The gut-enthesis axis and the pathogenesis of Spondyloarthritis

Subclinical inflammation is associated with Spondylarthritis (SpA). SpA patients show features of dysbiosis, altered gut barrier function, and local expansion of innate and innate-like cells involved in type 3 immune response. The recirculation of intestinal primed immune cells into the bloodstream and, in some cases, in the joints and the inflamed bone marrow of SpA patients gave the basis of the gut-joint axis theory. In the light of the critical role of enthesis in the pathogenesis of SpA and the identification of mucosal-derived immune cells residing into the normal human enthesis, a gut-enthesis axis is also likely to exist. This work reviews the current knowledge on enthesis-associated innate immune cells' primary involvement in enthesitis development, questions their origin, and critically discusses the clues supporting the existence of a gut-enthesis axis contributing to SpA development. • Enthesitis is central in the initiation and perpetuation of the disease and damage accrual in Spondyloarthritis. • Normal human enthesis harbours conventional T cells, innate-like T cells, and myeloid cells commonly also present in the gut. • Dysbiosis and gut inflammation might contribute to local priming and expansion of mucosa-associated immune cells. • Bidirectional gut-entheseal recirculation of immune cells may be involved in the pathogenesis of SpA.