Cannabinoid receptor activation on hematopoietic cells and enterocytes protects against colitis

Background and aims: Cannabinoid receptor (CB) activation can attenuate inflammatory bowel disease (IBD) in experimental models and human cohorts. However, the role of the microbiome, metabolome, or the respective contributions of hematopoietic and non-hematopoietic cells in the anti-colitic effects of cannabinoids has yet to be determined.

Methods: Female C57BL/6 mice were treated with either cannabidiol (CBD), Δ 9-tetrahydrocannabinol (THC), a combination of CBD and THC or vehicle, in several models of chemically induced colitis. Clinical parameters of colitis were assessed by colonoscopy, histology, flow cytometry and detection of serum biomarkers; single-cell RNA sequencing and qRT-PCR were used to evaluate the effects of cannabinoids on enterocytes. Immune cell transfer from CB2 knockout mice was used to evaluate the contribution of hematopoietic and non-hematopoietic cells to colitis protection.

Results: We found that THC prevented colitis, and that CBD, at the dose tested, provided little benefit to the amelioration of colitis, or when added synergistically with THC. THC increased colonic barrier integrity by stimulating mucus, tight junction and antimicrobial peptide production, and these effects were specific to the large intestine. THC increased colonic gram-negative bacteria, but the anti-colitic effects of THC were independent of the microbiome. THC acted on both immune cells via CB2 and on enterocytes to attenuate colitis.

Conclusions: Our findings demonstrate how cannabinoid receptor activation on both immune cells and colonocytes is critical to prevent colonic inflammation. These studies also suggest how cannabinoid receptor activation can be used as a preventive and therapeutic modality against colitis.