Early-life antibiotic treatment enhances the pathogenicity of CD4+ T cells during intestinal inflammation

Sebastian Scheer, Tiago S. Medina, Alex Murison, Matthew D. Taves, Frann Antignano, Alistair L Chenery, Kiran K. Soma, Georgia Perona-Wright, Mathieu Lupien, Cheryl H Arrowsmith, Daniel R. Carvalho, Colby Zaph

Research output: Contribution to journalArticleResearchpeer-review

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 in Rag1-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 into Rag1-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.

Original languageEnglish
Pages (from-to)893-900
Number of pages8
JournalJournal of leukocyte biology
Volume101
Issue number4
DOIs
Publication statusPublished - 1 Apr 2017

Keywords

  • Antibiotics
  • Corticosterone
  • Inflammatory bowel disease
  • Mouse model
  • Stress

Cite this

Scheer, Sebastian ; Medina, Tiago S. ; Murison, Alex ; Taves, Matthew D. ; Antignano, Frann ; Chenery, Alistair L ; Soma, Kiran K. ; Perona-Wright, Georgia ; Lupien, Mathieu ; Arrowsmith, Cheryl H ; Carvalho, Daniel R. ; Zaph, Colby. / Early-life antibiotic treatment enhances the pathogenicity of CD4+ T cells during intestinal inflammation. In: Journal of leukocyte biology. 2017 ; Vol. 101, No. 4. pp. 893-900.
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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 in Rag1-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 into Rag1-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.",
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author = "Sebastian Scheer and Medina, {Tiago S.} and Alex Murison and Taves, {Matthew D.} and Frann Antignano and Chenery, {Alistair L} and Soma, {Kiran K.} and Georgia Perona-Wright and Mathieu Lupien and Arrowsmith, {Cheryl H} and Carvalho, {Daniel R.} and Colby Zaph",
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Scheer, S, Medina, TS, Murison, A, Taves, MD, Antignano, F, Chenery, AL, Soma, KK, Perona-Wright, G, Lupien, M, Arrowsmith, CH, Carvalho, DR & Zaph, C 2017, 'Early-life antibiotic treatment enhances the pathogenicity of CD4+ T cells during intestinal inflammation' Journal of leukocyte biology, vol. 101, no. 4, pp. 893-900. https://doi.org/10.1189/jlb.3MA0716-334RR

Early-life antibiotic treatment enhances the pathogenicity of CD4+ T cells during intestinal inflammation. / Scheer, Sebastian; Medina, Tiago S.; Murison, Alex; Taves, Matthew D.; Antignano, Frann; Chenery, Alistair L; Soma, Kiran K.; Perona-Wright, Georgia; Lupien, Mathieu; Arrowsmith, Cheryl H; Carvalho, Daniel R.; Zaph, Colby.

In: Journal of leukocyte biology, Vol. 101, No. 4, 01.04.2017, p. 893-900.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Scheer, Sebastian

AU - Medina, Tiago S.

AU - Murison, Alex

AU - Taves, Matthew D.

AU - Antignano, Frann

AU - Chenery, Alistair L

AU - Soma, Kiran K.

AU - Perona-Wright, Georgia

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AU - Arrowsmith, Cheryl H

AU - Carvalho, Daniel R.

AU - Zaph, Colby

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