title: Implication of the intestinal microbiome as a potential surrogate marker of immune responsiveness to experimental therapies in autoimmune diabetes.
abstract: Type 1 diabetes (T1D) is an autoimmune proinflammatory disease with no effective intervention. A major obstacle in developing new immunotherapies for T1D is the lack of means for monitoring immune responsiveness to experimental therapies. The LEW1.WR1 rat develops autoimmunity following infection with the parvovirus Kilham rat virus (KRV) via mechanisms linked with activation of proinflammatory pathways and alterations in the gut bacterial composition. We used this animal to test the hypothesis that intervention with agents that block innate immunity and diabetes is associated with a shift in the gut microbiota. We observed that infection with KRV results in the induction of proinflammatory gene activation in both the spleen and pancreatic lymph nodes. Furthermore, administering animals the histone deacetylase inhibitor ITF-2357 and IL-1 receptor antagonist (Anakinra) induced differential STAT-1 and the p40 unit of IL-12/IL-23 gene expression. Sequencing of bacterial 16S rRNA genes demonstrated that both ITF-2357 and Anakinra alter microbial diversity. ITF-2357 and Anakinra modulated the abundance of 23 and 8 bacterial taxa in KRV-infected animals, respectively, of which 5 overlapped between the two agents. Lastly, principal component analysis implied that ITF-2357 and Anakinra induce distinct gut microbiomes compared with those from untreated animals or rats provided KRV only. Together, the data suggest that ITF-2357 and Anakinra differentially influence the innate immune system and the intestinal microbiota and highlight the potential use of the gut microbiome as a surrogate means of assessing anti-inflammatory immune effects in type 1 diabetes.
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: James C
authors.initials: JC
authors.lastname: Needell
authors.affiliation: Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.affiliation: Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Diana
authors.initials: D
authors.lastname: Ir
authors.affiliation: Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, United States of America.|University of Colorado Microbiome Research Consortium (MiRC), Aurora, Colorado, United States of America.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Robertson
authors.affiliation: Department of Biostatistics and Informatics, Colorado School of Public Health and University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Ryan
authors.affiliation: Department of Biostatistics and Informatics, Colorado School of Public Health and University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Miranda E
authors.initials: ME
authors.lastname: Kroehl
authors.affiliation: Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, United States of America.|University of Colorado Microbiome Research Consortium (MiRC), Aurora, Colorado, United States of America.
authors.forename: Daniel N
authors.initials: DN
authors.lastname: Frank
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Danny
authors.initials: D
authors.lastname: Zipris
mesh_terms: D000818:Animals; D044822:Biodiversity; D015415:Biomarkers / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000382:microbiology / Q000628:therapy*; D005243:Feces / Q000382:microbiology; D059014:High-Throughput Nucleotide Sequencing; D006877:Hydroxamic Acids / Q000494:pharmacology; D007113:Immunity, Innate; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D007422:Intestines / Q000382:microbiology*; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D064307:Microbiota / Q000187:drug effects; D020799:Pancrelipase / Q000187:drug effects / Q000276:immunology; D017992:Parvovirus / Q000472:pathogenicity; D025341:Principal Component Analysis; D012336:RNA, Ribosomal, 16S / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000187:drug effects / Q000276:immunology
chemical_list: D015415:Biomarkers; D006877:Hydroxamic Acids; D053590:Interleukin 1 Receptor Antagonist Protein; D012336:RNA, Ribosomal, 16S; D020799:Pancrelipase; C502418:givinostat hydrochloride