title: NLRP12 attenuates colon inflammation by maintaining colonic microbial diversity and promoting protective commensal bacterial growth.
abstract: Inflammatory bowel diseases involve the dynamic interaction of host genetics, the microbiome and inflammatory responses. Here we found lower expression of NLRP12 (which encodes a negative regulator of innate immunity) in human ulcerative colitis, by comparing monozygotic twins and other patient cohorts. In parallel, Nlrp12 deficiency in mice caused increased basal colonic inflammation, which led to a less-diverse microbiome and loss of protective gut commensal strains (of the family Lachnospiraceae) and a greater abundance of colitogenic strains (of the family Erysipelotrichaceae). Dysbiosis and susceptibility to colitis associated with Nlrp12 deficency were reversed equally by treatment with antibodies targeting inflammatory cytokines and by the administration of beneficial commensal Lachnospiraceae isolates. Fecal transplants from mice reared in specific-pathogen-free conditions into germ-free Nlrp12-deficient mice showed that NLRP12 and the microbiome each contributed to immunological signaling that culminated in colon inflammation. These findings reveal a feed-forward loop in which NLRP12 promotes specific commensals that can reverse gut inflammation, while cytokine blockade during NLRP12 deficiency can reverse dysbiosis.
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.|Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Justin E
authors.initials: JE
authors.lastname: Wilson
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Koenigsknecht
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Wei-Chun
authors.initials: WC
authors.lastname: Chou
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.|Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Montgomery
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.|Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Agnieszka D
authors.initials: AD
authors.lastname: Truax
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: W June
authors.initials: WJ
authors.lastname: Brickey
authors.affiliation: Division of Digestive and Liver Diseases, Columbia University Medical Center, New York, New York, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Packey
authors.affiliation: Department of Gastroenterology, Tel-Aviv Sourasky Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Nitsan
authors.initials: N
authors.lastname: Maharshak
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA.|UNC Neuroscience Center and Integrative Program for Biological Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Glenn K
authors.initials: GK
authors.lastname: Matsushima
authors.affiliation: Immunology Research and Development, Janssen Pharmaceuticals, Spring House, Pennsylvania, USA.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Plevy
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Vincent B
authors.initials: VB
authors.lastname: Young
authors.affiliation: Center for Gastrointestinal Biology and Disease and the Departments of Medicine, of Microbiology and of Immunology, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: R Balfour
authors.initials: RB
authors.lastname: Sartor
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.|Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Jenny P-Y
authors.initials: JP
authors.lastname: Ting
mesh_terms: D000818:Animals; D044822:Biodiversity; D000068016:Eubacteriales / Q000502:physiology*; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000276:immunology* / Q000382:microbiology; D003106:Colon / Q000382:microbiology / Q000502:physiology*; D016264:Dextran Sulfate; D005243:Feces / Q000382:microbiology; D000068536:Bacillota / Q000502:physiology*; D059647:Gene-Environment Interaction; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064307:Microbiota / Q000235:genetics / Q000276:immunology; D012336:RNA, Ribosomal, 16S / Q000032:analysis*; D013559:Symbiosis; D014430:Twins, Monozygotic
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C553199:NLRP12 protein, mouse; D012336:RNA, Ribosomal, 16S; D016264:Dextran Sulfate