Delta-8-tetrahydrocannabinol attenuates colitis and is associated with changes in myeloid cell phenotypes and let-7a-5p expression

Colitis is a form of inflammatory bowel disease characterized by chronic inflammation of the colon. In this study, we investigated the therapeutic potential of Δ8-tetrahydrocannabinol (Δ8-THC), a cannabinoid with lower psychoactive potency than the well-characterized Δ9-THC, in murine models of colitis. Colitis was induced with dextran sulfate sodium (DSS) in C57BL/6J mice or 2,4,6-trinitrobenzenesulfonic acid (TNBS) in BALB/c mice, and Δ8-THC was administered intraperitoneally at 20 mg/kg. Treatment with Δ8-THC significantly attenuated disease severity, as evidenced by improved colonoscopic findings and restoration of colon length. At the cellular level, Δ8-THC reduced the infiltration of myeloid cells and shifted macrophage polarization from a pro-inflammatory M1 phenotype toward an anti-inflammatory M2 phenotype. Exploratory miRNA sequencing in colonic samples identified alterations in regulatory miRNAs, with mmu-let-7a-5p emerging as a key candidate. Differential expression of let-7a-5p was validated by qPCR. In the RAW 264.7 macrophage cell line, mimic and inhibitor experiments showed that manipulation of let-7a-5p modulated Cd86 transcript levels. Computational analyses predicted a potential let-7a-5p–Cd86 interaction. Together, these findings demonstrate that Δ8-THC attenuates colitis, which is associated with increased let-7a-5p expression in the colon, and support a potential role for this miRNA in regulating macrophage-associated inflammatory responses.