title: Akkermansia muciniphila and Helicobacter typhlonius modulate intestinal tumor development in mice.
abstract: Gastrointestinal tumor growth is thought to be promoted by gastrointestinal bacteria and their inflammatory products. We observed that intestine-specific conditional Apc mutant mice (FabplCre;Apc (15lox/+)) developed many more colorectal tumors under conventional than under pathogen-low housing conditions. Shotgun metagenomic sequencing plus quantitative PCR analysis of feces DNA revealed the presence of two bacterial species in conventional mice, absent from pathogen-low mice. One, Helicobacter typhlonius, has not been associated with cancer in man, nor in immune-competent mice. The other species, mucin-degrading Akkermansia muciniphila, is abundantly present in healthy humans, but reduced in patients with inflammatory gastrointestinal diseases and in obese and type 2 diabetic mice. Eradication of H.typhlonius in young conventional mice by antibiotics decreased the number of intestinal tumors. Additional presence of A.muciniphila prior to the antibiotic treatment reduced the tumor number even further. Colonization of pathogen-low FabplCre;Apc (15lox/+) mice with H.typhlonius or A.muciniphila increased the number of intestinal tumors, the thickness of the intestinal mucus layer and A.muciniphila colonization without H.typhlonius increased the density of mucin-producing goblet cells. However, dual colonization with H.typhlonius and A.muciniphila significantly reduced the number of intestinal tumors, the mucus layer thickness and goblet cell density to that of control mice. By global microbiota composition analysis, we found a positive association of A.muciniphila, and of H.typhlonius, and a negative association of unclassified Clostridiales with increased tumor burden. We conclude that A.muciniphila and H.typhlonius can modulate gut microbiota composition and intestinal tumor development in mice.
authors: Celia
authors: C
authors: Dingemanse
authors: Laboratory of Microbiology, Wageningen University 6703 HB, Wageningen, The Netherlands.
authors: Clara
authors: C
authors: Belzer
authors: Centre for Molecular and Biomolecular Informatics Bacterial Genomics, Radboud University Medical Centre 6525 GA, Nijmegen, The Netherlands, NIZO Food Research BV 6718 ZB, Ede, The Netherlands.
authors: Sacha A F T
authors: SA
authors: van Hijum
authors: Marie
authors: M
authors: Günthel
authors: Department of Anatomy and Embryology, Central Animal Facility and.
authors: Daniela
authors: D
authors: Salvatori
authors: Johan T
authors: JT
authors: den Dunnen
authors: Department of Medical Microbiology, Leiden University Medical Center 2300 RC, Leiden, The Netherlands and.
authors: Ed J
authors: EJ
authors: Kuijper
authors: Peter
authors: P
authors: Devilee
authors: Laboratory of Microbiology, Wageningen University 6703 HB, Wageningen, The Netherlands, Department of Veterinary Biosciences, University of Helsinki 00014, Helsinki, Finland.
authors: Willem M
authors: WM
authors: de Vos
authors: GertJan B
authors: GB
authors: van Ommen
authors: Els C
authors: EC
authors: Robanus-Maandag
mesh_terms: D000658:Amoxicillin / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D063646:Carcinogenesis; D017291:Clarithromycin / Q000494:pharmacology; D004359:Drug Therapy, Combination; D005260:Female; D000069196:Gastrointestinal Microbiome; D020397:Goblet Cells / Q000382:microbiology; D016998:Helicobacter / Q000187:drug effects*; D016481:Helicobacter Infections / Q000150:complications* / Q000188:drug therapy; D007414:Intestinal Neoplasms / Q000382:microbiology* / Q000517:prevention & control; D007422:Intestines / Q000382:microbiology / Q000473:pathology; D008297:Male; D008795:Metronidazole / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D009853:Omeprazole / Q000494:pharmacology; D061327:Verrucomicrobia / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D008795:Metronidazole; D000658:Amoxicillin; D017291:Clarithromycin; D009853:Omeprazole