Beschreibung:
The gut-joint axis has drawn intense attention in the past decade. There is growing evidence that dysbiosis of the gut microbiota is associated with the development of autoimmune disease. However, how microbial dysbiosis can impact the transition from asymptomatic autoimmunity to inflammatory disease is mainly unknown. Here, we identified the intestinal barrier integrity as a key factor for this transition. The permeability of the intestinal epithelium depends on the regulation of intercellular tight junctions (TJ) and zonulin was shown to be a master regulator of intercellular TJ competency and intestinal barrier function, but little is known about their effect on the onset of arthritis. We found that zonulin as a main regulator of intestinal tight junctions was elevated in collagen induced arthritis (CIA) mice and rheumatoid arthritis (RA) patients before the onset of clinical symptoms. Moreover, the disruption of intestinal barrier integrity occurs prior to the onset of the inflammatory phase of arthritis and zonulin was considered as the main factor in this process. As it disrupted intestinal TJ proteins, increased intestinal permeability, changed gut microbiota, infiltrated the pro-arthritic immune cells to the lamina propria and controlled the transmigration of immune cells from the gut into the joints before at the onset of arthritis. Therapeutic restoration of the intestinal barrier in the pre-phase of arthritis using butyrate or cannabinoid type 1 receptor (CB1R) agonist inhibited the development of arthritis. Moreover, treatment with the zonulin antagonist, larazotide acetate, which specifically increases intestinal barrier integrity, effectively reduced arthritis onset. In summary, these data support a gut-joint axis in RA, which is based on zonulin-mediated impairment of intestinal barrier function and which is specifically drugable by the zonulin antagonist larazotide.