Evidence of Silencing of Intestinal Inflammatory and Immune Transcripts Following Induction of Joint Inflammation

Disrupted intestinal epithelial barrier function has been proposed to be integral to rheumatoid arthritis (RA) progression and pathogenesis. To further define the molecular pathways in synovial inflammation and a response of the intestinal tissues, we have now used a rat model of mono-joint inflammatory arthritis, induced by intra-articular injection (IAI) of Complete Freund’s adjuvant (CFA). The predominant inflammatory response of a single injection of the adjuvant into the knee joint resulted in rapid and reproducible formation of a fibrotic myeloid-infiltrated synovial pannus. Our aim was to determine how intestinal tissues, including the proximal and distal ileum and distal colon, respond to inflammatory changes in the synovium in a temporally coordinated manner by comparing their transcriptomic landscapes using RNASeq analyses. We confirmed the timeline of joint inflammation by knee joint swelling measurement, synovial fluid levels of the acute phase protein Inter-α-trypsin inhibitor heavy chains (ITIH) and demonstrated a self-correcting response of trabecular and cortical bone to the CFA challenge. Intestine-specific responses were monitored by 16S microbiome amplicon sequencing, histopathology for mucus layer integrity, and immune cell immunohistochemistry. We present data showing that the intestinal tissue response to the acute joint inflammation was region specific, with the ileum primarily responding with increased mucus secretion and silencing of T cell specific pathways, whereas the colon showed a transient upregulation of macrophages, with a broader suppression of immune related and metabolic pathway related transcripts. However, at no time after CFA-IAI were there significant changes in the fecal microbiome composition of the ileum or the colon. In summary, our data report for the first time a suppression of intestinal inflammatory and immune responses following the induction of joint inflammation and only minimal and transient changes in the microbiome.