PI, Haigh WG, Lee SP. Bacterial DNA in mixed cholesterol gallstones. Am J Gastroenterol 1999;94(12):3502-3506.
5. Kawai M, Iwahashi M, Uchiyama K, Ochiai M, Tanimura H, Yamaue H. Gram-positive cocci are associated with the formation of completely pure cholesterol stones. Am J Gastroenterol 2002;97(1):83-88.
6. Hazrah P, Oahn KT, Tewari M, Pandey AK, Kumar K, Mohapatra TM, Shukla HS. The frequency of live bacteria in gallstones. HPB (Oxford) 2004;6(1):28-32.
7. Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML, Jones WJ, Roe BA, Affourtit JP, Egholm M, Henrissat B, Heath AC, Knight R, Gordon JI. A core gut microbiome in obese and lean twins. Nature 2009;457(7228):480-484.
8. Manichanh C, Rigottier-Gois L, Bonnaud E, Gloux K, Pelletier E, Frangeul L, Nalin R, Jarrin C, Chardon P, Marteau P, Roca J, Dore J. Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach. Gut 2006;55(2):205-211.
9. Le Roy T, Llopis M, Lepage P, Bruneau A, Rabot S, Bevilacqua C, Martin P, Philippe C, Walker F, Bado A, Perlemuter G, Cassard-Doulcier A-M, Gerard P. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut 2012.
10. Jeffery IB, O'Toole PW, Ohman L, Claesson MJ, Deane J, Quigley EMM, Simren M. An irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota. Gut 2011.
11. Portincasa P, Moschetta A, Palasciano G. Cholesterol gallstone disease. The Lancet 2006;368(9531):230-239.
12. Toller IM, Neelsen KJ, Steger M, Hartung ML, Hottiger MO, Stucki M, Kalali B, Gerhard M, Sartori AA, Lopes M, Muller A. Carcinogenic bacterial pathogen Helicobacter pylori triggers DNA double-strand breaks and a DNA damage response in its host cells. Proceedings of the National Academy of Sciences 2011;108(36):14944-14949.
13. Salama NR, Hartung ML, Muller A. Life in the human stomach:persistence strategies of the bacterial pathogen Helicobacter pylori. Nat Rev Micro 2013;11(6):385-399.
14. Polk DB, Peek RM. Helicobacter pylori:gastric cancer and beyond. Nat Rev Cancer 2010;10(6):403-414.
15. Costello EK, Lauber CL, Hamady M, Fierer N, Gordon JI, Knight R. Bacterial Community Variation in Human Body Habitats Across Space and Time. Science 2009;326:1694-1697
16. Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, et al. Knight R. QIIME allows analysis of high-throughput community sequencing data. Nat Methods 2010;7(5):335-6.
17. Reeder J, Knight R. Rapidly denoising pyrosequencing amplicon reads by exploiting rank-abundance distributions. Nat Meth 2010;7(9):668-669. 18. Li W, Godzik A. Cd-hit:a fast program for clustering and comparing large sets of protein or nucleotide sequences. Bioinformatics 2006;22(13):1658-1659.
19. Price MN, Dehal PS, Arkin AP. FastTree:Computing Large Minimum Evolution Trees with Profiles instead of a Distance Matrix. Molecular Biology and Evolution 2009;26(7):1641-1650.
20. Wang Q, Garrity GM, Tiedje JM, Cole JR. Naive Bayesian Classifier for Rapid Assignment of rRNA Sequences into the New Bacterial Taxonomy. Appl. Environ. Microbiol. 2007;73(16):5261-5267.
21. Siedel J, Hagele EO, Ziegenhorn J, Wahlefeld AW. Reagent for the enzymatic determination of serum total cholesterol with improved lipolytic efficiency. Clinical Chemistry 1983;29(6):1075-80.
22. Marschall HU, Einarsson C. Gallstone disease. Journal of Internal Medicine 2007;261(6):529-542.
23. Swidsinski A, Schlien P, Pernthaler A, Gottschalk U, Barlehner E, Decker G, Swidsinski S, Strassburg J, Loening-Baucke V, Hoffmnann U, Seehofer D, Hale LP, Lochs H. Bacterial biofilm within diseased pancreatic and biliary tracts. Gut 2005;54(3):388-395.
24. Good IJ. Thepopulationfrequencies ofspeciesand theestimaton of populationparameters. Biometrika 1953;40(3-4):237-264.
25. Kemp PF, Aller JY. Bacterial diversity in aquatic and other environments:what 16S rDNA libraries can tell us. FEMS Microbiology Ecology 2004;47(2):161-177.
26. Shade A, Handelsman J. Beyond the Venn diagram:the hunt for a core microbiome. Environmental Microbiology 2012;14(1):4-12.
27. Arumugam M,et al. Enterotypes of the human gut microbiome. Nature 2011;473(7346):174-180.
28.韩天权,蒋兆彦,张圣道.胆固醇结石形成机制的基因研究现状与展望.外科理论与实践2009：14：125-127.
29. Yang Q. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 2005;436:356-362.
30. Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L, Stonebraker AC, Hu C, Wong FS, Szot GL, Bluestone JA, Gordon JI, Chervonsky AV. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature 2008;455(7216):1109-1113.
31. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, DuGar B, Feldstein AE, Britt EB, Fu X, Chung Y-M, Wu Y, Schauer P, Smith JD, Allayee H, Tang WHW, DiDonato JA, Lusis AJ, Hazen SL. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011;472(7341):57-63.
32. Jones BV, Begley M, Hill C, Gahan CGM, Marchesi JR. Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome. Proceedings of the National Academy of Sciences 2008;105(36):13580-13585.
33. Sekirov I, Russell SL, Antunes LCM, Finlay BB. Gut Microbiota in Health and Disease. Physiol. Rev.2010;90(3):859-904.
34. Kelly D, Conway S, Aminov R. Commensal gut bacteria:mechanisms of immune modulation. Trends in Immunology 2005;26(6):326-333.
35. Lathrop SK, Bloom SM, Rao SM, Nutsch K, Lio C-W, Santacruz N, Peterson DA, Stappenbeck TS, Hsieh C-S. Peripheral education of the immune system by colonic commensal microbiota. Nature 2011;advance online publication.
36. Hooper LV. Do symbiotic bacteria subvert host immunity? Nat Rev Micro 2009;7(5):367-374.
37. Van Erpecum KJ, Van Berge-Henegouwen GP. Gallstones:an intestinal disease? Gut 1999;44(3):435-8.
38. Sayin Sama I, Wahlstrom A, Felin J, Jantti S, Marschall H-U, Bamberg K, Angelin B, Hyotylainen T, Oresic M, Backhed F. Gut Microbiota Regulates Bile Acid Metabolism by Reducing the Levels of Tauro-beta-muricholic Acid, a Naturally Occurring FXR Antagonist. Cell Metabolism 2013;17(2):225-235.
39. Capoor MR, Nair D, Rajni, Khanna G, Krishna SV, Chintamani MS, Aggarwal P. Microflora of bile aspirates in patients with acute cholecystitis With or without cholelithiasis:a tropical experience. Brazilian Journal of Infectious Diseases 2008;12:222-225.
40. Jiang Z-Y, Jiang C-Y, Wang L, Wang J-C, Zhang S-D, Einarsson C, Eriksson M, Han T-Q, Parini P, Eggertsen G. Increased NPC1L1 and ACAT2 expression in the jejunal mucosa from Chinese gallstone patients. Biochemical and Biophysical Research Communications 2009;379(1):49-54.
41. Buhman KK, Accad M, Novak S, Choi RS, Wong JS, Hamilton RL, Turley S, Farese RV, Jr. Resistance to diet-induced hypercholesterolemia and gallstone formation in ACAT2-deficient mice. Nat Med 2000;6(12):1341-7.
42. Wang HH, Wang DQH. Reduced susceptibility to cholesterol gallstone formation in mice that do not produce apolipoprotein B48 in the intestine. Hepatology 2005;42(4):894-904.
43. Csendes A, Becerra M, Burdiles P, Demian I, Bancalari K, Csendes P. Bacteriological studies of bile from the gallbladder in patients with carcinoma of the gallbladder, cholelithiasis, common bile duct stones and no gallstones disease. Eur J Surg 1994;160(6-7):363-7.
44. Edlund YA, Mollstedt BO, Ouchterlony O. Bacteriological investigation of the biliary system and liver in biliary tract disease correlated to clinical data and microstructure of the gallbladder and liver. Acta Chir Scand 1959;116(5-6):461-76.
45. Csendes A, Fernandez M, Uribe P. Bacteriology of the gallbladder bile in normal subjects. Am J Surg 1975;129(6):629-31.
46.朱雷明,赵洪,蔡端,张延龄,吕元,陈为欢,王文风.胆固醇结石中细菌对人胆汁胆固醇晶体形成的作用.中华肝胆外科杂志2005；11(3)：180-183.
47.朱雷明,李军,王学志,蔡端,张延龄.细菌对模拟胆汁热力学平衡的影响.外科理论和实践2005；10(4)：349-353.
48. Binette JP, Binette MB. The proteins and the formation of gallstones. Clinica Chimica Acta 2000;296(1-2):59-69.
49. Choi J, Klinkspoor JH, Yoshida T, Lee SP. Lipopolysaccharide from escherichia coli stimulates mucin secretion by cultured dog gallbladder epithelial cells. Hepatology 1999;29(5):1352-1357.
50.朱雷明,张辉,李军,王学志,蔡端,张延龄.细菌促胆固醇晶体成核的机制研究.肝胆胰外科杂志2009；21(2)：122-125.
51.朱雷明,蔡端,吕元.胆固醇结石病人与非胆石症人群胆道细菌感染状况与免疫球蛋白相关性的对照研究.中华肝胆外科杂志2003；9(7)：419422.
52. Maki T. Pathogenesis of calcium bilirubinate gallstone:role of E. coli, beta-glucuronidase and coagulation by inorganic ions, polyelectrolytes and agitation. Ann Surg 1966;164(1):90-100.
53. Monstein H-J, Jonsson Y, Zdolsek J, Svanvik J. Identification of Helicobacter pylori DNA in Human Cholesterol Gallstones. Scandinavian Journal of Gastroenterology 2002;37(1):112-119.
54. Swidsinski A, Khilkin M, Pahlig H, Swidsinski S, Priem F. Time dependent changes in the concentration and type of bacterial sequences found in cholesterol gallstones. Hepatology 1998;27(3):662-665.
55. Cahalane MJ, Neubrand MW, Carey MC. Physical-chemical pathogenesis of pigment gallstones. Semin Liver Dis 1988;8(4):317-28.
56. Stewart L, Grifiss JM, Jarvis GA, Way LW. Biliary bacterial factors determine the path of gallstone formation. The American Journal of Surgery 2006;192(5):598-603.
57. Metzker ML. Sequencing technologies - the next generation. Nat Rev Genet 2010;11(1):31-46.
58. Kenneth Nelson F, Snyder M, Gardner AF, Hendrickson CL, Shendure JA, Porreca GJ, Church GM, Ausubel FM, Ju J, Kieleczawa J, Slatko BE. Introduction and Historical Overview of DNA Sequencing. In. Current Protocols in Molecular Biology:John Wiley & Sons, Inc.; 2011.
59. Maloy KJ, Powrie F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 2011;474(7351):298-306.
60. Peterson DA, Frank DN, Pace NR, Gordon JI. Metagenomic Approaches for Defining the Pathogenesis of Inflammatory Bowel Diseases. Cell Host & Microbe 2008;3(6):417-427.
61. Bloom Seth M, Bijanki Vinieth N, Nava Gerardo M, Sun L, Malvin Nicole P, Donermeyer David L, Dunne WM, Allen Paul M, Stappenbeck Thaddeus S. Commensal Bacteroides Species Induce Colitis in Host-Genotype-Specific Fashion in a Mouse Model of Inflammatory Bowel Disease. Cell Host & Microbe 2011;9(5):390-403.
62. Dicksved J, Halfvarson J, Rosenquist M, Jarnerot G, Tysk C, Apajalahti J, Engstrand L, Jansson JK. Molecular analysis of the gut microbiota of identical twins with Crohn's disease. ISME J2008;2(7):716-727.
63. Joossens M, Huys G, Cnockaert M, De Preter V, Verbeke K, Rutgeerts P, Vandamme P, Vermeire S. Dysbiosis of the faecal microbiota in patients with Crohn's disease and their unaffected relatives. Gut 2011;60(5):631-637.
64. Garrett WS, Gallini CA, Yatsunenko T, Michaud M, DuBois A, Delaney ML, Punit S, Karlsson M, Bry L, Glickman JN, Gordon JI, Onderdonk AB, Glimcher LH. Enterobacteriaceae Act in Concert with the Gut Microbiota to Induce Spontaneous and Maternally Transmitted Colitis. Cell Host & Microbe 2010;8(3):292-300.
65. Wang Y, Hoenig JD, Malin KJ, Qamar S, Petrof EO, Sun J, Antonopoulos DA, Chang EB, Claud EC.16S rRNA gene-based analysis of fecal microbiota from preterm infants with and without necrotizing enterocolitis. ISME J 2009;3(8):944-954.
66. Wu S, Rhee K-J, Albesiano E, Rabizadeh S, Wu X, Yen H-R, Huso DL, Brancati FL, Wick E, McAllister F, Housseau F, Pardoll DM, Sears CL. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med 2009;15(9):1016-1022.
67. Mazmanian SK, Round JL, Kasper DL. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 2008;453(7195):620-625.
68.叶国良,陈会松,盛红,程德希.胆石症并胆道感染患者胆汁细菌分布及与年龄性别关系探讨.浙江临床医学2005；6：626-627.
69. Karch H, Denamur E, Dobrindt U, Finlay BB, Hengge R, Johannes L, Ron EZ, Tonjum T, Sansonetti PJ, Vicente M. The enemy within us:lessons from the 2011 European Escherichia coli O104:H4 outbreak. EMBO Molecular Medicine 2012;4(9):841-848.
70. Sokol H, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proceedings of the National Academy of Sciences 2008;105(43):16731-16736.
71. Ramirez-Farias C, Slezak K, Fuller Z, Duncan A, Holtrop G, Louis P. Effect of inulin on the human gut microbiota:stimulation of Bifidobacterium adolescentis and Faecalibacterium prausnitzii. Br J Nutr 2009;101(4):541-50.
72. Scott KP, Martin JC, Chassard C, Clerget M, Potrykus J, Campbell G, Mayer C-D, Young P, Rucklidge G, Ramsay AG, Flint HJ. Substrate-driven gene expression in Roseburia inulinivorans: Importance of inducible enzymes in the utilization of inulin and starch. Proceedings of the National Academy of Sciences 2011;108(Supplement 1):4672-4679.
73. Rode LM, Genthner BRS, Bryant MP. Syntrophic Association by Cocultures of the Methanol-and CO2-H2-Utilizing Species Eubacterium limosum and Pectin-Fermenting Lachnospira multiparus During Growth in a Pectin Medium. Applied and Environmental Microbiology 1981;42(1):20-22.
74. Crawford RW, Rosales-Reyes R, Ramirez-Aguilar MdIL, Chapa-Azuela O, Alpuche-Aranda C, Gunn JS. Gallstones play a significant role in Salmonella spp. gallbladder colonization and carriage. Proceedings of the National Academy of Sciences 2010;107(9):4353-4358.
75. Piddock LJV. Multidrug-resistance efflux pumps? not just for resistance. Nat Rev Micro 2006;4(8):629-636.
76. Lin J, Sahin O, Michel LO, Zhang Q. Critical Role of Multidrug Efflux Pump CmeABC in Bile Resistance and In Vivo Colonization of Campylobacter jejuni. Infection and Immunity 2003;71(8):4250-4259.
77. Kullak-ublick GA, Stieger B, Meier PJ. Enterohepatic bile salt transporters in normal physiology and liver disease. Gastroenterology 2004;126(1):322-342.
78. Glavinas H, Krajcsi P, Cserepes J, Sarkadi B. The role of ABC transporters in drug resistance, metabolism and toxicity. Curr Drug Deliv 2004;1(1):27-42.
79. Begley M, Gahan CGM, Hill C. The interaction between bacteria and bile. FEMS Microbiology Reviews 2005;29(4):625-651.
80. De Smet I, Van Hoorde L, Vande Woestyne M, Christiaens H, Verstraete W. Significance of bile salt hydrolytic activities of lactobacilli. Journal of Applied Microbiology 1995;79(3):292-301.
81. Wang DQ, Carey MC. Complete mapping of crystallization pathways during cholesterol precipitation from model bile:influence of physical-chemical variables of pathophysiologic relevance and identification of a stable liquid crystalline state in cold, dilute and hydrophilic bile salt-containing systems. Journal of Lipid Research 1996;37(3):606-30.
82. Somjen GJ, Gilat T. A non-micellar mode of cholesterol transport in human bile. FEBS Letters 1983;156(2):265-268.
83. Moschetta A, vanBerge-Henegouwen GP, Portincasa P, Palasciano G, van Erpecum KJ. Cholesterol crystallization in model biles:effects of bile salt and phospholipid species composition. Journal of Lipid Research 2001;42(8):1273-1281.
84. Mazer NA, Carey MC. Quasi-elastic light-scattering studies of aqueous biliary lipid systems. Cholesterol solubilization and precipitation in model bile solutions. Biochemistry 1983;22(2):426-442.
85. Maurer KJ. Identification of cholelithogenic enterohepatic Helicobacter species and their role in murine cholesterol gallstone formation. Gastroenterology 2005;128:1023-1033.
86. Nakano T, Yanagisawa J, Nakayama F. Phospholipase activity in human bile. Hepatology 1988;8(6):1560-1564.
87. Garcia-Vallve S, Romeu A, Palau J. Horizontal Gene Transfer in Bacterial and Archaeal Complete Genomes. Genome Research 2000;10(11):1719-1725.
1. Maki T. Pathogenesis of calcium bilirubinate gallstone:role of E. coli, beta-glucuronidase and coagulation by inorganic ions, polyelectrolytes and agitation. Ann Surg 1966;164(1):90-100.
2. Alexander S, Wolfgang L, Hartmut P, Friedrich P. Molecular genetic evidence of bacterial colonization of cholesterol gallstones. Gastroenterology 1995;108(3):860-864.
3. Maurer KJ. Identification of cholelithogenic enterohepatic Helicobacter species and their role in murine cholesterol gallstone formation. Gastroenterology 2005;128:1023-1033.
4. Julka K, Ko CW. Infectious Diseases and the Gallbladder. Infectious Disease Clinics of North America 2010;24(4):885-898.
5. Portincasa P, Moschetta A, Palasciano G. Cholesterol gallstone disease. The Lancet 2006;368(9531):230-239.
6. Portincasa P, Di Ciaula A, Wang HH, Palasciano G, van Erpecum KJ, Moschetta A, Wang DQH. Coordinate regulation of gallbladder motor function in the gut-liver axis. Hepatology 2008;47(6):2112-2126.
7. Xiao L, Wang K, Teng Y, Zhang J. Component plane presentation integrated self-organizing map for microarray data analysis. FEBS Letters 2003;538(1-3):117-124.
8. Jiang Z-Y, Parini P, Eggertsen G, Davis MA, Hu H, Suo G-J, Zhang S-D, Rudel LL, Han T-Q, Einarsson C. Increased expression of LXRa, ABCG5, ABCG8, and SR-BI in the liver from normolipidemic, nonobese Chinese gallstone patients. Journal of Lipid Research 2008;49(2):464-472.
9. Wang Y, Jiang Z-Y, Fei J, Xin L, Cai Q, Jiang Z-H, Zhu Z-G, Han T-Q, Zhang S-D. ATP binding cassette G8 T400K polymorphism may affect the risk of gallstone disease among Chinese males. Clinica Chimica Acta 2007;384(1-2):80-85.
10.王勇,韩天权,费健,蒋兆彦,蔡劬,姜志宏,张圣道.胆囊黏膜ABCG5和ABCG8基因在胆固醇结石病中的作用.中华实验外科杂志2007；24：51-52.
11. Pramfalk C, Jiang Z-Y, Cai Q, Hu H, Zhang S-D, Han T-Q, Eriksson M, Parini P. HNF1α and SREBP2 are important regulators of NPC1L1 in human liver. Journal of Lipid Research 2010;51(6):1354-1362.
12. Parini P, Jiang ZY, Einarsson C, Eggertsen G, Zhang SD, Rudel LL, Han TQ, Eriksson M. ACAT2 and human hepatic cholesterol metabolism:identification of important gender-related differences in normolipidemic, non-obese Chinese patients. Atherosclerosis 2009;207(1):266-71.
13. Jiang Z-Y, Jiang C-Y, Wang L, Wang J-C, Zhang S-D, Einarsson C, Eriksson M, Han T-Q, Parini P, Eggertsen G. Increased NPC1L1 and ACAT2 expression in the jejunal mucosa from Chinese gallstone patients. Biochemical and Biophysical Research Communications 2009;379(1):49-54.
14. Wang HH, Wang DQH. Reduced susceptibility to cholesterol gallstone formation in mice that do not produce apolipoprotein B48 in the intestine. Hepatology 2005;42(4):894-904.
15. Buhman KK, Accad M, Novak S, Choi RS, Wong JS, Hamilton RL, Turley S, Farese RV, Jr. Resistance to diet-induced hypercholesterolemia and gallstone formation in ACAT2-deficient mice. Nat Med 2000;6(12):1341-7.
16. Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger M. Identification of Scavenger Receptor SR-BI as a High Density Lipoprotein Receptor. Science 1996;271(5248):518-520.
17. Labonte ED, Howles PN, Granholm NA, Rojas JC, Davies JP, Ioannou YA, Hui DY. Class B type I scavenger receptor is responsible for the high affinity cholesterol binding activity of intestinal brush border membrane vesicles. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids 2007;1771(9):1132-1139.
18. Davies JP, Levy B, Ioannou YA. Evidence for a Niemann-Pick C (NPC) Gene Family: Identification and Characterization of NPC1L1. Genomics 2000;65(2):137-145.
19. Altmann SW, Davis HR, Zhu L-j, Yao X, Hoos LM, Tetzloff G, Iyer SPN, Maguire M, Golovko A, Zeng M, Wang L, Murgolo N, Graziano MP. Niemann-Pick Cl Like 1 Protein Is Critical for Intestinal Cholesterol Absorption. Science 2004;303(5661):1201-1204.
20. Friedrich S. Ezetimibe in search of receptor(s)-Still a never-ending challenge in cholesterol absorption and transport. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids2007;1771(9):1113-1116.
21. Yu L, Li-Hawkins J, Hammer RE, Berge KE, Horton JD, Cohen JC, Hobbs HH. Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol. The Journal of Clinical Investigation 2002;110(5):671-680.
22. Lee J, Shirk A, Oram JF, Lee SP, Kuver R. Polarized cholesterol and phospholipid efflux in cultured gall-bladder epithelial cells:evidence for an ABCAl-mediated pathway. Biochem. J. 2002;364(2):475-484.
23.姜种弋,韩天权,蒋兆彦,蔡劬,吴卫泽,张圣道.肝脏X受体对小鼠胆汁脂质成分与胆固醇代谢基因表达的影响.中华实验外科杂志2007；24：1457-1459.
24.王蕾,蔡劬,蒋兆彦,施敏敏,崔巍,韩天权,袁耀宗,吴卫泽,张圣道.肝脏X受体a对肝细胞HepG2胆固醇代谢基因表达的调控.内科理论与实践2010；5：165-169.
25. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37(12):1595-607.
26. Kuipers F, Groen AK. Chipping away at gallstones. Nat Med 2008;14(7):715-716.
27. Tsai C-J, Leitzmann MF, Willett WC, Giovannucci EL. Prospective study of abdominal adiposity and gallstone disease in US men. The American Journal of Clinical Nutrition 2004;80(1):38-44.
28.蒋兆彦,韩天权,陈胜,乙芳,姜志宏,商俊,蔡杏兴,张圣道,顾建平,黄桂余.胆囊结石病高危人群预测结果的随访研究和预测准确性评判.消化外科2002；1：400-403.
29.陈胜,张圣道,蒋兆彦,韩天权,朱全梅,沈树权,何小伟,黄桂余,顾建平,乙芳.胆固醇结石病高危人群预测的进一步研究.中华医学杂志2001；81：1010-1011.
30. Biddinger SB, Haas JT, Yu BB, Bezy O, Jing E, Zhang W, Unterman TG, Carey MC, Kahn CR. Hepatic insulin resistance directly promotes formation of cholesterol gallstones. Nat Med 2008;14(7):778-782.
31. Khanuja B, Cheah YC, Hunt M, Nishina PM, Wang DQ, Chen HW, Billheimer JT, Carey MC, Paigen B. Lithl, a major gene affecting cholesterol gallstone formation among inbred strains of mice. Proceedings of the National Academy of Sciences 1995;92(17):7729-7733.
32.秦俭,韩天权,蒋兆彦.Lith基因和胆固醇结石病.国外医学·外科学分册2003；30(4)：229-231.
33. Lammert F, Carey MC, Paigen B. Chromosomal organization of candidate genes involved in cholesterol gallstone formation:A murine gallstone map. Gastroenterology 2001;120(1):221-238.
34. Puppala S, Dodd GD, Fowler S, Arya R, Schneider J, Farook VS, Granato R, Dyer TD, Almasy L, Jenkinson CP, Diehl AK, Stern MP, Blangero J, Duggirala R. A Genomewide Search Finds Major Susceptibility Loci for Gallbladder Disease on Chromosome 1 in Mexican Americans. The American Journal of Human Genetics 2006;78(3):377-392.
35.秦俭,韩天权,袁文涛.胆囊结石病致病基因的定位研究.中华外科杂志2006；44(7)：485-487.
36.陶太珍,沈靖,姚才良.胆石症家族聚集性的病因和流行病学研究.中国公共卫生1999；15(2)：169-170.
37. Lammert F, Matern S. The genetic background of cholesterol gallstone formation:an inventory of human lithogenic genes. Curr Drug Targets Immune Endocr Metabol Disord 2005;5(2):163-70.
38. Lammert F, Sauerbruch T. Mechanisms of Disease:the genetic epidemiology of gallbladder stones. Nat Clin Pract Gastroenterol Hepatol 2005;2(9):423-433.
39.张宇,韩天权,张圣道.人类胆囊胆固醇结石易感基因的研究进展.中国现代普通外科进展2004；7(5)：257-259.
40.蒋兆彦,韩天权,所广军.胆固醇结石病人肝脏胆小管侧膜ATP基因表达差异的研究.外科理论与实践2005；10(1)：61-65.
41. Schafinayer C, Tepel J, Franke A, Buch S, Lieb S, Seeger M, Lammert F, Kremer B, Folsch UR, Fandrich F, Schreiber S, Hampe J. Investigation of the Lith1 candidate genes ABCB11 and LXRA in human gallstone disease. Hepatology 2006;44(3):650-657.
42. Maselli MA, Piepoli AL, Pezzolla F, Guerra V, Caruso ML, Mennuni L, Lorusso D, Makovec F. Effect of Three Nonpeptide Cholecystokinin Antagonists on Human Isolated Gallbladder. Digestive Diseases and Sciences 2001;46(12):2773-2778.
43. Zhu J, Han TQ, Chen S, Jiang Y, Zhang SD. Gallbladder motor function, plasma cholecystokinin and cholecystokinin receptor of gallbladder in cholesterol stone patients. World J Gastroenterol 2005;11(11):1685-9.
44. Choi M, Moschetta A, BookOTU AL, Peng L, Umetani M, Holmstrom SR, Suino-Powell K, Xu HE, Richardson JA, Gerard RD, Mangelsdorf DJ, Kliewer SA. Identification of a hormonal basis for gallbladder filling. Nat Med 2006;12(11):1253-1255.
45.韩天权,蒋兆彦,张圣道.胆固醇结石形成机制的基因研究现状与展望.外科理论与实践2009；14：125-127.
46. Carey MC, Paigen B. Epidemiology of the American Indians 'burden and its likely genetic origins. Hepatology 2002;36(4):781-791.
47.方东生,李李,熊奇如.膳食因素与胆囊结石症关联的研究.疾病控制杂志2000；4(4)：337-339.
48. Watson JD, Crick FH. The structure of DNA. Cold Spring Harb Symp Quant Biol 1953;18:123-31.
49. Fleischmann R, Adams M, White O, Clayton R, Kirkness E, Kerlavage A, Bult C, Tomb J, Dougherty B, Merrick J, al. e. Whole-genome random sequencing and assembly of Haemophilus influenzae Rd. Science 1995;269(5223):496-512.
50. Lander ES, et al. Initial sequencing and analysis of the human genome. Nature 2001;409(6822):860-921.
51. Venter JC, Adams MD, Myers EW, Li PW,et al.. The Sequence of the Human Genome. Science 2001;291(5507):1304-1351.
52. Margulies M, et al. Genome sequencing in microfabricated high-density picolitre reactors. Nature 2005;437(7057):376-380.
53. Metzker ML. Sequencing technologies - the next generation. Nat Rev Genet 2010;11(1):31-46.
54. Glenn TC. Field guide to next-generation DNA sequencers. Molecular Ecology Resources 2011;11(5):759-769.
55. Kenneth Nelson F, Snyder M, Gardner AF, Hendrickson CL, Shendure JA, Porreca GJ, Church GM, Ausubel FM, Ju J, Kieleczawa J, Slatko BE. Introduction and Historical Overview of DNA Sequencing. In. Current Protocols in Molecular Biology:John Wiley & Sons, Inc.; 2011.
56. Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature 2009;458(7239):719-724.
57. Puente XS, et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 2011;475(7354):101-105.
58. Qin J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010;464(7285):59-65.
59. Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML, Jones WJ, Roe BA, Affourtit JP, Egholm M, Henrissat B, Heath AC, Knight R, Gordon JI. A core gut microbiome in obese and lean twins. Nature 2009;457(7228):480-484.
60. Diamant M, Blaak EE, de Vos WM. Do nutrient-gut-microbiota interactions play a role in human obesity, insulin resistance and type 2 diabetes? Obesity Reviews 2011;12(4):272-281.
61., Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L, Stonebraker AC, Hu C, Wong FS, Szot GL, Bluestone JA, Gordon JI, Chervonsky AV. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature 2008;455(7216):1109-1113.
62. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, DuGar B, Feldstein AE, Britt EB, Fu X, Chung Y-M, Wu Y, Schauer P, Smith JD, Allayee H, Tang WHW, DiDonato JA, Lusis AJ, Hazen SL. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011;472(7341):57-63.
63. Jones BV, Begley M, Hill C, Gahan CGM, Marchesi JR. Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome. Proceedings of the National Academy of Sciences 2008; 105(36):13580-13585.
64. Ridlon JM, Kang D-J, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. Journal of Lipid Research 2006;47(2):241-259.
65. Wang DQ-H, Cohen DE, Carey MC. Biliary lipids and cholesterol gallstone disease. Journal of Lipid Research 2009;50(Supplement):S406-S411.
66.方驰华,杨继震.胆囊结石需氧菌和厌氧菌分子生物学研究及意义.第四军医大学学报1998；19(6)：681-682.
67. Lee DK, Tarr PI, Haigh WG, Lee SP. Bacterial DNA in mixed cholesterol gallstones. Am J Gastroenterol 1999;94(12):3502-3506.
68. Kawai M, Iwahashi M, Uchiyama K, Ochiai M, Tanimura H, Yamaue H. Gram-positive cocci are associated with the formation of completely pure cholesterol stones. Am J Gastroenterol 2002;97(1):83-88.
69. Cariati A, Cetta F. Re:Kawai et al.[mdash]bacteria are not important in the formation of pure cholesterol stones. Am J Gastroenterol 2002;97(11):2921-2922.
70.杨玉龙,刘小北,谭文翔,李雪驼.胆固醇结石中的细菌及其在成石机制中的作用.肝胆胰外科杂志2005；17(1)：14-16.
71.吴汉平,康生朝,张方信.ERCP在胆总管结石患者胆汁细菌学研究中的价值.世界华人消化杂志2007；15(17)：1965-1967.
72.李奉达,邱法波,宁刘.胆石病患者胆汁细菌学检查分析.世界华人消化杂志2008；16(35)：4004-4007.
73.田志杰,韩天权,姜志宏.胆囊结石病胆道系统螺杆菌DNA的研究.中国实用外科杂志2004；24(2)：84-87.
74.蔡端,朱雷明,吕元,刘维薇,张延龄.胆固醇结石、胆囊黏膜和胆汁细菌DNA的检测.中华消化杂志2004；24(11)：647-650.
75. Hazrah P, Oahn KT, Tewari M, Pandey AK, Kumar K, Mohapatra TM, Shukla HS. The frequency of live bacteria in gallstones. HPB (Oxford) 2004;6(1):28-32.
76.陈晓文,智发朝,武金宝,万田谟,周丹.聚合酶链式反应和常规培养检测胆总管结石中细菌及其意义的研究.临床肝胆病杂志2005；21(3)：173-175.
77.陈晓文,智发朝,曹东林,周思朗,陈勇伟,谢栋.胆总管结石的成因观察.第四军医大学学报2006；27(3)：261-263.
78.朱雷明,蔡端,吕元.胆固醇结石病人与非胆石症人群胆道细菌感染状况与免疫球蛋白相关性的对照研究.中华肝胆外科杂志2003；9(7)：419-422.
79.王学军,李玉民,李世雄.细菌在胆固醇结石形成中的作用研究.中国现代医学杂志2003；13(3)：4-7.
80.朱雷明,蔡端,吕元,陈为欢,王文风,张延龄.胆固醇结石病人与非胆石症人群胆道细菌感染状况及与免疫球蛋白相关性的对照研究.中华外科杂志2004；42(24)：1501-1504.
81.朱雷明,赵洪,蔡端,张延龄,吕元,陈为欢,王文风.胆固醇结石中细菌对人胆汁胆固醇晶体形成的作用.中华肝胆外科杂志2005；11(3)：180-183.
82.朱雷明,李军,王学志,蔡端,张延龄.细菌对模拟胆汁热力学平衡的影响.外科理论和实践2005；10(4)：349-353.
83. Choi J, Klinkspoor JH, Yoshida T, Lee SP. Lipopolysaccharide from escherichia coli stimulates mucin secretion by cultured dog gallbladder epithelial cells. Hepatology 1999;29(5):1352-1357.
84. Binette JP, Binette MB. The proteins and the formation of gallstones. Clinica Chimica Acta 2000;296(1-2):59-69.
85.朱雷明,张辉,李军,王学志,蔡端,张延龄.细菌促胆固醇晶体成核的机制研究.肝胆胰外科杂志2009；21(2)：122-125.
86. Bloom Seth M, Bijanki Vinieth N, Nava Gerardo M, Sun L, Malvin Nicole P, Donermeyer David L, Dunne WM, Allen Paul M, Stappenbeck Thaddeus S. Commensal Bacteroides Species Induce Colitis in Host-Genotype-Specific Fashion in a Mouse Model of Inflammatory Bowel Disease. Cell Host & Microbe 2011;9(5):390-403.
87. Dicksved J, Halfvarson J, Rosenquist M, Jarnerot G, Tysk C, Apajalahti J, Engstrand L, Jansson JK. Molecular analysis of the gut microbiota of identical twins with Crohn's disease. ISME J 2008;2(7):716-727.
88. Garrett WS, Gallini CA, Yatsunenko T, Michaud M, DuBois A, Delaney ML, Punit S, Karlsson M, Bry L, Glickman JN, Gordon JI, Onderdonk AB, Glimcher LH. Enterobacteriaceae Act in Concert with the Gut Microbiota to Induce Spontaneous and Maternally Transmitted Colitis. Cell Host & Microbe 2010;8(3):292-300.
89. Joossens M, Huys G, Cnockaert M, De Preter V, Verbeke K, Rutgeerts P, Vandamme P, Vermeire S. Dysbiosis of the faecal microbiota in patients with Crohn's disease and their unaffected relatives. Gut 2011;60(5):631-637.
90. Peterson DA, Frank DN, Pace NR, Gordon JI. Metagenomic Approaches for Defining the Pathogenesis of Inflammatory Bowel Diseases. Cell Host & Microbe 2008;3(6):417-427.
91. Wang Y, Hoenig JD, Malin KJ, Qamar S, Petrof EO, Sun J, Antonopoulos DA, Chang EB, Claud EC.16S rRNA gene-based analysis of fecal microbiota from preterm infants with and withOTU necrotizing enterocolitis. ISME J 2009;3(8):944-954.
92. Wu S, Rhee K-J, Albesiano E, Rabizadeh S, Wu X, Yen H-R, Huso DL, Brancati FL, Wick E, McAllister F, Housseau F, Pardoll DM, Sears CL. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med 2009;15(9):1016-1022.
93. Kostic AD, Gevers D, Pedamallu CS, Michaud M, Duke F, Earl AM, Ojesina AI, Jung J, Bass AJ, Tabernero J, Baselga J, Liu C, Shivdasani RA, Ogino S, Birren BW, Huttenhower C, Garrett WS, Meyerson M. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Research 2011.
94. Castellarin M, Warren RL, Freeman JD, Dreolini L, Krzywinski M, Strauss J, Barnes R, Watson P, Allen-Vercoe E, Moore RA, Holt RA. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Research 2011.
2. Kaufman HS, Magnuson TH, Lillemoe KD, Frasca P, Pitt HA. The role of bacteria in gallbladder and common duct stone formation. Ann Surg 1989;209(5):584-91; discussion 591-2.
3. Alexander S, Wolfgang L, Hartmut P, Friedrich P. Molecular genetic evidence of bacterial colonization of cholesterol gallstones. Gastroenterology 1995;108(3):860-864.
4. Lee DK, Tarr PI, Haigh WG, Lee SP. Bacterial DNA in mixed cholesterol gallstones. Am J Gastroenterol 1999;94(12):3502-3506.
5. Kawai M, Iwahashi M, Uchiyama K, Ochiai M, Tanimura H, Yamaue H. Gram-positive cocci are associated with the formation of completely pure cholesterol stones. Am J Gastroenterol 2002;97(1):83-88.
6. Hazrah P, Oahn KT, Tewari M, Pandey AK, Kumar K, Mohapatra TM, Shukla HS. The frequency of live bacteria in gallstones. HPB (Oxford) 2004;6(1):28-32.
7. Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML, Jones WJ, Roe BA, Affourtit JP, Egholm M, Henrissat B, Heath AC, Knight R, Gordon JI. A core gut microbiome in obese and lean twins. Nature 2009;457(7228):480-484.
8. Manichanh C, Rigottier-Gois L, Bonnaud E, Gloux K, Pelletier E, Frangeul L, Nalin R, Jarrin C, Chardon P, Marteau P, Roca J, Dore J. Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach. Gut 2006;55(2):205-211.
9. Le Roy T, Llopis M, Lepage P, Bruneau A, Rabot S, Bevilacqua C, Martin P, Philippe C, Walker F, Bado A, Perlemuter G, Cassard-Doulcier A-M, Gerard P. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut 2012.
10. Jeffery IB, O'Toole PW, Ohman L, Claesson MJ, Deane J, Quigley EMM, Simren M. An irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota. Gut 2011.
11. Portincasa P, Moschetta A, Palasciano G. Cholesterol gallstone disease. The Lancet 2006;368(9531):230-239.
12. Toller IM, Neelsen KJ, Steger M, Hartung ML, Hottiger MO, Stucki M, Kalali B, Gerhard M, Sartori AA, Lopes M, Muller A. Carcinogenic bacterial pathogen Helicobacter pylori triggers DNA double-strand breaks and a DNA damage response in its host cells. Proceedings of the National Academy of Sciences 2011;108(36):14944-14949.
13. Salama NR, Hartung ML, Muller A. Life in the human stomach:persistence strategies of the bacterial pathogen Helicobacter pylori. Nat Rev Micro 2013;11(6):385-399.
14. Polk DB, Peek RM. Helicobacter pylori:gastric cancer and beyond. Nat Rev Cancer 2010;10(6):403-414.
15. Costello EK, Lauber CL, Hamady M, Fierer N, Gordon JI, Knight R. Bacterial Community Variation in Human Body Habitats Across Space and Time. Science 2009;326:1694-1697
16. Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, et al. Knight R. QIIME allows analysis of high-throughput community sequencing data. Nat Methods 2010;7(5):335-6.
17. Reeder J, Knight R. Rapidly denoising pyrosequencing amplicon reads by exploiting rank-abundance distributions. Nat Meth 2010;7(9):668-669. 18. Li W, Godzik A. Cd-hit:a fast program for clustering and comparing large sets of protein or nucleotide sequences. Bioinformatics 2006;22(13):1658-1659.
19. Price MN, Dehal PS, Arkin AP. FastTree:Computing Large Minimum Evolution Trees with Profiles instead of a Distance Matrix. Molecular Biology and Evolution 2009;26(7):1641-1650.
20. Wang Q, Garrity GM, Tiedje JM, Cole JR. Naive Bayesian Classifier for Rapid Assignment of rRNA Sequences into the New Bacterial Taxonomy. Appl. Environ. Microbiol. 2007;73(16):5261-5267.
21. Siedel J, Hagele EO, Ziegenhorn J, Wahlefeld AW. Reagent for the enzymatic determination of serum total cholesterol with improved lipolytic efficiency. Clinical Chemistry 1983;29(6):1075-80.
22. Marschall HU, Einarsson C. Gallstone disease. Journal of Internal Medicine 2007;261(6):529-542.
23. Swidsinski A, Schlien P, Pernthaler A, Gottschalk U, Barlehner E, Decker G, Swidsinski S, Strassburg J, Loening-Baucke V, Hoffmnann U, Seehofer D, Hale LP, Lochs H. Bacterial biofilm within diseased pancreatic and biliary tracts. Gut 2005;54(3):388-395.
24. Good IJ. Thepopulationfrequencies ofspeciesand theestimaton of populationparameters. Biometrika 1953;40(3-4):237-264.
25. Kemp PF, Aller JY. Bacterial diversity in aquatic and other environments:what 16S rDNA libraries can tell us. FEMS Microbiology Ecology 2004;47(2):161-177.
26. Shade A, Handelsman J. Beyond the Venn diagram:the hunt for a core microbiome. Environmental Microbiology 2012;14(1):4-12.
27. Arumugam M,et al. Enterotypes of the human gut microbiome. Nature 2011;473(7346):174-180.
28.韩天权,蒋兆彦,张圣道.胆固醇结石形成机制的基因研究现状与展望.外科理论与实践2009：14：125-127.
29. Yang Q. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 2005;436:356-362.
30. Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L, Stonebraker AC, Hu C, Wong FS, Szot GL, Bluestone JA, Gordon JI, Chervonsky AV. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature 2008;455(7216):1109-1113.
31. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, DuGar B, Feldstein AE, Britt EB, Fu X, Chung Y-M, Wu Y, Schauer P, Smith JD, Allayee H, Tang WHW, DiDonato JA, Lusis AJ, Hazen SL. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011;472(7341):57-63.
32. Jones BV, Begley M, Hill C, Gahan CGM, Marchesi JR. Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome. Proceedings of the National Academy of Sciences 2008;105(36):13580-13585.
33. Sekirov I, Russell SL, Antunes LCM, Finlay BB. Gut Microbiota in Health and Disease. Physiol. Rev.2010;90(3):859-904.
34. Kelly D, Conway S, Aminov R. Commensal gut bacteria:mechanisms of immune modulation. Trends in Immunology 2005;26(6):326-333.
35. Lathrop SK, Bloom SM, Rao SM, Nutsch K, Lio C-W, Santacruz N, Peterson DA, Stappenbeck TS, Hsieh C-S. Peripheral education of the immune system by colonic commensal microbiota. Nature 2011;advance online publication.
36. Hooper LV. Do symbiotic bacteria subvert host immunity? Nat Rev Micro 2009;7(5):367-374.
37. Van Erpecum KJ, Van Berge-Henegouwen GP. Gallstones:an intestinal disease? Gut 1999;44(3):435-8.
38. Sayin Sama I, Wahlstrom A, Felin J, Jantti S, Marschall H-U, Bamberg K, Angelin B, Hyotylainen T, Oresic M, Backhed F. Gut Microbiota Regulates Bile Acid Metabolism by Reducing the Levels of Tauro-beta-muricholic Acid, a Naturally Occurring FXR Antagonist. Cell Metabolism 2013;17(2):225-235.
39. Capoor MR, Nair D, Rajni, Khanna G, Krishna SV, Chintamani MS, Aggarwal P. Microflora of bile aspirates in patients with acute cholecystitis With or without cholelithiasis:a tropical experience. Brazilian Journal of Infectious Diseases 2008;12:222-225.
40. Jiang Z-Y, Jiang C-Y, Wang L, Wang J-C, Zhang S-D, Einarsson C, Eriksson M, Han T-Q, Parini P, Eggertsen G. Increased NPC1L1 and ACAT2 expression in the jejunal mucosa from Chinese gallstone patients. Biochemical and Biophysical Research Communications 2009;379(1):49-54.
41. Buhman KK, Accad M, Novak S, Choi RS, Wong JS, Hamilton RL, Turley S, Farese RV, Jr. Resistance to diet-induced hypercholesterolemia and gallstone formation in ACAT2-deficient mice. Nat Med 2000;6(12):1341-7.
42. Wang HH, Wang DQH. Reduced susceptibility to cholesterol gallstone formation in mice that do not produce apolipoprotein B48 in the intestine. Hepatology 2005;42(4):894-904.
43. Csendes A, Becerra M, Burdiles P, Demian I, Bancalari K, Csendes P. Bacteriological studies of bile from the gallbladder in patients with carcinoma of the gallbladder, cholelithiasis, common bile duct stones and no gallstones disease. Eur J Surg 1994;160(6-7):363-7.
44. Edlund YA, Mollstedt BO, Ouchterlony O. Bacteriological investigation of the biliary system and liver in biliary tract disease correlated to clinical data and microstructure of the gallbladder and liver. Acta Chir Scand 1959;116(5-6):461-76.
45. Csendes A, Fernandez M, Uribe P. Bacteriology of the gallbladder bile in normal subjects. Am J Surg 1975;129(6):629-31.
46.朱雷明,赵洪,蔡端,张延龄,吕元,陈为欢,王文风.胆固醇结石中细菌对人胆汁胆固醇晶体形成的作用.中华肝胆外科杂志2005；11(3)：180-183.
47.朱雷明,李军,王学志,蔡端,张延龄.细菌对模拟胆汁热力学平衡的影响.外科理论和实践2005；10(4)：349-353.
48. Binette JP, Binette MB. The proteins and the formation of gallstones. Clinica Chimica Acta 2000;296(1-2):59-69.
49. Choi J, Klinkspoor JH, Yoshida T, Lee SP. Lipopolysaccharide from escherichia coli stimulates mucin secretion by cultured dog gallbladder epithelial cells. Hepatology 1999;29(5):1352-1357.
50.朱雷明,张辉,李军,王学志,蔡端,张延龄.细菌促胆固醇晶体成核的机制研究.肝胆胰外科杂志2009；21(2)：122-125.
51.朱雷明,蔡端,吕元.胆固醇结石病人与非胆石症人群胆道细菌感染状况与免疫球蛋白相关性的对照研究.中华肝胆外科杂志2003；9(7)：419422.
52. Maki T. Pathogenesis of calcium bilirubinate gallstone:role of E. coli, beta-glucuronidase and coagulation by inorganic ions, polyelectrolytes and agitation. Ann Surg 1966;164(1):90-100.
53. Monstein H-J, Jonsson Y, Zdolsek J, Svanvik J. Identification of Helicobacter pylori DNA in Human Cholesterol Gallstones. Scandinavian Journal of Gastroenterology 2002;37(1):112-119.
54. Swidsinski A, Khilkin M, Pahlig H, Swidsinski S, Priem F. Time dependent changes in the concentration and type of bacterial sequences found in cholesterol gallstones. Hepatology 1998;27(3):662-665.
55. Cahalane MJ, Neubrand MW, Carey MC. Physical-chemical pathogenesis of pigment gallstones. Semin Liver Dis 1988;8(4):317-28.
56. Stewart L, Grifiss JM, Jarvis GA, Way LW. Biliary bacterial factors determine the path of gallstone formation. The American Journal of Surgery 2006;192(5):598-603.
57. Metzker ML. Sequencing technologies - the next generation. Nat Rev Genet 2010;11(1):31-46.
58. Kenneth Nelson F, Snyder M, Gardner AF, Hendrickson CL, Shendure JA, Porreca GJ, Church GM, Ausubel FM, Ju J, Kieleczawa J, Slatko BE. Introduction and Historical Overview of DNA Sequencing. In. Current Protocols in Molecular Biology:John Wiley & Sons, Inc.; 2011.
59. Maloy KJ, Powrie F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 2011;474(7351):298-306.
60. Peterson DA, Frank DN, Pace NR, Gordon JI. Metagenomic Approaches for Defining the Pathogenesis of Inflammatory Bowel Diseases. Cell Host & Microbe 2008;3(6):417-427.
61. Bloom Seth M, Bijanki Vinieth N, Nava Gerardo M, Sun L, Malvin Nicole P, Donermeyer David L, Dunne WM, Allen Paul M, Stappenbeck Thaddeus S. Commensal Bacteroides Species Induce Colitis in Host-Genotype-Specific Fashion in a Mouse Model of Inflammatory Bowel Disease. Cell Host & Microbe 2011;9(5):390-403.
62. Dicksved J, Halfvarson J, Rosenquist M, Jarnerot G, Tysk C, Apajalahti J, Engstrand L, Jansson JK. Molecular analysis of the gut microbiota of identical twins with Crohn's disease. ISME J2008;2(7):716-727.
63. Joossens M, Huys G, Cnockaert M, De Preter V, Verbeke K, Rutgeerts P, Vandamme P, Vermeire S. Dysbiosis of the faecal microbiota in patients with Crohn's disease and their unaffected relatives. Gut 2011;60(5):631-637.
64. Garrett WS, Gallini CA, Yatsunenko T, Michaud M, DuBois A, Delaney ML, Punit S, Karlsson M, Bry L, Glickman JN, Gordon JI, Onderdonk AB, Glimcher LH. Enterobacteriaceae Act in Concert with the Gut Microbiota to Induce Spontaneous and Maternally Transmitted Colitis. Cell Host & Microbe 2010;8(3):292-300.
65. Wang Y, Hoenig JD, Malin KJ, Qamar S, Petrof EO, Sun J, Antonopoulos DA, Chang EB, Claud EC.16S rRNA gene-based analysis of fecal microbiota from preterm infants with and without necrotizing enterocolitis. ISME J 2009;3(8):944-954.
66. Wu S, Rhee K-J, Albesiano E, Rabizadeh S, Wu X, Yen H-R, Huso DL, Brancati FL, Wick E, McAllister F, Housseau F, Pardoll DM, Sears CL. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med 2009;15(9):1016-1022.
67. Mazmanian SK, Round JL, Kasper DL. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 2008;453(7195):620-625.
68.叶国良,陈会松,盛红,程德希.胆石症并胆道感染患者胆汁细菌分布及与年龄性别关系探讨.浙江临床医学2005；6：626-627.
69. Karch H, Denamur E, Dobrindt U, Finlay BB, Hengge R, Johannes L, Ron EZ, Tonjum T, Sansonetti PJ, Vicente M. The enemy within us:lessons from the 2011 European Escherichia coli O104:H4 outbreak. EMBO Molecular Medicine 2012;4(9):841-848.
70. Sokol H, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proceedings of the National Academy of Sciences 2008;105(43):16731-16736.
71. Ramirez-Farias C, Slezak K, Fuller Z, Duncan A, Holtrop G, Louis P. Effect of inulin on the human gut microbiota:stimulation of Bifidobacterium adolescentis and Faecalibacterium prausnitzii. Br J Nutr 2009;101(4):541-50.
72. Scott KP, Martin JC, Chassard C, Clerget M, Potrykus J, Campbell G, Mayer C-D, Young P, Rucklidge G, Ramsay AG, Flint HJ. Substrate-driven gene expression in Roseburia inulinivorans: Importance of inducible enzymes in the utilization of inulin and starch. Proceedings of the National Academy of Sciences 2011;108(Supplement 1):4672-4679.
73. Rode LM, Genthner BRS, Bryant MP. Syntrophic Association by Cocultures of the Methanol-and CO2-H2-Utilizing Species Eubacterium limosum and Pectin-Fermenting Lachnospira multiparus During Growth in a Pectin Medium. Applied and Environmental Microbiology 1981;42(1):20-22.
74. Crawford RW, Rosales-Reyes R, Ramirez-Aguilar MdIL, Chapa-Azuela O, Alpuche-Aranda C, Gunn JS. Gallstones play a significant role in Salmonella spp. gallbladder colonization and carriage. Proceedings of the National Academy of Sciences 2010;107(9):4353-4358.
75. Piddock LJV. Multidrug-resistance efflux pumps? not just for resistance. Nat Rev Micro 2006;4(8):629-636.
76. Lin J, Sahin O, Michel LO, Zhang Q. Critical Role of Multidrug Efflux Pump CmeABC in Bile Resistance and In Vivo Colonization of Campylobacter jejuni. Infection and Immunity 2003;71(8):4250-4259.
77. Kullak-ublick GA, Stieger B, Meier PJ. Enterohepatic bile salt transporters in normal physiology and liver disease. Gastroenterology 2004;126(1):322-342.
78. Glavinas H, Krajcsi P, Cserepes J, Sarkadi B. The role of ABC transporters in drug resistance, metabolism and toxicity. Curr Drug Deliv 2004;1(1):27-42.
79. Begley M, Gahan CGM, Hill C. The interaction between bacteria and bile. FEMS Microbiology Reviews 2005;29(4):625-651.
80. De Smet I, Van Hoorde L, Vande Woestyne M, Christiaens H, Verstraete W. Significance of bile salt hydrolytic activities of lactobacilli. Journal of Applied Microbiology 1995;79(3):292-301.
81. Wang DQ, Carey MC. Complete mapping of crystallization pathways during cholesterol precipitation from model bile:influence of physical-chemical variables of pathophysiologic relevance and identification of a stable liquid crystalline state in cold, dilute and hydrophilic bile salt-containing systems. Journal of Lipid Research 1996;37(3):606-30.
82. Somjen GJ, Gilat T. A non-micellar mode of cholesterol transport in human bile. FEBS Letters 1983;156(2):265-268.
83. Moschetta A, vanBerge-Henegouwen GP, Portincasa P, Palasciano G, van Erpecum KJ. Cholesterol crystallization in model biles:effects of bile salt and phospholipid species composition. Journal of Lipid Research 2001;42(8):1273-1281.
84. Mazer NA, Carey MC. Quasi-elastic light-scattering studies of aqueous biliary lipid systems. Cholesterol solubilization and precipitation in model bile solutions. Biochemistry 1983;22(2):426-442.
85. Maurer KJ. Identification of cholelithogenic enterohepatic Helicobacter species and their role in murine cholesterol gallstone formation. Gastroenterology 2005;128:1023-1033.
86. Nakano T, Yanagisawa J, Nakayama F. Phospholipase activity in human bile. Hepatology 1988;8(6):1560-1564.
87. Garcia-Vallve S, Romeu A, Palau J. Horizontal Gene Transfer in Bacterial and Archaeal Complete Genomes. Genome Research 2000;10(11):1719-1725.
1. Maki T. Pathogenesis of calcium bilirubinate gallstone:role of E. coli, beta-glucuronidase and coagulation by inorganic ions, polyelectrolytes and agitation. Ann Surg 1966;164(1):90-100.
2. Alexander S, Wolfgang L, Hartmut P, Friedrich P. Molecular genetic evidence of bacterial colonization of cholesterol gallstones. Gastroenterology 1995;108(3):860-864.
3. Maurer KJ. Identification of cholelithogenic enterohepatic Helicobacter species and their role in murine cholesterol gallstone formation. Gastroenterology 2005;128:1023-1033.
4. Julka K, Ko CW. Infectious Diseases and the Gallbladder. Infectious Disease Clinics of North America 2010;24(4):885-898.
5. Portincasa P, Moschetta A, Palasciano G. Cholesterol gallstone disease. The Lancet 2006;368(9531):230-239.
6. Portincasa P, Di Ciaula A, Wang HH, Palasciano G, van Erpecum KJ, Moschetta A, Wang DQH. Coordinate regulation of gallbladder motor function in the gut-liver axis. Hepatology 2008;47(6):2112-2126.
7. Xiao L, Wang K, Teng Y, Zhang J. Component plane presentation integrated self-organizing map for microarray data analysis. FEBS Letters 2003;538(1-3):117-124.
8. Jiang Z-Y, Parini P, Eggertsen G, Davis MA, Hu H, Suo G-J, Zhang S-D, Rudel LL, Han T-Q, Einarsson C. Increased expression of LXRa, ABCG5, ABCG8, and SR-BI in the liver from normolipidemic, nonobese Chinese gallstone patients. Journal of Lipid Research 2008;49(2):464-472.
9. Wang Y, Jiang Z-Y, Fei J, Xin L, Cai Q, Jiang Z-H, Zhu Z-G, Han T-Q, Zhang S-D. ATP binding cassette G8 T400K polymorphism may affect the risk of gallstone disease among Chinese males. Clinica Chimica Acta 2007;384(1-2):80-85.
10.王勇,韩天权,费健,蒋兆彦,蔡劬,姜志宏,张圣道.胆囊黏膜ABCG5和ABCG8基因在胆固醇结石病中的作用.中华实验外科杂志2007；24：51-52.
11. Pramfalk C, Jiang Z-Y, Cai Q, Hu H, Zhang S-D, Han T-Q, Eriksson M, Parini P. HNF1α and SREBP2 are important regulators of NPC1L1 in human liver. Journal of Lipid Research 2010;51(6):1354-1362.
12. Parini P, Jiang ZY, Einarsson C, Eggertsen G, Zhang SD, Rudel LL, Han TQ, Eriksson M. ACAT2 and human hepatic cholesterol metabolism:identification of important gender-related differences in normolipidemic, non-obese Chinese patients. Atherosclerosis 2009;207(1):266-71.
13. Jiang Z-Y, Jiang C-Y, Wang L, Wang J-C, Zhang S-D, Einarsson C, Eriksson M, Han T-Q, Parini P, Eggertsen G. Increased NPC1L1 and ACAT2 expression in the jejunal mucosa from Chinese gallstone patients. Biochemical and Biophysical Research Communications 2009;379(1):49-54.
14. Wang HH, Wang DQH. Reduced susceptibility to cholesterol gallstone formation in mice that do not produce apolipoprotein B48 in the intestine. Hepatology 2005;42(4):894-904.
15. Buhman KK, Accad M, Novak S, Choi RS, Wong JS, Hamilton RL, Turley S, Farese RV, Jr. Resistance to diet-induced hypercholesterolemia and gallstone formation in ACAT2-deficient mice. Nat Med 2000;6(12):1341-7.
16. Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger M. Identification of Scavenger Receptor SR-BI as a High Density Lipoprotein Receptor. Science 1996;271(5248):518-520.
17. Labonte ED, Howles PN, Granholm NA, Rojas JC, Davies JP, Ioannou YA, Hui DY. Class B type I scavenger receptor is responsible for the high affinity cholesterol binding activity of intestinal brush border membrane vesicles. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids 2007;1771(9):1132-1139.
18. Davies JP, Levy B, Ioannou YA. Evidence for a Niemann-Pick C (NPC) Gene Family: Identification and Characterization of NPC1L1. Genomics 2000;65(2):137-145.
19. Altmann SW, Davis HR, Zhu L-j, Yao X, Hoos LM, Tetzloff G, Iyer SPN, Maguire M, Golovko A, Zeng M, Wang L, Murgolo N, Graziano MP. Niemann-Pick Cl Like 1 Protein Is Critical for Intestinal Cholesterol Absorption. Science 2004;303(5661):1201-1204.
20. Friedrich S. Ezetimibe in search of receptor(s)-Still a never-ending challenge in cholesterol absorption and transport. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids2007;1771(9):1113-1116.
21. Yu L, Li-Hawkins J, Hammer RE, Berge KE, Horton JD, Cohen JC, Hobbs HH. Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol. The Journal of Clinical Investigation 2002;110(5):671-680.
22. Lee J, Shirk A, Oram JF, Lee SP, Kuver R. Polarized cholesterol and phospholipid efflux in cultured gall-bladder epithelial cells:evidence for an ABCAl-mediated pathway. Biochem. J. 2002;364(2):475-484.
23.姜种弋,韩天权,蒋兆彦,蔡劬,吴卫泽,张圣道.肝脏X受体对小鼠胆汁脂质成分与胆固醇代谢基因表达的影响.中华实验外科杂志2007；24：1457-1459.
24.王蕾,蔡劬,蒋兆彦,施敏敏,崔巍,韩天权,袁耀宗,吴卫泽,张圣道.肝脏X受体a对肝细胞HepG2胆固醇代谢基因表达的调控.内科理论与实践2010；5：165-169.
25. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37(12):1595-607.
26. Kuipers F, Groen AK. Chipping away at gallstones. Nat Med 2008;14(7):715-716.
27. Tsai C-J, Leitzmann MF, Willett WC, Giovannucci EL. Prospective study of abdominal adiposity and gallstone disease in US men. The American Journal of Clinical Nutrition 2004;80(1):38-44.
28.蒋兆彦,韩天权,陈胜,乙芳,姜志宏,商俊,蔡杏兴,张圣道,顾建平,黄桂余.胆囊结石病高危人群预测结果的随访研究和预测准确性评判.消化外科2002；1：400-403.
29.陈胜,张圣道,蒋兆彦,韩天权,朱全梅,沈树权,何小伟,黄桂余,顾建平,乙芳.胆固醇结石病高危人群预测的进一步研究.中华医学杂志2001；81：1010-1011.
30. Biddinger SB, Haas JT, Yu BB, Bezy O, Jing E, Zhang W, Unterman TG, Carey MC, Kahn CR. Hepatic insulin resistance directly promotes formation of cholesterol gallstones. Nat Med 2008;14(7):778-782.
31. Khanuja B, Cheah YC, Hunt M, Nishina PM, Wang DQ, Chen HW, Billheimer JT, Carey MC, Paigen B. Lithl, a major gene affecting cholesterol gallstone formation among inbred strains of mice. Proceedings of the National Academy of Sciences 1995;92(17):7729-7733.
32.秦俭,韩天权,蒋兆彦.Lith基因和胆固醇结石病.国外医学·外科学分册2003；30(4)：229-231.
33. Lammert F, Carey MC, Paigen B. Chromosomal organization of candidate genes involved in cholesterol gallstone formation:A murine gallstone map. Gastroenterology 2001;120(1):221-238.
34. Puppala S, Dodd GD, Fowler S, Arya R, Schneider J, Farook VS, Granato R, Dyer TD, Almasy L, Jenkinson CP, Diehl AK, Stern MP, Blangero J, Duggirala R. A Genomewide Search Finds Major Susceptibility Loci for Gallbladder Disease on Chromosome 1 in Mexican Americans. The American Journal of Human Genetics 2006;78(3):377-392.
35.秦俭,韩天权,袁文涛.胆囊结石病致病基因的定位研究.中华外科杂志2006；44(7)：485-487.
36.陶太珍,沈靖,姚才良.胆石症家族聚集性的病因和流行病学研究.中国公共卫生1999；15(2)：169-170.
37. Lammert F, Matern S. The genetic background of cholesterol gallstone formation:an inventory of human lithogenic genes. Curr Drug Targets Immune Endocr Metabol Disord 2005;5(2):163-70.
38. Lammert F, Sauerbruch T. Mechanisms of Disease:the genetic epidemiology of gallbladder stones. Nat Clin Pract Gastroenterol Hepatol 2005;2(9):423-433.
39.张宇,韩天权,张圣道.人类胆囊胆固醇结石易感基因的研究进展.中国现代普通外科进展2004；7(5)：257-259.
40.蒋兆彦,韩天权,所广军.胆固醇结石病人肝脏胆小管侧膜ATP基因表达差异的研究.外科理论与实践2005；10(1)：61-65.
41. Schafinayer C, Tepel J, Franke A, Buch S, Lieb S, Seeger M, Lammert F, Kremer B, Folsch UR, Fandrich F, Schreiber S, Hampe J. Investigation of the Lith1 candidate genes ABCB11 and LXRA in human gallstone disease. Hepatology 2006;44(3):650-657.
42. Maselli MA, Piepoli AL, Pezzolla F, Guerra V, Caruso ML, Mennuni L, Lorusso D, Makovec F. Effect of Three Nonpeptide Cholecystokinin Antagonists on Human Isolated Gallbladder. Digestive Diseases and Sciences 2001;46(12):2773-2778.
43. Zhu J, Han TQ, Chen S, Jiang Y, Zhang SD. Gallbladder motor function, plasma cholecystokinin and cholecystokinin receptor of gallbladder in cholesterol stone patients. World J Gastroenterol 2005;11(11):1685-9.
44. Choi M, Moschetta A, BookOTU AL, Peng L, Umetani M, Holmstrom SR, Suino-Powell K, Xu HE, Richardson JA, Gerard RD, Mangelsdorf DJ, Kliewer SA. Identification of a hormonal basis for gallbladder filling. Nat Med 2006;12(11):1253-1255.
45.韩天权,蒋兆彦,张圣道.胆固醇结石形成机制的基因研究现状与展望.外科理论与实践2009；14：125-127.
46. Carey MC, Paigen B. Epidemiology of the American Indians 'burden and its likely genetic origins. Hepatology 2002;36(4):781-791.
47.方东生,李李,熊奇如.膳食因素与胆囊结石症关联的研究.疾病控制杂志2000；4(4)：337-339.
48. Watson JD, Crick FH. The structure of DNA. Cold Spring Harb Symp Quant Biol 1953;18:123-31.
49. Fleischmann R, Adams M, White O, Clayton R, Kirkness E, Kerlavage A, Bult C, Tomb J, Dougherty B, Merrick J, al. e. Whole-genome random sequencing and assembly of Haemophilus influenzae Rd. Science 1995;269(5223):496-512.
50. Lander ES, et al. Initial sequencing and analysis of the human genome. Nature 2001;409(6822):860-921.
51. Venter JC, Adams MD, Myers EW, Li PW,et al.. The Sequence of the Human Genome. Science 2001;291(5507):1304-1351.
52. Margulies M, et al. Genome sequencing in microfabricated high-density picolitre reactors. Nature 2005;437(7057):376-380.
53. Metzker ML. Sequencing technologies - the next generation. Nat Rev Genet 2010;11(1):31-46.
54. Glenn TC. Field guide to next-generation DNA sequencers. Molecular Ecology Resources 2011;11(5):759-769.
55. Kenneth Nelson F, Snyder M, Gardner AF, Hendrickson CL, Shendure JA, Porreca GJ, Church GM, Ausubel FM, Ju J, Kieleczawa J, Slatko BE. Introduction and Historical Overview of DNA Sequencing. In. Current Protocols in Molecular Biology:John Wiley & Sons, Inc.; 2011.
56. Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature 2009;458(7239):719-724.
57. Puente XS, et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 2011;475(7354):101-105.
58. Qin J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010;464(7285):59-65.
59. Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML, Jones WJ, Roe BA, Affourtit JP, Egholm M, Henrissat B, Heath AC, Knight R, Gordon JI. A core gut microbiome in obese and lean twins. Nature 2009;457(7228):480-484.
60. Diamant M, Blaak EE, de Vos WM. Do nutrient-gut-microbiota interactions play a role in human obesity, insulin resistance and type 2 diabetes? Obesity Reviews 2011;12(4):272-281.
61., Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L, Stonebraker AC, Hu C, Wong FS, Szot GL, Bluestone JA, Gordon JI, Chervonsky AV. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature 2008;455(7216):1109-1113.
62. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, DuGar B, Feldstein AE, Britt EB, Fu X, Chung Y-M, Wu Y, Schauer P, Smith JD, Allayee H, Tang WHW, DiDonato JA, Lusis AJ, Hazen SL. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011;472(7341):57-63.
63. Jones BV, Begley M, Hill C, Gahan CGM, Marchesi JR. Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome. Proceedings of the National Academy of Sciences 2008; 105(36):13580-13585.
64. Ridlon JM, Kang D-J, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. Journal of Lipid Research 2006;47(2):241-259.
65. Wang DQ-H, Cohen DE, Carey MC. Biliary lipids and cholesterol gallstone disease. Journal of Lipid Research 2009;50(Supplement):S406-S411.
66.方驰华,杨继震.胆囊结石需氧菌和厌氧菌分子生物学研究及意义.第四军医大学学报1998；19(6)：681-682.
67. Lee DK, Tarr PI, Haigh WG, Lee SP. Bacterial DNA in mixed cholesterol gallstones. Am J Gastroenterol 1999;94(12):3502-3506.
68. Kawai M, Iwahashi M, Uchiyama K, Ochiai M, Tanimura H, Yamaue H. Gram-positive cocci are associated with the formation of completely pure cholesterol stones. Am J Gastroenterol 2002;97(1):83-88.
69. Cariati A, Cetta F. Re:Kawai et al.[mdash]bacteria are not important in the formation of pure cholesterol stones. Am J Gastroenterol 2002;97(11):2921-2922.
70.杨玉龙,刘小北,谭文翔,李雪驼.胆固醇结石中的细菌及其在成石机制中的作用.肝胆胰外科杂志2005；17(1)：14-16.
71.吴汉平,康生朝,张方信.ERCP在胆总管结石患者胆汁细菌学研究中的价值.世界华人消化杂志2007；15(17)：1965-1967.
72.李奉达,邱法波,宁刘.胆石病患者胆汁细菌学检查分析.世界华人消化杂志2008；16(35)：4004-4007.
73.田志杰,韩天权,姜志宏.胆囊结石病胆道系统螺杆菌DNA的研究.中国实用外科杂志2004；24(2)：84-87.
74.蔡端,朱雷明,吕元,刘维薇,张延龄.胆固醇结石、胆囊黏膜和胆汁细菌DNA的检测.中华消化杂志2004；24(11)：647-650.
75. Hazrah P, Oahn KT, Tewari M, Pandey AK, Kumar K, Mohapatra TM, Shukla HS. The frequency of live bacteria in gallstones. HPB (Oxford) 2004;6(1):28-32.
76.陈晓文,智发朝,武金宝,万田谟,周丹.聚合酶链式反应和常规培养检测胆总管结石中细菌及其意义的研究.临床肝胆病杂志2005；21(3)：173-175.
77.陈晓文,智发朝,曹东林,周思朗,陈勇伟,谢栋.胆总管结石的成因观察.第四军医大学学报2006；27(3)：261-263.
78.朱雷明,蔡端,吕元.胆固醇结石病人与非胆石症人群胆道细菌感染状况与免疫球蛋白相关性的对照研究.中华肝胆外科杂志2003；9(7)：419-422.
79.王学军,李玉民,李世雄.细菌在胆固醇结石形成中的作用研究.中国现代医学杂志2003；13(3)：4-7.
80.朱雷明,蔡端,吕元,陈为欢,王文风,张延龄.胆固醇结石病人与非胆石症人群胆道细菌感染状况及与免疫球蛋白相关性的对照研究.中华外科杂志2004；42(24)：1501-1504.
81.朱雷明,赵洪,蔡端,张延龄,吕元,陈为欢,王文风.胆固醇结石中细菌对人胆汁胆固醇晶体形成的作用.中华肝胆外科杂志2005；11(3)：180-183.
82.朱雷明,李军,王学志,蔡端,张延龄.细菌对模拟胆汁热力学平衡的影响.外科理论和实践2005；10(4)：349-353.
83. Choi J, Klinkspoor JH, Yoshida T, Lee SP. Lipopolysaccharide from escherichia coli stimulates mucin secretion by cultured dog gallbladder epithelial cells. Hepatology 1999;29(5):1352-1357.
84. Binette JP, Binette MB. The proteins and the formation of gallstones. Clinica Chimica Acta 2000;296(1-2):59-69.
85.朱雷明,张辉,李军,王学志,蔡端,张延龄.细菌促胆固醇晶体成核的机制研究.肝胆胰外科杂志2009；21(2)：122-125.
86. Bloom Seth M, Bijanki Vinieth N, Nava Gerardo M, Sun L, Malvin Nicole P, Donermeyer David L, Dunne WM, Allen Paul M, Stappenbeck Thaddeus S. Commensal Bacteroides Species Induce Colitis in Host-Genotype-Specific Fashion in a Mouse Model of Inflammatory Bowel Disease. Cell Host & Microbe 2011;9(5):390-403.
87. Dicksved J, Halfvarson J, Rosenquist M, Jarnerot G, Tysk C, Apajalahti J, Engstrand L, Jansson JK. Molecular analysis of the gut microbiota of identical twins with Crohn's disease. ISME J 2008;2(7):716-727.
88. Garrett WS, Gallini CA, Yatsunenko T, Michaud M, DuBois A, Delaney ML, Punit S, Karlsson M, Bry L, Glickman JN, Gordon JI, Onderdonk AB, Glimcher LH. Enterobacteriaceae Act in Concert with the Gut Microbiota to Induce Spontaneous and Maternally Transmitted Colitis. Cell Host & Microbe 2010;8(3):292-300.
89. Joossens M, Huys G, Cnockaert M, De Preter V, Verbeke K, Rutgeerts P, Vandamme P, Vermeire S. Dysbiosis of the faecal microbiota in patients with Crohn's disease and their unaffected relatives. Gut 2011;60(5):631-637.
90. Peterson DA, Frank DN, Pace NR, Gordon JI. Metagenomic Approaches for Defining the Pathogenesis of Inflammatory Bowel Diseases. Cell Host & Microbe 2008;3(6):417-427.
91. Wang Y, Hoenig JD, Malin KJ, Qamar S, Petrof EO, Sun J, Antonopoulos DA, Chang EB, Claud EC.16S rRNA gene-based analysis of fecal microbiota from preterm infants with and withOTU necrotizing enterocolitis. ISME J 2009;3(8):944-954.
92. Wu S, Rhee K-J, Albesiano E, Rabizadeh S, Wu X, Yen H-R, Huso DL, Brancati FL, Wick E, McAllister F, Housseau F, Pardoll DM, Sears CL. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med 2009;15(9):1016-1022.
93. Kostic AD, Gevers D, Pedamallu CS, Michaud M, Duke F, Earl AM, Ojesina AI, Jung J, Bass AJ, Tabernero J, Baselga J, Liu C, Shivdasani RA, Ogino S, Birren BW, Huttenhower C, Garrett WS, Meyerson M. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Research 2011.
94. Castellarin M, Warren RL, Freeman JD, Dreolini L, Krzywinski M, Strauss J, Barnes R, Watson P, Allen-Vercoe E, Moore RA, Holt RA. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Research 2011.