Intestinal barrier dysfunction plays an integral role in arthritis pathology and can be targeted to ameliorate disease

Diana E Matei; Madhvi Menon; Dagmar G Alber; Andrew M Smith; Bahman Nedjat-Shokouhi; Alessio Fasano; Laura Magill; Amanda Duhlin; Samuel Bitoun; Aude Gleizes; Salima Hacein-Bey-Abina; Jessica J Manson; Elizabeth C Rosser; ABIRISK Consortium; Nigel Klein; Paul A Blair; Claudia Mauri

doi:10.1016/j.medj.2021.04.013

Intestinal barrier dysfunction plays an integral role in arthritis pathology and can be targeted to ameliorate disease

Med. 2021 Jul 9;2(7):864-883.e9. doi: 10.1016/j.medj.2021.04.013.

Authors

Diana E Matei¹, Madhvi Menon^{1

2

3

4}, Dagmar G Alber⁵, Andrew M Smith⁶, Bahman Nedjat-Shokouhi^{6

7}, Alessio Fasano⁸, Laura Magill¹, Amanda Duhlin¹, Samuel Bitoun⁹, Aude Gleizes^{10

11}, Salima Hacein-Bey-Abina^{10

12}, Jessica J Manson¹³, Elizabeth C Rosser^{1

14}; ABIRISK Consortium; Nigel Klein⁵, Paul A Blair¹, Claudia Mauri¹

Affiliations

¹ Centre for Rheumatology, Division of Medicine and Division of Infection and Immunity and Transplantation, University College London, London WC1E 6JF, UK.
² Evergrande Center for Immunologic Diseases, Harvard Medical School, Boston, MA 02115, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁴ Lydia Becker Institute of Immunology and Inflammation, Division of Infection, Immunity & Respiratory Medicine, University of Manchester, Manchester M13 9PL, UK.
⁵ Infection, Immunity and Inflammation Programme, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK.
⁶ Eastman Dental Institute, School of Life and Medical Sciences, UCL, London WC1X 8LD, UK.
⁷ Centre for Molecular Medicine, Division of Medicine, UCL, London WC1E 6BT, UK.
⁸ MassGeneral Hospital for Children, Boston, MA 02114, USA.
⁹ Rheumatology Department, Bicêtre Hospital AP-HP, Université Paris-Saclay and INSERM UMR 1184 IMVA 78 Avenue du Général Leclerc, 94270 Le Kremlin Bicêtre, France.
¹⁰ Université de Paris, CNRS, INSERM, UTCBS, Unité des Technologies Chimiques et Biologiques pour la Santé, 75006 Paris, France.
¹¹ Clinical Immunology Laboratory, Groupe Hospitalier Universitaire Paris-Sud, Hôpital Kremlin-Bicêtre, Assistance Publique-Hôpitaux de Paris, 94270 Le-Kremlin-Bicêtre, France.
¹² Assistance Publique - Hôpitaux Paris Saclay, Clinical Immunology Laboratory, Hôpital Bicêtre, 94275 Le-Kremlin-Bicêtre, France.
¹³ Department of Rheumatology, University College London Hospital, London NW1 2BU, UK.
¹⁴ Centre for Adolescent Rheumatology Versus Arthritis at UCL, UCLH and GOSH, London WC1E 6JF, UK.

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.

Funding: Funded by Versus Arthritis (21140 and 21257) and UKRI/MRC (MR/T000910/1).

Keywords: arthritis; gut mucosa; gut permeability; inflammation; therapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arthritis, Rheumatoid* / metabolism
Dysbiosis / metabolism
Gastrointestinal Microbiome*
Humans
Inflammation / metabolism
Intestinal Diseases* / metabolism
Intestinal Mucosa / metabolism
Mice

Abstract

Publication types

MeSH terms

Grants and funding