Tu1818 - Vitamin a Modulates Mucosal Inflammation by Augmenting Th1/Th17 Differentiation in Inflammatory Bowel Disease

All trans retinoic acid (ATRA) plays a critical role in maintaining mucosal immune homeostasis, where it promotes lymphocyte imprinting and Foxp3+ iTreg generation while reciprocally inhibiting Th1/Th17 differentiation. Recent murine studies have highlighted the pro inflammatory role of retinoic acid in sustaining inflammation. However, there are limited human data on the role of RA in modulating the gut immunological responses in disease state. We investigated the role of RA in modulating mucosal inflammation in Inflammatory bowel disease (IBD) in vivo and in vitro. This cross-sectional study included controls, steroid naïve ulcerative colitis (UC) and Crohn’s disease (CD) patients. Mucosal biopsies and blood were evaluated for RA levels and immunophenotypic profiles (CD4, CD8, MAIT, T cells). Additionally, in healthy volunteers, we assessed the effect of RA on CD4⁺ T cell responses differentiated in the presence and absence of polarising (Th1/Th17) and inflammatory (LPS induced dendritic cells) conditions. 29 UC patients (35.58.3 years),13 CD patients (37.511.5 years) and 15 healthy controls (31.710 years) were included. IBD patients had an increased tissue (UC: 3.4 vs. 0.8 ng/ml; p < 0.0001, CD: 3.5 vs. 0.8 ng/ml; p < 0.0001) and serum (UC: 1.4 vs. 0.7 ng/ml; p < 0.05, CD: 1.7 vs. 0.7 ng/ml; p < 0.01) RA levels than controls. Active UC had higher tissue RA levels than patients in remission (4.0 vs. 2.5 ng/ml; p < 0.01). This effect was accompanied by significantly increased pro-inflammatory cytokines- IL-17 and IFN in colonic and serum CD4+, CD8+, MAIT+ and + T cells in IBD patients. Furthermore, IL-17 and IFN significantly positively correlated with tissue RA levels in IBD. In vitro inflammatory conditions demonstrated that RA primed dendritic cells (RA-MoDCs) upregulated CCR9⁺T cells which expressed induced levels of IFN and IL-17 in the presence of Th1/Th17 conditions. This is the first study to estimate RA levels in human gut showing that tissue RA levels are significantly increased in IBD and correlate significantly with pro-inflammatory cytokines in mucosa as well as serum. Like CD4 cells, MAIT, CD8 and γ/δ T cells propagate mucosal inflammation by upregulating IL-17 and IFNg. We report a novel role of RA where RA-MoDCs upregulated IFNγ in the presence of Th1/Th17 conditions.