title: The ATG16L1-T300A allele impairs clearance of pathosymbionts in the inflamed ileal mucosa of Crohn's disease patients.
abstract: OBJECTIVE
  Crohn's disease (CD) is caused by a complex interplay among genetic, microbial and environmental factors. ATG16L1 is an important genetic factor involved in innate immunity, including autophagy and phagocytosis of microbial components from the gut. We investigated the effect of inflammation on the composition of microbiota in the ileal mucosa of CD patients in relation to the ATG16L1 risk status.
  
  
  METHODS
  Biopsies (n=35) were obtained from inflamed and non-inflamed regions of the terminal ileum of 11 CD patients homozygous for the ATG16L1 risk allele (ATG16L1-T300A) and 9 CD patients homozygous for the ATG16L1 protective allele (ATG16L1-T300). Biopsy DNA was extracted and the bacterial composition analysed by pyrosequencing. Intracellular survival rates of adherent-invasive Escherichia coli (AIEC) were analysed by determining colony forming units after exposure to monocytes isolated from healthy volunteers homozygous for the ATG16L1 risk or protective allele.
  
  
  RESULTS
  Inflamed ileal tissue from patients homozygous for the ATG16L1 risk allele contained increased numbers of Fusobacteriaceae, whereas inflamed ileal tissue of patients homozygous for the ATG16L1 protective allele showed decreased numbers of Bacteroidaceae and Enterobacteriaceae and increased Lachnospiraceae. The ATG16L1 allele did not affect the bacterial composition in the non-inflamed ileal tissue. Monocytes homozygous for the ATG16L1 risk allele showed impaired killing of AIEC under inflammatory conditions compared with those homozygous for the ATG16L1 protective allele.
  
  
  CONCLUSIONS
  CD patients homozygous for the ATG16L1-T300A risk allele show impaired clearance of pathosymbionts in ileal inflammation indicating that ATG16L1 is essential for effective elimination of pathosymbionts upon inflammation.
authors.affiliation: Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Sadaghian Sadabad
authors.affiliation: Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Anouk
authors.initials: A
authors.lastname: Regeling
authors.affiliation: Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Marcus C
authors.initials: MC
authors.lastname: de Goffau
authors.affiliation: Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Tjasso
authors.initials: T
authors.lastname: Blokzijl
authors.affiliation: Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Rinse K
authors.initials: RK
authors.lastname: Weersma
authors.affiliation: Department of Medical Microbiology, School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: John
authors.initials: J
authors.lastname: Penders
authors.affiliation: Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Klaas Nico
authors.initials: KN
authors.lastname: Faber
authors.affiliation: Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Hermie J M
authors.initials: HJ
authors.lastname: Harmsen
authors.affiliation: Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Gerard
authors.initials: G
authors.lastname: Dijkstra
mesh_terms: D000483:Alleles; D001343:Autophagy / Q000235:genetics; D000071183:Autophagy-Related Proteins; D001706:Biopsy; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D003424:Crohn Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004247:DNA / Q000235:genetics*; D005260:Female; D006720:Homozygote; D006801:Humans; D007082:Ileum / Q000378:metabolism / Q000473:pathology*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D004247:DNA
keywords: CROHN'S DISEASE; GENOTYPE; IBD; INTESTINAL BACTERIA; INTESTINAL MICROBIOLOGY