Cannabigerol at the Interface of the Gut Microbiota and EndoCannabinoidome: Mechanistic Insights into Inflammation and Pain Modulation.

Recent years have seen growing medical interest in the influence of crosstalk between the gut microbiota and the endocannabinoidome (eCBome) on inflammation and pain modulation. Growing evidence indicates that gut microbiota can modify the effects of several marketed drugs, including analgesics. Cannabigerol (CBG) is an overlooked phytocannabinoid with a broad pharmacological spectrum and no psychotropic effects, which has anti-inflammatory and antinociceptive properties. This review aims to provide a comprehensive exploration of CBG and its role at the intersection of gut microbiota and eCBome, detailing the pharmacological mechanisms by which it acts as a promising therapeutic agent to modulate chronic inflammation and pain. Our data review suggests that CBG could act on the eCBome by activating CB2, PPARs, TRPV1, TRPA1, and α2-adrenergic receptors, while suppressing cellular and molecular mechanisms of inflammation, such as TNFα, COX-2, iNOS, IL-1β, and IL-6, and increasing antioxidant factors. These receptors and enzymes are distributed across neurons, glial, immune, and epithelial cells, which can also positively modulate gut microbiota and its metabolites, producing neurotransmitters, cytokines, and enzymes that regulate eCBome tone, and generating cannabinoid-mimetic compounds as part of pleiotropic functions. Nevertheless, CBG may exert direct effects on gut microbiota, promoting eubiosis and symbiotic bacteria. Moreover, there are no specific preclinical assays that demonstrate how CBG modulates the bidirectional communication between the gut microbiota and eCBome, addressing the specific mechanism involved in eCBome activation, and determining whether its anti-inflammatory and analgesic effects are dependent on gut microbiota type. Therefore, studies are required to evaluate this hypothesis to achieve translational medicine impact.