title: Gastrointestinal pathology in juvenile and adult CFTR-knockout ferrets.
abstract: Cystic fibrosis (CF) is a multiorgan disease caused by loss of a functional cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel in many epithelia of the body. Here we report the pathology observed in the gastrointestinal organs of juvenile to adult CFTR-knockout ferrets. CF gastrointestinal manifestations included gastric ulceration, intestinal bacterial overgrowth with villous atrophy, and rectal prolapse. Metagenomic phylogenetic analysis of fecal microbiota by deep sequencing revealed considerable genotype-independent microbial diversity between animals, with the majority of taxa overlapping between CF and non-CF pairs. CF hepatic manifestations were variable, but included steatosis, necrosis, biliary hyperplasia, and biliary fibrosis. Gallbladder cystic mucosal hyperplasia was commonly found in 67% of CF animals. The majority of CF animals (85%) had pancreatic abnormalities, including extensive fibrosis, loss of exocrine pancreas, and islet disorganization. Interestingly, 2 of 13 CF animals retained predominantly normal pancreatic histology (84% to 94%) at time of death. Fecal elastase-1 levels from these CF animals were similar to non-CF controls, whereas all other CF animals evaluated were pancreatic insufficient (<2 μg elastase-1 per gram of feces). These findings suggest that genetic factors likely influence the extent of exocrine pancreas disease in CF ferrets and have implications for the etiology of pancreatic sufficiency in CF patients. In summary, these studies demonstrate that the CF ferret model develops gastrointestinal pathology similar to CF patients.
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa.
authors.forename: Xingshen
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Pathology, University of Iowa, Iowa City, Iowa.
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Olivier
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa.
authors.forename: Yaling
authors.initials: Y
authors.lastname: Yi
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington; Department of Microbiology, University of Washington, Seattle, Washington.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Pope
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington.
authors.forename: Hillary S
authors.initials: HS
authors.lastname: Hayden
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa.
authors.forename: Bo
authors.initials: B
authors.lastname: Liang
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa.
authors.forename: Hongshu
authors.initials: H
authors.lastname: Sui
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa.
authors.forename: Weihong
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington.
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Hager
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa.
authors.forename: Ziying
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa.
authors.forename: John T
authors.initials: JT
authors.lastname: Fisher
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Keiser
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa.
authors.forename: Yi
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Tyler
authors.affiliation: Department of Pathology, University of Iowa, Iowa City, Iowa.
authors.forename: J Adam
authors.initials: JA
authors.lastname: Goeken
authors.affiliation: Department of Veterinary Diagnostic & Production Animal Medicine, College of Veterinary Medicine, Iowa State University, Ames, Iowa.
authors.forename: Joann M
authors.initials: JM
authors.lastname: Kinyon
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Radey
authors.affiliation: Department of Veterinary Diagnostic & Production Animal Medicine, College of Veterinary Medicine, Iowa State University, Ames, Iowa.
authors.forename: Danielle
authors.initials: D
authors.lastname: Fligg
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Xie
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Lynch
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Kaminsky
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington.
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Brittnacher
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington; Department of Genome Sciences, University of Washington, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington.
authors.forename: Samuel I
authors.initials: SI
authors.lastname: Miller
authors.affiliation: Department of Cardiothoracic Surgery, University of Iowa, Iowa City, Iowa.
authors.forename: Kalpaj
authors.initials: K
authors.lastname: Parekh
authors.affiliation: Department of Pathology, University of Iowa, Iowa City, Iowa.
authors.forename: David K
authors.initials: DK
authors.lastname: Meyerholz
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington; Department of Microbiology, University of Washington, Seattle, Washington.
authors.forename: Lucas R
authors.initials: LR
authors.lastname: Hoffman
authors.affiliation: Department of Veterinary Diagnostic & Production Animal Medicine, College of Veterinary Medicine, Iowa State University, Ames, Iowa.
authors.forename: Timothy
authors.initials: T
authors.lastname: Frana
authors.affiliation: Department of Surgery, University of Iowa, Iowa City, Iowa.
authors.forename: Zoe A
authors.initials: ZA
authors.lastname: Stewart
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa. Electronic address: john-engelhardt@uiowa.edu.
authors.forename: John F
authors.initials: JF
authors.lastname: Engelhardt
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D001284:Atrophy; D001419:Bacteria / Q000254:growth & development; D003550:Cystic Fibrosis / Q000382:microbiology / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000172:deficiency* / Q000378:metabolism; D005289:Ferrets; D041981:Gastrointestinal Tract / Q000002:abnormalities / Q000473:pathology*; D055786:Gene Knockout Techniques; D006801:Humans; D009093:Mucus / Q000378:metabolism; D009928:Organ Specificity
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator