More than a leaky gut: how gut priming shapes arthritis

The gut microbiome forms an ecosystem that provides the host with numerous benefits such as digestion with nutrient generation, protection from pathogens and immune system maturation. Alterations in the microbial ecosystem associated with rheumatoid arthritis and spondyloarthritis have led to the gut–joint hypothesis, which postulates that these ecological changes cause immune dysfunction that contributes to the development of arthritis. Mechanisms by which dysbiosis might trigger arthritis include molecular mimicry, dysregulation of mucosal immunity, microbial translocation, production of immunomodulatory metabolites and immune cell trafficking. We discuss the data supporting each of these mechanisms, and highlight misconceptions, limitations and gaps in knowledge. In particular, we advise against the term ‘leaky-gut’ as the mechanisms and effects on the immune system of intestinal permeability and bacterial translocation are distinct. Nevertheless, rheumatoid arthritis and spondyloarthritis possibly result from the convergence of multiple pathways that could be unique to subgroups of individuals within these diseases. To move the field forward, each mechanism needs to be considered through the use of model organisms and interventional trials, individually and in concert. This Review discusses how alterations in the gut are linked to the development of arthritis. The authors challenge the concept of the ‘leaky gut’ hypothesis, stating that the effects of intestinal permeability and bacterial translocation on the immune system are distinct.