ABSTRACT
There are limited pharmacological treatment options for inflammatory bowel disease (IBD), and some of these options are expensive and administered by injection or infusion. Thus, new cheaper and easier (oral) treatment options are needed. ALDH1A enzymes produce retinoic acid that can affect intestinal diseases such as IBD by regulating immune cells in the gut. We previously demonstrated that an orally deliverable ALDH1A inhibitor, WIN 18,466, can suppress colitis in an acute mouse model of IBD. Here, we tested the efficacy of ALDH1A inhibition in a chronic mouse model of IBD. Mdr1a-/- mice were treated with a diet containing WIN 18,446 starting 1 week prior to inducing colitis by H. bilis inoculation. Treatment was continued until the study end point and colitis was monitored based on clinical symptoms and confirmed by histological analysis. Immune cell phenotypes in colon-draining lymph nodes (cMLN) were analyzed. WIN 18,446 treatment reduced clinical symptoms and improved histopathologic colitis scores. This was associated with decreased expression of the gut homing integrin, α4ß7, on T cells in cMLN; increased expression of CD103, a protein associated with tissue-resident memory T cells; and changes in dendritic cells, plasmacytoid dendritic cells and B cells in inhibitor-treated mice. ALDH1A inhibition broadly influences immune cells during colitis and is a potential new target for IBD treatment. Future studies will be needed to determine the efficacy of ALDH1A inhibition on active colitis and to evaluate its relative efficacy in comparison to approved drugs.
