Targeting FTO by Dac51 contributes to attenuating DSS-induced colitis

Dextran Sulphate Sodium (DSS)-induced colitis in mice is used to mimic human Ulcerative colitis (UC) and has been used to explore the pathogenesis of UC and also to evaluate the effectiveness of the therapeutic agent. Various epigenetic pathways have been shown to play important regulatory roles in UC. Reversible N6-methyladenosine (m6A) methylation represented a new layer of post-transcriptional gene regulation that affected a variety of biological processes. Since UC patients may present the up-regulation of FTO-mediated-the reduced total m6A level, our aim was to determine the effects of Dac51, which is an inhibitor of FTO, in DSS induced colitis in mice. Acute colitis was induced by 3 % DSS in drinking water for 7 days and Dac51 treatment was administered to intraperitoneal injection from days 4–10. Clinical symptoms were analyzed, and biological samples were further collected for histological analysis and the analysis of m6A, respectively. Dac51 treatment attenuated the colitis of DSS treated mice, characterized by the reduced colon shorting and histological damage. The colitis development was due to the reduced m6A level since the increased FTO expression resulted in the colitis phenotype. Dac51 treatment notably attenuated the colitis development. The inhibition of FTO activity in mice by Dac51 treatment was further confirmed by qPCR and western blotting analysis of colon tissues. These results indicated that Dac51 improved DSS-induced colitis through suppression of FTO expression and provided a preclinical testing of therapeutic agents for inflammatory bowel disease.