Matei, DE;
Menon, M;
Alber, DG;
Smith, AM;
Nedjat-Shokouhi, B;
Fasano, A;
Magill, L;
... Mauri, C; + view all
(2021)
Intestinal barrier dysfunction plays an integral role in arthritis pathology and can be targeted to ameliorate disease.
Med
10.1016/j.medj.2021.04.013.
(In press).
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Abstract
Background: Evidence suggests an important role for gut-microbiota dysbiosis in the development of rheumatoid arthritis (RA). The link between changes in gut bacteria and the development of joint inflammation is missing. Here, we address whether there are changes to the gut environment and how they contribute to arthritis pathogenesis. Methods: We analyzed changes in markers of gut permeability, damage, and inflammation in peripheral blood and serum of RA patients. Serum, intestines, and lymphoid organs isolated from K/BxN mice with spontaneous arthritis or from wild-type, genetically modified interleukin (IL)-10R−/− or claudin-8−/− mice with induced arthritis were analyzed by immunofluorescence/histology, ELISA, and flow cytometry. Findings: RA patients display increased levels of serum markers of gut permeability and damage and cellular gut-homing markers, both parameters positively correlating with disease severity. Arthritic mice display increased gut permeability from early stages of disease, as well as bacterial translocation, inflammatory gut damage, increases in interferon γ (IFNγ)+ and decreases in IL-10+ intestinal-infiltrating leukocyte frequency, and reduced intestinal epithelial IL-10R expression. Mechanistically, both arthritogenic bacteria and leukocytes are required to disrupt gut-barrier integrity. We show that exposing intestinal organoids to IFNγ reduces IL-10R expression by epithelial cells and that mice lacking epithelial IL-10R display increased intestinal permeability and exacerbated arthritis. Claudin-8−/− mice with constitutively increased gut permeability also develop worse joint disease. Treatment of mice with AT-1001, a molecule that prevents development of gut permeability, ameliorates arthritis. Conclusions: We suggest that breakdown of gut-barrier integrity contributes to arthritis development and propose restoration of gut-barrier homeostasis as a new therapeutic approach for RA.
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