title: Intestinal aganglionosis is associated with early and sustained disruption of the colonic microbiome.
abstract: BACKGROUND
  Congenital aganglionosis (Hirschsprung's disease) results in colonic dysmotility and a risk for Hirschsprung's-associated enterocolitis (HAEC), whose cause is unknown. We hypothesized that aganglionosis leads to microbiome changes that may contribute to HAEC risk.
  
  
  METHODS
  Colon and fecal samples were collected from endothelin receptor B-null (Ednrb(-/-) ) mice, an established model of colorectal aganglionosis, at postnatal day 7 (P7), P20, and P24. We determined microbiome composition by 16S ribosomal RNA gene pyrosequencing and fecal metabolite profile by nuclear magnetic resonance spectroscopy.
  
  
  RESULTS
  Wild-type (WT) mice exhibited increasing species diversity with age, with mutant mice possessing even greater diversity. WT and mutant microbiomes, both fecal and colonic, significantly segregated by principal coordinates analysis based on species composition at all ages examined. Importantly, mutant mice contained more Bacteroidetes and less Firmicutes than WT, with additional genus- and species-level differences observed. Notably, mutant P7 colon was dominated by coagulase-negative Staphylococcus species, which were rare in WT. Mutant fecal metabolite profiles also differed, particularly in the abundance of formate, a short-chain fatty acid product of microbial fermentation.
  
  
  CONCLUSIONS
  Colorectal aganglionosis is associated with early and sustained disruption of the normal colonic and fecal microbiome, supporting the enteric nervous system as a determinant of microbiome composition. Furthermore, the differences observed suggest a potential contributory role for the microbiome in the etiology of HAEC. These findings provide a basis for further studies to determine the causative role of specific bacterial communities in HAEC and the potential to restore the normal microbiome in Hirschsprung's disease.
authors.affiliation: Department of Molecular Biology, University of Wyoming, Laramie, WY, USA.
authors.forename: N L
authors.initials: NL
authors.lastname: Ward
authors.forename: A
authors.initials: A
authors.lastname: Pieretti
authors.forename: S E
authors.initials: SE
authors.lastname: Dowd
authors.forename: S B
authors.initials: SB
authors.lastname: Cox
authors.forename: A M
authors.initials: AM
authors.lastname: Goldstein
mesh_terms: D000818:Animals; D001419:Bacteria / Q000145:classification / Q000235:genetics; D044822:Biodiversity; D003106:Colon / Q000382:microbiology*; D004195:Disease Models, Animal; D004760:Enterocolitis / Q000209:etiology / Q000382:microbiology*; D005243:Feces / Q000737:chemistry*; D006627:Hirschsprung Disease / Q000150:complications / Q000382:microbiology*; D009682:Magnetic Resonance Spectroscopy; D054892:Metagenome / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D012336:RNA, Ribosomal, 16S / Q000032:analysis*
chemical_list: D012336:RNA, Ribosomal, 16S