Background/Purpose: Intestinal inflammation (I-Inf) and increased intestinal permeability (IP) and intestinal damage (ID) have been observed in patients with spondyloarthritis (SpA). However, whether these changes might be causal or are the consequence of SpA is unknown. To answer this question, the present study investigated the time-course of I-Inf and IP in a rat model of reactive arthritis, a subgroup of SpA, the adjuvant-induced arthritis model.

Methods: Adjuvant-induced arthritis (AIA) was induced in 6-week-old male Lewis rats by injection at the base of the tail of Mycobacterium butyricum in incomplete Freund’s adjuvant (Day 0). Control rats received saline. I-Inf and IP were studied at 3 phases of arthritis: pre-arthritic phase (Day 4, AIA-preclinical), onset of arthritis (Day 11, AIA-onset) and acute inflammatory phase (Day 28, AIA-acute). IP was assessed by measuring plasma levels of zonulin (ELISA) and ileal mRNA expression of zonulin and occludin (RT-qPCR). Ileal inflammation was assessed by TCD4+ and TCD8+ lymphocyte count from rat ileum (immunohistochemistry) and by measuring ileal mRNA expression of IL-8, IL-33, IL-17, IL-23p19 and TNF-α (RT-qPCR). The integrity of the intestinal barrier was evaluated by measuring plasma levels of intestinal fatty acid binding protein (iFABP) by ELISA. Joint damage was assessed by determination of an arthritis score (Sa) and of a radiographic score (Sr) of hind paws.

Results: AIA induced arthritis symptoms beginning at day 11, leading to a severe clinical and radiographic arthritic disease at day 28 (Sa=3.9±1.0; Sr=23.8±8.1). Compared to control rats, plasma levels of zonulin increased at preclinical phase, at onset but not at the acute phase. While ileal zonulin mRNA expression was enhanced at the onset phase, no change in occludin mRNA expression was observed. Plasma levels of iFABP levels were increased in AIA rats at all stages of arthritis course. Regarding inflammation, preclinical phase was characterized by increased mRNA expression of IL-8, IL-33 and IL-17. At the onset phase, TNF-α, IL-23p19 and IL-8 mRNA expression were increased. No changes in cytokines mRNA expression were observed at the acute phase. Consistent with these findings, increased TCD4+ and TCD8+ number was measured in AIA ileum as compared to controls at Day 4 and Day D11. No correlation was found between clinical and radiographic arthritis scores and zonulin levels. A negative correlation was observed between intestinal IL-8 mRNA expression and Sa. A positive correlation was observed between Sa and the CD4 lymphocyte count.

Conclusion: Intestinal changes associated to reactive arthritis occurred prior the development of articular symptoms. These data are in favour of the “causative” hypothesis of intestinal changes in SpA.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/time-course-of-intestinal-permeability-and-intestinal-inflammation-in-rat-adjuvant-induced-arthritis/