Gut microbial alterations associated with protection from autoimmune uveitis

Yukiko K. Nakamura, Christina Metea, Lisa Karstens, Mark Asquith, Henry Gruner, Cathleen Moscibrocki, Iris Lee, Colin J. Brislawn, Janet K. Jansson, James (Jim) Rosenbaum, Phoebe Lin

Research output: Contribution to journalArticle

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Abstract

PURPOSE. To investigate the contribution of the gut microbiota to the pathogenesis of uveitis. METHODS. Experimental autoimmune uveitis (EAU) in B10.RIII mice was induced using interphotoreceptor binding protein peptide. Mice were treated with oral or intraperitoneal (IP) antibiotics. Effector (Teff) and regulatory (Treg) T lymphocytes were identified using flow cytometry; 16S rRNA gene sequencing and qPCR were performed on gastrointestinal (GI) contents. RESULTS. Broad-spectrum (four antibiotics given simultaneously) oral, but not IP, antibiotics reduced mean uveitis clinical scores significantly compared with water-treated animals (0.5 vs. 3.0, P < 0.0001 for oral; 3.4 vs. 3.4, P > 0.99 for IP). Both oral metronidazole (P = 0.02) and vancomycin (P < 0.0001) alone decreased inflammation, whereas neomycin (P = 0.7) and ampicillin (P = 0.4) did not change mean uveitis scores. Oral broad-spectrum antibiotics increased Tregs in the GI lamina propria of EAU animals at 1 week, and in extraintestinal lymphoid tissues later, whereas Teff and inflammatory cytokines were reduced. 16S sequencing of GI contents revealed altered microbiota in immunized mice compared with nonimmunized mice, and microbial diversity clustering in EAU mice treated with uveitisprotective antibiotics. Experimental autoimmune uveitis mice also demonstrated gut microbial diversity clustering associated with clinical score severity. CONCLUSIONS. Oral antibiotics modulate the severity of inducible EAU by increasing Tregs in the gut and extraintestinal tissues, as well as decreasing effector T cells and cytokines. 16S sequencing suggests that there may be protective and, conversely, potentially uveitogenic, gut microbiota. These findings may lead to a better understanding of how uveitis can be treated or prevented by modulating the gut microbiome.

Original languageEnglish (US)
Pages (from-to)3747-3758
Number of pages12
JournalInvestigative Ophthalmology and Visual Science
Volume57
Issue number8
DOIs
StatePublished - Jul 1 2016

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Uveitis
Anti-Bacterial Agents
Eragrostis
Gastrointestinal Contents
Cluster Analysis
Cytokines
Neomycin
Microbiota
Metronidazole
Lymphoid Tissue
Regulatory T-Lymphocytes
Vancomycin
Ampicillin
rRNA Genes
Carrier Proteins
Flow Cytometry
Mucous Membrane
Inflammation
T-Lymphocytes
Peptides

Keywords

  • Antibiotics
  • Microbiome
  • Regulatory T cells
  • Uveitis

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Gut microbial alterations associated with protection from autoimmune uveitis. / Nakamura, Yukiko K.; Metea, Christina; Karstens, Lisa; Asquith, Mark; Gruner, Henry; Moscibrocki, Cathleen; Lee, Iris; Brislawn, Colin J.; Jansson, Janet K.; Rosenbaum, James (Jim); Lin, Phoebe.

In: Investigative Ophthalmology and Visual Science, Vol. 57, No. 8, 01.07.2016, p. 3747-3758.

Research output: Contribution to journalArticle

Nakamura, Yukiko K. ; Metea, Christina ; Karstens, Lisa ; Asquith, Mark ; Gruner, Henry ; Moscibrocki, Cathleen ; Lee, Iris ; Brislawn, Colin J. ; Jansson, Janet K. ; Rosenbaum, James (Jim) ; Lin, Phoebe. / Gut microbial alterations associated with protection from autoimmune uveitis. In: Investigative Ophthalmology and Visual Science. 2016 ; Vol. 57, No. 8. pp. 3747-3758.
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abstract = "PURPOSE. To investigate the contribution of the gut microbiota to the pathogenesis of uveitis. METHODS. Experimental autoimmune uveitis (EAU) in B10.RIII mice was induced using interphotoreceptor binding protein peptide. Mice were treated with oral or intraperitoneal (IP) antibiotics. Effector (Teff) and regulatory (Treg) T lymphocytes were identified using flow cytometry; 16S rRNA gene sequencing and qPCR were performed on gastrointestinal (GI) contents. RESULTS. Broad-spectrum (four antibiotics given simultaneously) oral, but not IP, antibiotics reduced mean uveitis clinical scores significantly compared with water-treated animals (0.5 vs. 3.0, P < 0.0001 for oral; 3.4 vs. 3.4, P > 0.99 for IP). Both oral metronidazole (P = 0.02) and vancomycin (P < 0.0001) alone decreased inflammation, whereas neomycin (P = 0.7) and ampicillin (P = 0.4) did not change mean uveitis scores. Oral broad-spectrum antibiotics increased Tregs in the GI lamina propria of EAU animals at 1 week, and in extraintestinal lymphoid tissues later, whereas Teff and inflammatory cytokines were reduced. 16S sequencing of GI contents revealed altered microbiota in immunized mice compared with nonimmunized mice, and microbial diversity clustering in EAU mice treated with uveitisprotective antibiotics. Experimental autoimmune uveitis mice also demonstrated gut microbial diversity clustering associated with clinical score severity. CONCLUSIONS. Oral antibiotics modulate the severity of inducible EAU by increasing Tregs in the gut and extraintestinal tissues, as well as decreasing effector T cells and cytokines. 16S sequencing suggests that there may be protective and, conversely, potentially uveitogenic, gut microbiota. These findings may lead to a better understanding of how uveitis can be treated or prevented by modulating the gut microbiome.",
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AU - Karstens, Lisa

AU - Asquith, Mark

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AU - Moscibrocki, Cathleen

AU - Lee, Iris

AU - Brislawn, Colin J.

AU - Jansson, Janet K.

AU - Rosenbaum, James (Jim)

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N2 - PURPOSE. To investigate the contribution of the gut microbiota to the pathogenesis of uveitis. METHODS. Experimental autoimmune uveitis (EAU) in B10.RIII mice was induced using interphotoreceptor binding protein peptide. Mice were treated with oral or intraperitoneal (IP) antibiotics. Effector (Teff) and regulatory (Treg) T lymphocytes were identified using flow cytometry; 16S rRNA gene sequencing and qPCR were performed on gastrointestinal (GI) contents. RESULTS. Broad-spectrum (four antibiotics given simultaneously) oral, but not IP, antibiotics reduced mean uveitis clinical scores significantly compared with water-treated animals (0.5 vs. 3.0, P < 0.0001 for oral; 3.4 vs. 3.4, P > 0.99 for IP). Both oral metronidazole (P = 0.02) and vancomycin (P < 0.0001) alone decreased inflammation, whereas neomycin (P = 0.7) and ampicillin (P = 0.4) did not change mean uveitis scores. Oral broad-spectrum antibiotics increased Tregs in the GI lamina propria of EAU animals at 1 week, and in extraintestinal lymphoid tissues later, whereas Teff and inflammatory cytokines were reduced. 16S sequencing of GI contents revealed altered microbiota in immunized mice compared with nonimmunized mice, and microbial diversity clustering in EAU mice treated with uveitisprotective antibiotics. Experimental autoimmune uveitis mice also demonstrated gut microbial diversity clustering associated with clinical score severity. CONCLUSIONS. Oral antibiotics modulate the severity of inducible EAU by increasing Tregs in the gut and extraintestinal tissues, as well as decreasing effector T cells and cytokines. 16S sequencing suggests that there may be protective and, conversely, potentially uveitogenic, gut microbiota. These findings may lead to a better understanding of how uveitis can be treated or prevented by modulating the gut microbiome.

AB - PURPOSE. To investigate the contribution of the gut microbiota to the pathogenesis of uveitis. METHODS. Experimental autoimmune uveitis (EAU) in B10.RIII mice was induced using interphotoreceptor binding protein peptide. Mice were treated with oral or intraperitoneal (IP) antibiotics. Effector (Teff) and regulatory (Treg) T lymphocytes were identified using flow cytometry; 16S rRNA gene sequencing and qPCR were performed on gastrointestinal (GI) contents. RESULTS. Broad-spectrum (four antibiotics given simultaneously) oral, but not IP, antibiotics reduced mean uveitis clinical scores significantly compared with water-treated animals (0.5 vs. 3.0, P < 0.0001 for oral; 3.4 vs. 3.4, P > 0.99 for IP). Both oral metronidazole (P = 0.02) and vancomycin (P < 0.0001) alone decreased inflammation, whereas neomycin (P = 0.7) and ampicillin (P = 0.4) did not change mean uveitis scores. Oral broad-spectrum antibiotics increased Tregs in the GI lamina propria of EAU animals at 1 week, and in extraintestinal lymphoid tissues later, whereas Teff and inflammatory cytokines were reduced. 16S sequencing of GI contents revealed altered microbiota in immunized mice compared with nonimmunized mice, and microbial diversity clustering in EAU mice treated with uveitisprotective antibiotics. Experimental autoimmune uveitis mice also demonstrated gut microbial diversity clustering associated with clinical score severity. CONCLUSIONS. Oral antibiotics modulate the severity of inducible EAU by increasing Tregs in the gut and extraintestinal tissues, as well as decreasing effector T cells and cytokines. 16S sequencing suggests that there may be protective and, conversely, potentially uveitogenic, gut microbiota. These findings may lead to a better understanding of how uveitis can be treated or prevented by modulating the gut microbiome.

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KW - Regulatory T cells

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