Intestinal epithelial expression of human TNF is sufficient to induce small bowel inflammation and sacroiliitis mimicking human Spondyloarthritis.

Abstract

Gut and joint disease commonly co-occur in spondyloarthritis (SpA). Up to 50% of SpA-patients show signs of subclinical gut inflammation and 10% evolves into inflammatory bowel disease (IBD). However, the mechanisms underlying this gut-joint axis are still unclear. Here we tested the hypothesis whether restricted expression of a pro-inflammatory cytokine in the intestine may trigger onset of combined gut and joint inflammation. Intestinal expression of human TNF (hTNF) was achieved by driving hTNF gene expression under control of the rat FAPB2 promoter, creating a new animal model, the TNFgut mice, which expresses hTNF in the proximal intestinal tract. Intestinal-specific TNFgut mice were examined for pathological changes in the intestine and extra-intestinal tissues by means of histology, qPCR and flow cytometry, along with 16S sequencing on stools. Local expression of hTNF in the epithelium of the small intestine induces a pro-inflammatory state of the proximal intestinal tract with epithelial alterations and induction of members of the S100 family, as well as local upregulation of T helper 17 and regulatory T cells, but no obvious signs of dysbiosis. Curiously, TNFgut mice develop sacroiliitis (p< 0.05) in addition to small bowel inflammation (p< 0.05). However, no signs of peripheral arthritis nor enthesitis could be documented. Intestinal expression of hTNF is sufficient to initiate a pro-inflammatory cascade culminating in small bowel inflammation and sacroiliitis. Thus, gut-derived cytokines are sufficient to induce spondyloarthritis.