Antibiotics induce sustained dysregulation of intestinal T cell immunity by perturbing macrophage homeostasis

Nicholas A. Scott, Anna Andrusaite, Peter Andersen, Melissa Lawson, Cristina Alcon-Giner, Charlotte Leclaire, Shabhonam Caim, Gwenaelle Le Gall, Tovah Shaw, James P.R. Connolly, Andrew J. Roe, Hannah Wessel, Alberto Bravo-Blas, Carolyn A. Thomson, Verena Kästele, Ping Wang, Daniel A. Peterson, Allison Bancroft, Xuhang Li, Richard Grencis & 5 others Allan McI Mowat, Lindsay J. Hall, Mark A. Travis, Simon W.F. Milling, Elizabeth R. Mann

Research output: Contribution to journalArticle

Abstract

Macrophages in the healthy intestine are highly specialized and usually respond to the gut microbiota without provoking an inflammatory response. A breakdown in this tolerance leads to inflammatory bowel disease (IBD), but the mechanisms by which intestinal macrophages normally become conditioned to promote microbial tolerance are unclear. Strong epidemiological evidence linking disruption of the gut microbiota by antibiotic use early in life to IBD indicates an important role for the gut microbiota in modulating intestinal immunity. Here, we show that antibiotic use causes intestinal macrophages to become hyperresponsive to bacterial stimulation, producing excess inflammatory cytokines. Re-exposure of antibiotic-treated mice to conventional microbiota induced a long-term, macrophage-dependent increase in inflammatory T helper 1 (TH1) responses in the colon and sustained dysbiosis. The consequences of this dysregulated macrophage activity for T cell function were demonstrated by increased susceptibility to infections requiring TH17 and TH2 responses for clearance (bacterial Citrobacter rodentium and helminth Trichuris muris infections), corresponding with increased inflammation. Short-chain fatty acids (SCFAs) were depleted during antibiotic administration; supplementation of antibiotics with the SCFA butyrate restored the characteristic hyporesponsiveness of intestinal macrophages and prevented T cell dysfunction. Butyrate altered the metabolic behavior of macrophages to increase oxidative phosphorylation and also promoted alternative macrophage activation. In summary, the gut microbiota is essential to maintain macrophage-dependent intestinal immune homeostasis, mediated by SCFA-dependent pathways. Oral antibiotics disrupt this process to promote sustained T cell-mediated dysfunction and increased susceptibility to infections, highlighting important implications of repeated broad-spectrum antibiotic use.

Original languageEnglish (US)
Article numbereaao4755
JournalScience Translational Medicine
Volume10
Issue number464
DOIs
StatePublished - Oct 24 2018

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Immunity
Homeostasis
Macrophages
Anti-Bacterial Agents
T-Lymphocytes
Volatile Fatty Acids
Butyrates
Inflammatory Bowel Diseases
Citrobacter rodentium
Infection
Dysbiosis
Trichuris
Macrophage Activation
Helminths
Microbiota
Oxidative Phosphorylation
Intestines
Colon
Cytokines
Inflammation

ASJC Scopus subject areas

  • Medicine(all)

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Antibiotics induce sustained dysregulation of intestinal T cell immunity by perturbing macrophage homeostasis. / Scott, Nicholas A.; Andrusaite, Anna; Andersen, Peter; Lawson, Melissa; Alcon-Giner, Cristina; Leclaire, Charlotte; Caim, Shabhonam; Le Gall, Gwenaelle; Shaw, Tovah; Connolly, James P.R.; Roe, Andrew J.; Wessel, Hannah; Bravo-Blas, Alberto; Thomson, Carolyn A.; Kästele, Verena; Wang, Ping; Peterson, Daniel A.; Bancroft, Allison; Li, Xuhang; Grencis, Richard; McI Mowat, Allan; Hall, Lindsay J.; Travis, Mark A.; Milling, Simon W.F.; Mann, Elizabeth R.

In: Science Translational Medicine, Vol. 10, No. 464, eaao4755, 24.10.2018.

Research output: Contribution to journalArticle

Scott, NA, Andrusaite, A, Andersen, P, Lawson, M, Alcon-Giner, C, Leclaire, C, Caim, S, Le Gall, G, Shaw, T, Connolly, JPR, Roe, AJ, Wessel, H, Bravo-Blas, A, Thomson, CA, Kästele, V, Wang, P, Peterson, DA, Bancroft, A, Li, X, Grencis, R, McI Mowat, A, Hall, LJ, Travis, MA, Milling, SWF & Mann, ER 2018, 'Antibiotics induce sustained dysregulation of intestinal T cell immunity by perturbing macrophage homeostasis', Science Translational Medicine, vol. 10, no. 464, eaao4755. https://doi.org/10.1126/scitranslmed.aao4755
Scott, Nicholas A. ; Andrusaite, Anna ; Andersen, Peter ; Lawson, Melissa ; Alcon-Giner, Cristina ; Leclaire, Charlotte ; Caim, Shabhonam ; Le Gall, Gwenaelle ; Shaw, Tovah ; Connolly, James P.R. ; Roe, Andrew J. ; Wessel, Hannah ; Bravo-Blas, Alberto ; Thomson, Carolyn A. ; Kästele, Verena ; Wang, Ping ; Peterson, Daniel A. ; Bancroft, Allison ; Li, Xuhang ; Grencis, Richard ; McI Mowat, Allan ; Hall, Lindsay J. ; Travis, Mark A. ; Milling, Simon W.F. ; Mann, Elizabeth R. / Antibiotics induce sustained dysregulation of intestinal T cell immunity by perturbing macrophage homeostasis. In: Science Translational Medicine. 2018 ; Vol. 10, No. 464.
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abstract = "Macrophages in the healthy intestine are highly specialized and usually respond to the gut microbiota without provoking an inflammatory response. A breakdown in this tolerance leads to inflammatory bowel disease (IBD), but the mechanisms by which intestinal macrophages normally become conditioned to promote microbial tolerance are unclear. Strong epidemiological evidence linking disruption of the gut microbiota by antibiotic use early in life to IBD indicates an important role for the gut microbiota in modulating intestinal immunity. Here, we show that antibiotic use causes intestinal macrophages to become hyperresponsive to bacterial stimulation, producing excess inflammatory cytokines. Re-exposure of antibiotic-treated mice to conventional microbiota induced a long-term, macrophage-dependent increase in inflammatory T helper 1 (TH1) responses in the colon and sustained dysbiosis. The consequences of this dysregulated macrophage activity for T cell function were demonstrated by increased susceptibility to infections requiring TH17 and TH2 responses for clearance (bacterial Citrobacter rodentium and helminth Trichuris muris infections), corresponding with increased inflammation. Short-chain fatty acids (SCFAs) were depleted during antibiotic administration; supplementation of antibiotics with the SCFA butyrate restored the characteristic hyporesponsiveness of intestinal macrophages and prevented T cell dysfunction. Butyrate altered the metabolic behavior of macrophages to increase oxidative phosphorylation and also promoted alternative macrophage activation. In summary, the gut microbiota is essential to maintain macrophage-dependent intestinal immune homeostasis, mediated by SCFA-dependent pathways. Oral antibiotics disrupt this process to promote sustained T cell-mediated dysfunction and increased susceptibility to infections, highlighting important implications of repeated broad-spectrum antibiotic use.",
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T1 - Antibiotics induce sustained dysregulation of intestinal T cell immunity by perturbing macrophage homeostasis

AU - Scott, Nicholas A.

AU - Andrusaite, Anna

AU - Andersen, Peter

AU - Lawson, Melissa

AU - Alcon-Giner, Cristina

AU - Leclaire, Charlotte

AU - Caim, Shabhonam

AU - Le Gall, Gwenaelle

AU - Shaw, Tovah

AU - Connolly, James P.R.

AU - Roe, Andrew J.

AU - Wessel, Hannah

AU - Bravo-Blas, Alberto

AU - Thomson, Carolyn A.

AU - Kästele, Verena

AU - Wang, Ping

AU - Peterson, Daniel A.

AU - Bancroft, Allison

AU - Li, Xuhang

AU - Grencis, Richard

AU - McI Mowat, Allan

AU - Hall, Lindsay J.

AU - Travis, Mark A.

AU - Milling, Simon W.F.

AU - Mann, Elizabeth R.

PY - 2018/10/24

Y1 - 2018/10/24

N2 - Macrophages in the healthy intestine are highly specialized and usually respond to the gut microbiota without provoking an inflammatory response. A breakdown in this tolerance leads to inflammatory bowel disease (IBD), but the mechanisms by which intestinal macrophages normally become conditioned to promote microbial tolerance are unclear. Strong epidemiological evidence linking disruption of the gut microbiota by antibiotic use early in life to IBD indicates an important role for the gut microbiota in modulating intestinal immunity. Here, we show that antibiotic use causes intestinal macrophages to become hyperresponsive to bacterial stimulation, producing excess inflammatory cytokines. Re-exposure of antibiotic-treated mice to conventional microbiota induced a long-term, macrophage-dependent increase in inflammatory T helper 1 (TH1) responses in the colon and sustained dysbiosis. The consequences of this dysregulated macrophage activity for T cell function were demonstrated by increased susceptibility to infections requiring TH17 and TH2 responses for clearance (bacterial Citrobacter rodentium and helminth Trichuris muris infections), corresponding with increased inflammation. Short-chain fatty acids (SCFAs) were depleted during antibiotic administration; supplementation of antibiotics with the SCFA butyrate restored the characteristic hyporesponsiveness of intestinal macrophages and prevented T cell dysfunction. Butyrate altered the metabolic behavior of macrophages to increase oxidative phosphorylation and also promoted alternative macrophage activation. In summary, the gut microbiota is essential to maintain macrophage-dependent intestinal immune homeostasis, mediated by SCFA-dependent pathways. Oral antibiotics disrupt this process to promote sustained T cell-mediated dysfunction and increased susceptibility to infections, highlighting important implications of repeated broad-spectrum antibiotic use.

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