Matei, Diana-Elena; (2021) The relationship between intestinal barrier dysfunction and dysbiosis and the pathogenesis of arthritis. Doctoral thesis (Ph.D), UCL (University College London).

Abstract

Evidence suggests an important role for gut microbiota dysbiosis in the development of rheumatoid arthritis (RA). The link between changes to the gut bacteria and the development of joint inflammation is missing. In this study we address whether there are changes to the gut environment and how they contribute to RA pathogenesis. Using a combination of RA patient samples and mice with spontaneous and inducible models of arthritis, we show increased intestinal permeability in arthritis, which positively correlates with disease severity. Arthritic mice display inflammatory gut damage and increased gut permeability from early stages of disease, as well as bacterial translocation. Mechanistically, both arthritogenic bacteria and lymphocytes are required for the disruption of gut barrier integrity. Arthritis is accompanied by an increase in Th17 differentiation and infiltrating IFNg+ myeloid cells, as well as a loss of IL-10-IL- 10R signalling in the intestines. We also show an increased intestinal permeability and arthritis severity in epithelial-il10r-/- mice, highlighting a role for IL-10-IL10R signalling in the maintenance of gut barrier integrity. In addition, mice lacking Claudin-8, protein involved in the maintenance of epithelial tight junctions, present with constitutively increased gut permeability and develop worse joint disease. Treatment of mice with AT-1001, a molecule that inhibits paracellular permeability, ameliorates arthritis. We also show an increase in leukocyte recruitment, in particular of innate cells, to the intestine during arthritis, and that blocking CCR9-dependent recirculation can ameliorate arthritis severity. Lastly, longitudinal analysis of changes in gut microbiota composition during the development of arthritis shows that dysbiosis occurs prior to joint inflammation. The recovery of intestinal permeability observed in mice in the remission phase of arthritis is also accompanied by the ‘normalisation’ of gut microbiota composition. In conclusion, we suggest that breakdown of the gut barrier contributes to the development of arthritis and propose restoration of gut barrier homeostasis as a new therapeutic approach for RA.

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