title: Disease phenotype and genotype are associated with shifts in intestinal-associated microbiota in inflammatory bowel diseases.
abstract: 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.
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado 80045, USA. Daniel.Frank@Colorado.edu
authors.forename: Daniel N
authors.initials: DN
authors.lastname: Frank
authors.forename: Charles E
authors.initials: CE
authors.lastname: Robertson
authors.forename: Christina M
authors.initials: CM
authors.lastname: Hamm
authors.forename: Zegbeh
authors.initials: Z
authors.lastname: Kpadeh
authors.forename: Tianyi
authors.initials: T
authors.lastname: Zhang
authors.forename: Hongyan
authors.initials: H
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.forename: R Balfour
authors.initials: RB
authors.lastname: Sartor
authors.forename: Edgar C
authors.initials: EC
authors.lastname: Boedeker
authors.forename: Noam
authors.initials: N
authors.lastname: Harpaz
authors.forename: Norman R
authors.initials: NR
authors.lastname: Pace
authors.forename: Ellen
authors.initials: E
authors.lastname: Li
mesh_terms: D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000382:microbiology* / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics* / Q000382:microbiology* / Q000473:pathology; D005838:Genotype; D006801:Humans; D007422:Intestines / Q000382:microbiology* / Q000473:pathology; D054892:Metagenome / Q000235:genetics*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis; D012335:RNA, Ribosomal / Q000235:genetics
chemical_list: C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D012335:RNA, Ribosomal