Δ9-tetrahydrocannabinol (THC) activation of cannabinoid receptors induces unique changes in the murine gut microbiome and associated induction of myeloid-derived suppressor cells and Th17 cells.

Abstract

Abstract Δ9-tetrahydrocannabinol (THC) is a partial agonist for cannabinoid receptors (CB1 & CB2), is the main psychoactive ingredient found in the Cannabis plant, and can modulate the nervous and immune system. Our intestine harbors a diverse array of bacteria, referred to as the microbiome, which is known to impact many bodily functions, including the immune system. In the current study, we investigated the effect of THC on the gut microbiome and the naïve immune response. We tested the effect of acute or chronic exposure of C57BL/6 mice to THC on the immune system, and correlated said changes with a flux in intestinal bacteria. Intraperitoneal exposure to THC resulted in migration of CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs) from the bone marrow to the peritoneal cavity. These MDSCs remained in the peritoneum throughout chronic THC administration, where they proliferated and produced IL-6. The peritoneal IL-6 led to an increase in T helper 17 (Th17) cells in the mesenteric lymph node (mLN), as well as increases of IL-17A in the serum and mLN supernatant of THC-treated mice. Indeed, an adoptive transfer of THC MDSCs increased the number of Th17 cells compared to bone marrow (BM) MDSCS, and in-vitro polarization experiments revealed THC MDSCs to be more potent inducers of Th17 cells than BM MDSCs. The alterations in the gut immune cells occurred in tandem with an increase in the number of Alphaproteobacteria in the cecum and feces of mice treated with THC compared to vehicle and naïve mice, and this effect was replicated after an adoptive transfer of THC MDSCS, but not BM MDSCs. Together, these data demonstrated that marijuana use can alter the gut microbiota as well as cause significant changes in the naïve immune system.