title: Early-life antibiotic treatment enhances the pathogenicity of CD4+T cells during intestinal inflammation.
abstract: The incidence of inflammatory bowel diseases (IBDs) has steadily increased in recent decades-a phenomenon that cannot be explained by genetic mutations alone. Other factors, including the composition of the intestinal microbiome, are potentially important contributors to the increased occurrence of this group of diseases. Previous reports have shown a correlation between early-life antibiotic (Abx) treatment and an increased incidence of IBD. In this report, we investigated the effects of early-life Abx treatments on the pathogenicity of CD4+T cells using an experimental T cell transfer model of IBD. Our results show that CD4+T cells isolated from adult mice that had been treated with Abx during gestation and in early life induced a faster onset of IBD inRag1-deficient mice compared with CD4+T cells of untreated mice. Ex vivo functional analyses of IBD-inducing CD4+T cells did not show significant differences in their immunologic potential ex vivo, despite their in vivo phenotype. However, genome-wide gene-expression analysis revealed that these cells displayed dysregulated expression of genes associated with cell-cycle regulation, metabolism, and cellular stress. Analysis of Abx-treated CD4+T cell donors showed systemically elevated levels of the stress hormone corticosterone throughout life compared with untreated donors. The cohousing of Abx-treated mice with untreated mice decreased serum corticosterone, and a consequent transfer of the cells from cohoused mice intoRag1-deficient mice restored the onset and severity of disease to that of untreated animals. Thus, our results suggest that early-life Abx treatment results in a stress response with high levels of corticosterone that influences CD4+T cell function.
authors.affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.|Infection and Immunity Program, Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Scheer
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Tiago S
authors.initials: TS
authors.lastname: Medina
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Alex
authors.initials: A
authors.lastname: Murison
authors.affiliation: Department of Psychology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Taves
authors.affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Frann
authors.initials: F
authors.lastname: Antignano
authors.affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Alistair
authors.initials: A
authors.lastname: Chenery
authors.affiliation: Department of Psychology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Kiran K
authors.initials: KK
authors.lastname: Soma
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Georgia
authors.initials: G
authors.lastname: Perona-Wright
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Ontario, Canada.|Ontario Institute for Cancer Research, Ontario, Canada; and.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lupien
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Ontario, Canada.|Structural Genomics Consortium, University of Toronto, Ontario, Canada.
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: De Carvalho
authors.affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada; colby.zaph@monash.edu.|Infection and Immunity Program, Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Colby
authors.initials: C
authors.lastname: Zaph
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D003345:Corticosterone / Q000097:blood; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D016678:Genome; D006799:Housing, Animal; D007249:Inflammation / Q000097:blood / Q000276:immunology* / Q000473:pathology*; D015212:Inflammatory Bowel Diseases / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology*; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D003345:Corticosterone
keywords: antibiotics; corticosterone; inflammatory bowel disease; mouse model; stress