All-trans retinoic acid alleviates collagen-induced arthritis in rats through gut-joint axis

Background: Many rheumatoid arthritis (RA) patients exhibit inadequate responses to current clinical treatments, necessitating the exploration of novel therapeutic approaches. All-trans retinoic acid (ATRA), a derivative of vitamin A, has emerged as a promising adjunctive treatment for RA. However, the precise mechanism through which ATRA mitigates arthritis remains elusive. This study aims to investigate the potential involvement of the gut-joint axis in ATRA-mediated arthritis alleviation.Methods: We established a collagen-induced arthritis (CIA) model in Wistar rats and administered oral gavages of 1.5 mg/kg ATRA for six weeks. We assessed inflammatory factor levels in serum and intestine using ELISA. Flow cytometry was employed to measure CD4+IL17A+ Th17 cell and CD4+CD25+FoxP3+ Treg cell proportions. Relative expression levels of FoxP3 and IL-17 mRNA in colon and ileum tissues were determined via RT-qPCR. Transmission electron microscopy (TEM) was used to examine tight junctions (TJs) of the colon and ileum. Expression levels of TJ proteins were detected using immunofluorescence. The type and structure of intestinal flora in fecal samples were determined through 16S rRNA sequencing.Results: Following ATRA intervention, arthritis index of CIA rats decreased, synovial inflammation alleviated, and the imbalanced Th17/Treg differentiation in peripheral blood mononuclear cell was revised. Additionally, the Th17/Treg ratio in the mesenteric lymph nodes decreased, alongside elevated expression of Foxp3 mRNA and reduced expression of IL-17 mRNA in the colon and ileum. Microscopically, we observed a reduction in intestinal inflammation. TEM revealed that ATRA could repair TJs, accompanied by increased expression of Claudin-1, Occludin, and ZO-1 in the colon and ileum. Moreover, ATRA regulated the community structure of gut microbiota, decreasing the abundance of Desulfobacterota and Patescibacteria, and increasing the abundance of Lactobacillus.Conclusions: ATRA demonstrates the potential to alleviate arthritis in CIA rats by modulating the gut microbiota, down-regulating the Th17/Treg ratio in the intestine, and fortifying the intestinal barrier. Therefore, ATRA holds promise as a valuable adjunctive therapy for clinical applications.