title: Dietary modulation of the microbiome affects autoinflammatory disease.
abstract: The incidences of chronic inflammatory disorders have increased considerably over the past three decades. Recent shifts in dietary consumption may have contributed importantly to this surge, but how dietary consumption modulates inflammatory disease is poorly defined. Pstpip2(cmo) mice, which express a homozygous Leu98Pro missense mutation in the Pombe Cdc15 homology family protein PSTPIP2 (proline-serine-threonine phosphatase interacting protein 2), spontaneously develop osteomyelitis that resembles chronic recurrent multifocal osteomyelitis in humans. Recent reports demonstrated a crucial role for interleukin-1β (IL-1β) in osteomyelitis, but deletion of the inflammasome components caspase-1 and NLRP3 failed to rescue Pstpip2(cmo) mice from inflammatory bone disease. Thus, the upstream mechanisms controlling IL-1β production in Pstpip2(cmo) mice remain to be identified. In addition, the environmental factors driving IL-1β-dependent inflammatory bone erosion are unknown. Here we show that the intestinal microbiota of diseased Pstpip2(cmo) mice was characterized by an outgrowth of Prevotella. Notably, Pstpip2(cmo) mice that were fed a diet rich in fat and cholesterol maintained a normal body weight, but were markedly protected against inflammatory bone disease and bone erosion. Diet-induced protection against osteomyelitis was accompanied by marked reductions in intestinal Prevotella levels and significantly reduced pro-IL-1β expression in distant neutrophils. Furthermore, pro-IL-1β expression was also decreased in Pstpip2(cmo) mice treated with antibiotics, and in wild-type mice that were kept under germ-free conditions. We further demonstrate that combined deletion of caspases 1 and 8 was required for protection against IL-1β-dependent inflammatory bone disease, whereas the deletion of either caspase alone or of elastase or neutrophil proteinase 3 failed to prevent inflammatory disease. Collectively, this work reveals diet-associated changes in the intestinal microbiome as a crucial factor regulating inflammasome- and caspase-8-mediated maturation of IL-1β and osteomyelitis in Pstpip2(cmo) mice.
authors.affiliation: Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Lukens
authors.affiliation: Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Prajwal
authors.initials: P
authors.lastname: Gurung
authors.affiliation: Animal Resources Center and the Veterinary Pathology Core, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.affiliation: Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Gordon R
authors.initials: GR
authors.lastname: Johnson
authors.affiliation: Hartwell Center for Bioinformatics and Biotechnology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Carter
authors.affiliation: Hartwell Center for Bioinformatics and Biotechnology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: McGoldrick
authors.affiliation: Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Srinivasa Rao
authors.initials: SR
authors.lastname: Bandi
authors.affiliation: Small Animal Imaging Core, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Calabrese
authors.affiliation: 1] Department of Medical Protein Research, VIB, B-9000 Ghent, Belgium [2] Department of Biochemistry, Ghent University, B-9000 Ghent, Belgium.
authors.forename: Lieselotte
authors.initials: L
authors.lastname: Vande Walle
authors.affiliation: 1] Department of Medical Protein Research, VIB, B-9000 Ghent, Belgium [2] Department of Biochemistry, Ghent University, B-9000 Ghent, Belgium.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Lamkanfi
authors.affiliation: Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D020170:Caspase 1 / Q000172:deficiency / Q000235:genetics; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005260:Female; D058847:Inflammasomes / Q000378:metabolism; D007249:Inflammation / Q000178:diet therapy / Q000473:pathology; D053583:Interleukin-1beta / Q000097:blood / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D064307:Microbiota / Q000187:drug effects*; D053146:Myeloblastin / Q000172:deficiency; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010019:Osteomyelitis / Q000178:diet therapy* / Q000473:pathology*; D010196:Pancreatic Elastase / Q000172:deficiency; D018720:Prevotella / Q000254:growth & development / Q000302:isolation & purification
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; C486383:Pstpip2 protein, mouse; D002784:Cholesterol; D010196:Pancreatic Elastase; D053146:Myeloblastin; D053181:Caspase 8; D020170:Caspase 1