LAUSR

Nature reviews | Rheumatology Reducing intestinal permeability in the period before clinical arthritis ... delayed disease onset The mucosal origins hypothesis postulates that, in rheumatoid arthritis (RA), disease begins to develop at mucosal sites such as the gums, lungs and intestines and then transitions to involve synovial joints. Links between gut microbiota dysbiosis and RA, and between dietary intake of shortchain fatty acids (SCFAs) and autoimmune arthritis in mice, have provided support for this hypothesis, but a direct link between mucosal sites and the transition from systemic autoimmunity to arthritis has been missing. A new study published in Nature Communications has revealed a role for intestinal barrier function, and specifically for zonulin, a precursor of haptoglobin 2 that controls epithelial tight junction permeability, in regulating the onset of joint disease in mice with collageninduced arthritis (CIA) and potentially also in patients with RA. Mice with CIA had increased intestinal permeability in the period between the induction of autoimmunity and the onset of clinical symptoms, which corresponded with a rise in serum zonulin. This reduction in intestinal barrier function was accompanied by an influx of effector T cells in the small intestine. Interestingly, arthritis only developed in mice that had this increased intestinal permeability. Reducing intestinal permeability in the period before clinical arthritis, either by dietary supplementation with the SCFA butyrate, treatment with a selective intestinal cannabinoid receptor 1 agonist (cannabinoid receptor 1 regulates intestinal epithelial barrier function) or treatment with larazotide acetate (which blocks zonulin and is currently in phase III clinical trials for coeliac disease) delayed disease onset and reduced the severity of arthritis. “The most significant finding is that improving the intestinal barrier function in mice with nonclinical CIA positively affects subsequent disease onset and severity,” states corresponding author Mario Zaiss. “These results relate nicely to data published very recently by other groups showing mucosal inflammation in animal models of arthritis, and complete these interesting studies by providing a treatment opportunity.” In a cohort of patients with RAspecific autoimmunity but no clinical symptoms (described as preRA), Zaiss and colleagues R H E U M ATO I D A RT H R I T I S