Disease Phenotype and Genotype Are Associated with Shifts in Intestinal-associated Microbiota in Inflammatory Bowel Diseases

被引:453
作者
Frank, Daniel N. [1 ,2 ]
Robertson, Charles E.
Hamm, Christina M. [3 ]
Kpadeh, Zegbeh [3 ]
Zhang, Tianyi [4 ]
Chen, Hongyan [4 ]
Zhu, Wei [4 ]
Sartor, R. Balfour [5 ]
Boedeker, Edgar C. [6 ]
Harpaz, Noam [7 ]
Pace, Norman R.
Li, Ellen [8 ]
机构
[1] Univ Colorado, Sch Med, Div Infect Dis, Dept Mol Cellular & Dev Biol, Aurora, CO 80045 USA
[2] Mucosal & Vaccine Res Colorado, Denver, CO USA
[3] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA
[4] SUNY Stony Brook, Dept Appl Math & Stat, Stony Brook, NY 11794 USA
[5] Univ N Carolina, Dept Med, Chapel Hill, NC USA
[6] Univ New Mexico, Dept Med, Albuquerque, NM 87131 USA
[7] Mt Sinai Sch Med, Dept Pathol, New York, NY USA
[8] SUNY Stony Brook, Dept Med, Stony Brook, NY 11794 USA
基金
美国国家卫生研究院;
关键词
NOD2; ATG16L1; inflammatory bowel diseases; microbiota; GENOME-WIDE ASSOCIATION; ILEAL CROHNS-DISEASE; PANETH CELLS; SUSCEPTIBILITY LOCI; NOD2; PATHOGENESIS; COMMUNITIES; IMBALANCES; MECHANISMS; EXPRESSION;
D O I
10.1002/ibd.21339
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Background: Abnormal host-microbe interactions are implicated in the pathogenesis of inflammatory bowel diseases. Previous 16S rRNA sequence analysis of intestinal tissues demonstrated that a subset of Crohn's disease (CD) and ulcerative colitis (UC) samples exhibited altered intestinal-associated microbial compositions characterized by depletion of Bacteroidetes and Firmicutes (particularly Clostridium taxa). We hypothesize that NOD2 and ATG16L1 risk alleles may be associated with these alterations. Methods: To test this hypothesis, we genotyped 178 specimens collected from 35 CD, 35 UC, and 54 control patients for the three major NOD2 risk alleles (Leu 1007fs, R702W, and G908R) and the ATG16L1T300A risk allele, that had undergone previous 16S rRNA sequence analysis. Our statistical models incorporated the following independent variables: 1) disease phenotype (CD, UC, non-IBD control); 2) NOD2 composite genotype (NOD2(R) = at least one risk allele, NOD2(NR) = no risk alleles); 3) ATG16L1T300A genotype (ATG16L1(R/R), ATG16L1(R/NR), ATG16L1(NR/NR)); 4) patient age at time of surgery and all first-order interactions. The dependent variable(s) were the relative frequencies of bacterial taxa classified by applying the RDP 2.1 classifier to previously reported 16S rRNA sequence data. Results: Disease phenotype, NOD2 composite genotype and ATG16L1 genotype were significantly associated with shifts in microbial compositions by nonparametric multivariate analysis of covariance (MANCOVA). Shifts in the relative frequencies of Faecalibacterium and Escherichia taxa were significantly associated with disease phenotype by nonparametric ANCOVA. Conclusions: These results support the concept that disease phenotype and genotype are associated with compositional changes in intestinal-associated microbiota.
引用
收藏
页码:179 / 184
页数:6
相关论文
共 32 条
[1]   MECHANISMS OF DISEASE Inflammatory Bowel Disease [J].
Abraham, Clara ;
Cho, Judy H. .
NEW ENGLAND JOURNAL OF MEDICINE, 2009, 361 (21) :2066-2078
[2]   Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn's disease [J].
Abreu, MT ;
Taylor, KD ;
Lin, YC ;
Hang, T ;
Gaiennie, J ;
Landers, CJ ;
Vasiliauskas, EA ;
Kam, LY ;
Rojany, M ;
Papadakis, KA ;
Rotter, JI ;
Targan, SR ;
Yang, HY .
GASTROENTEROLOGY, 2002, 123 (03) :679-688
[3]  
Anderson MJ, 2001, AUSTRAL ECOL, V26, P32, DOI 10.1111/j.1442-9993.2001.01070.pp.x
[4]   Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease [J].
Barrett, Jeffrey C. ;
Hansoul, Sarah ;
Nicolae, Dan L. ;
Cho, Judy H. ;
Duerr, Richard H. ;
Rioux, John D. ;
Brant, Steven R. ;
Silverberg, Mark S. ;
Taylor, Kent D. ;
Barmada, M. Michael ;
Bitton, Alain ;
Dassopoulos, Themistocles ;
Datta, Lisa Wu ;
Green, Todd ;
Griffiths, Anne M. ;
Kistner, Emily O. ;
Murtha, Michael T. ;
Regueiro, Miguel D. ;
Rotter, Jerome I. ;
Schumm, L. Philip ;
Steinhart, A. Hillary ;
Targan, Stephan R. ;
Xavier, Ramnik J. ;
Libioulle, Cecile ;
Sandor, Cynthia ;
Lathrop, Mark ;
Belaiche, Jacques ;
Dewit, Olivier ;
Gut, Ivo ;
Heath, Simon ;
Laukens, Debby ;
Mni, Myriam ;
Rutgeerts, Paul ;
Van Gossum, Andre ;
Zelenika, Diana ;
Franchimont, Denis ;
Hugot, Jean-Pierre ;
de Vos, Martine ;
Vermeire, Severine ;
Louis, Edouard ;
Cardon, Lon R. ;
Anderson, Carl A. ;
Drummond, Hazel ;
Nimmo, Elaine ;
Ahmad, Tariq ;
Prescott, Natalie J. ;
Onnie, Clive M. ;
Fisher, Sheila A. ;
Marchini, Jonathan ;
Ghori, Jilur .
NATURE GENETICS, 2008, 40 (08) :955-962
[5]   A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells [J].
Cadwell, Ken ;
Liu, John Y. ;
Brown, Sarah L. ;
Miyoshi, Hiroyuki ;
Loh, Joy ;
Lennerz, Jochen K. ;
Kishi, Chieko ;
Kc, Wumesh ;
Carrero, Javier A. ;
Hunt, Steven ;
Stone, Christian D. ;
Brunt, Elizabeth M. ;
Xavier, Ramnik J. ;
Sleckman, Barry P. ;
Li, Ellen ;
Mizushima, Noboru ;
Stappenbeck, Thaddeus S. ;
Virgin, Herbert W. .
NATURE, 2008, 456 (7219) :259-U62
[6]   The Ribosomal Database Project: improved alignments and new tools for rRNA analysis [J].
Cole, J. R. ;
Wang, Q. ;
Cardenas, E. ;
Fish, J. ;
Chai, B. ;
Farris, R. J. ;
Kulam-Syed-Mohideen, A. S. ;
McGarrell, D. M. ;
Marsh, T. ;
Garrity, G. M. ;
Tiedje, J. M. .
NUCLEIC ACIDS RESEARCH, 2009, 37 :D141-D145
[7]   THE PHYLOGENY OF THE GENUS CLOSTRIDIUM - PROPOSAL OF 5 NEW GENERA AND 11 NEW SPECIES COMBINATIONS [J].
COLLINS, MD ;
LAWSON, PA ;
WILLEMS, A ;
CORDOBA, JJ ;
FERNANDEZGARAYZABAL, J ;
GARCIA, P ;
CAI, J ;
HIPPE, H ;
FARROW, JAE .
INTERNATIONAL JOURNAL OF SYSTEMATIC BACTERIOLOGY, 1994, 44 (04) :812-826
[8]   Greengenes, a chimera-checked 16S rRNA gene database and workbench compatible with ARB [J].
DeSantis, T. Z. ;
Hugenholtz, P. ;
Larsen, N. ;
Rojas, M. ;
Brodie, E. L. ;
Keller, K. ;
Huber, T. ;
Dalevi, D. ;
Hu, P. ;
Andersen, G. L. .
APPLIED AND ENVIRONMENTAL MICROBIOLOGY, 2006, 72 (07) :5069-5072
[9]   The role of microbes in Crohn's disease [J].
Eckburg, Paul B. ;
Relman, David A. .
CLINICAL INFECTIOUS DISEASES, 2007, 44 (02) :256-262
[10]   Experimental models of inflammatory bowel disease reveal innate, adaptive, and regulatory mechanisms of host dialogue with the microbiota [J].
Elson, CO ;
Cong, Y ;
McCracken, VJ ;
Dimmitt, RA ;
Lorenz, RG ;
Weaver, CT .
IMMUNOLOGICAL REVIEWS, 2005, 206 :260-276