Abstract
Gut microbial dysbiosis is associated with the development of autoimmune disease, but the mechanisms by which microbial dysbiosis affects the transition from asymptomatic autoimmunity to inflammatory disease are incompletely characterized. Here, we identify intestinal barrier integrity as an important checkpoint in translating autoimmunity to inflammation. Zonulin family peptide (zonulin), a potent regulator for intestinal tight junctions, is highly expressed in autoimmune mice and humans and can be used to predict transition from autoimmunity to inflammatory arthritis. Increased serum zonulin levels are accompanied by a leaky intestinal barrier, dysbiosis and inflammation. Restoration of the intestinal barrier in the pre-phase of arthritis using butyrate or a cannabinoid type 1 receptor agonist inhibits the development of arthritis. Moreover, treatment with the zonulin antagonist larazotide acetate, which specifically increases intestinal barrier integrity, effectively reduces arthritis onset. These data identify a preventive approach for the onset of autoimmune disease by specifically targeting impaired intestinal barrier function.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Animals
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Arthritis, Experimental / blood
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Arthritis, Experimental / immunology
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Arthritis, Experimental / microbiology
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Arthritis, Experimental / prevention & control
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Arthritis, Rheumatoid / blood
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Arthritis, Rheumatoid / immunology
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Arthritis, Rheumatoid / microbiology
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Arthritis, Rheumatoid / prevention & control*
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Bacterial Translocation / drug effects
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Bacterial Translocation / immunology
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Caco-2 Cells
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Cell Membrane Permeability / drug effects*
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Cell Membrane Permeability / immunology
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Cohort Studies
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Cross-Sectional Studies
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Dysbiosis / complications*
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Dysbiosis / immunology
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Dysbiosis / microbiology
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Female
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Gastrointestinal Microbiome / immunology
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Haptoglobins / antagonists & inhibitors*
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Haptoglobins / metabolism
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Healthy Volunteers
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Humans
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Ileum / cytology
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Ileum / drug effects
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Ileum / microbiology
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Ileum / pathology
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Intestinal Mucosa / cytology
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Intestinal Mucosa / drug effects*
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Intestinal Mucosa / microbiology
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Intestinal Mucosa / pathology
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Male
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Mice
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Middle Aged
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Oligopeptides / administration & dosage*
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Protein Precursors / antagonists & inhibitors*
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Protein Precursors / blood
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Protein Precursors / metabolism
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Tight Junctions / drug effects
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Tight Junctions / metabolism
Substances
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Haptoglobins
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Oligopeptides
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Protein Precursors
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zonulin
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larazotide acetate