Blocking fatty acid amide hydrolase reduces T cell activation and attenuates experimental colitis (IRC10P.405)

Abstract

Abstract Inflammatory bowel disease (IBD) refers to chronic inflammatory disorders of the gut with unknown etiology. Fatty acid amide hydrolase (FAAH) is the enzyme crucially involved in the modulation of intestinal physiology. We investigated the effects of FAAH inhibitors on the dextran sodium sulfate (DSS) induced model of colitis. FAAH inhibitors diminished the overall clinical score, reversed the colitis-associated inflammation score, and reversed body weight loss after DSS induced colitis. The frequency of activated CD4+ T cells in the spleen, mesenteric lymph node (MLN), and Peyer’s patches (PP) was reduced after FAAH inhibition as compared to the control group. Further, the frequency of macrophages, natural killer (NK1.1), and NKT cells in PP, and the concentration of inflammatory cytokines and chemokines also declined after FAAH inhibition. FAAH treatment also resulted in greater than 1.5 fold changes in 26 miRs in MLN and 217 miRNAs in PP. Among these, eight anti-inflammatory miRNAs were validated by RT-PCR analysis. Pathway analysis also validated that differentially regulated miRNAs target mRNA associated with inflammation. Taken together, these results indicate that FAAH modulates colitis severity by reducing activated T cells at sites of inflammation and suppresses other immune mediators such as systemic cytokines and inflammatory miRNAs through regulation of miRs. In summary, our results suggest that FAAH inhibitors may be developed as a novel therapeutic agent for IBD.