Growing public interest and concomitant government deregulation of cannabis-derived compounds have shined the spotlight on their physiological effects and therapeutic benefits. Among the major phytocannabinoids, Delta-(9)-tetrahydrocannabinol (THC), the well-known psychoactive cannabis component, and cannabidiol (CBD) its non-psychotropic counterpart, together with their targets in the CNS, have been extensively studied.
The endogenous cannabinoid system (ECS) includes endogenously produced cannabinoids and their receptors, along with synthesis and breakdown enzymes. This system is also represented at several levels along the gastrointestinal tract (GIT) putting it on the frontline during oral intake of exogenous cannabinoids. It is an important player in visceral physiology with essential roles on GIT motility, sensitivity, intestinal permeability, and inflammatory processes along with an apparent function in gut-brain communication (i.e. CB1 expression on vagus nerve afferents, modulation by mental states). These features contributed to making the ECS an attractive target for GI disorders’ treatment, such as inflammatory bowel disease (IBD), and gut-brain axis-linked pathophysiology (e.g. irritable bowel syndrome). Several cannabinoid receptor ligands were suggested as effective in ameliorating IBD symptoms in animal models, however, these results did not translate into successful clinical outcomes. Side effects, presumably emanating from central structures altering brain and energy balance, accounted as major drawbacks, highlighting the need to develop compounds that act peripherally.
While these synthetic drugs are being developed, unraveling the cellular and molecular mechanisms underlying cannabis-derived compounds’ impact along the GIT, is crucial to refining our understanding of their therapeutic potentials and limitations. New research exposing the promiscuous interactions of phytocannabinoids, such as CBD, with receptors and proteins (GPR18, GPR55, TrpV1R, 5-HT1AR, PPAR, etc.) beyond the ECS, and the potential cross-talks between ECS and the systems these receptors engage, opens to conceptualizing a more complex network at play. Meanwhile, the growing availability of minor phytocannabinoids (e.g. CBG, CBN, CBA) is fueling more investigations into the synergies amongst phytocannabinoids, a phenomenon known as the “entourage effect”. Ongoing research into these interactions is expanding this concept to other chemicals present in hemp, and other plants, as well those produced endogenously (e.g. Terpenes, phenolic acids, N-acylethanolamines, N-acyl-neurotransmitters, etc.), known to have functional properties of their own.
A better understanding of the pharmacological, biochemical, and functional interactions of these compounds along the GIT should provide promising grounds to improve current therapeutics by leveraging these synergies. Just as important as understanding these molecular interactions, are studies shedding light onto the genetic, epigenetic, circadian, dietary, microbiotic, and age-related factors, susceptible to modulate these therapeutic effects through the ECS. Understanding the interplays between these factors, systems and cellular pathways along the gut-brain axis could set the stage for more robust, personalized, and precise interventions.
This Research Topic aims to collect the latest molecular, cellular, and pre-clinical research outputs on the impact of cannabis-derived compounds derived from cannabis or other sources on the gut-brain axis fostering hope for new therapeutic outcomes. We welcome authors to address the following topics:
- Mechanistic interactions between diet-microbiota and the ECS.
- Hemp-derived compounds (Cannabinoids, terpenes, phenolic acids etc.) interactions and functional properties along the GIT.
- Experimental evidence supporting the cross-talk between the ECS and other systems (i.e. serotoninergic) throughout the digestive tract.
- Pre-clinical and clinical-based evidence supporting therapeutic applications of drugs leveraging synergies for the treatment of gut-brain axis-linked pathologies.
We hope to contribute to our understanding of the mechanisms underlying the potential contribution of hemp-derived compounds to improving pathologies along the gut-brain axis while pointing out current hurdles and gaps in our knowledge. We anticipate it will spur emerging and future research as we try to close the gap between pre-clinical and clinical outcomes.
Dr. Francesca Borrelli received research grants from GW pharmaceuticals to perform preclinical studies on phytocannabinoids and intestinal diseases. She holds patents on phytocannabinoids and colorectal cancer and inflammatory bowel diseases. The other Topics Editors declare no conflicts of interest with regard to their Research Topic.
Growing public interest and concomitant government deregulation of cannabis-derived compounds have shined the spotlight on their physiological effects and therapeutic benefits. Among the major phytocannabinoids, Delta-(9)-tetrahydrocannabinol (THC), the well-known psychoactive cannabis component, and cannabidiol (CBD) its non-psychotropic counterpart, together with their targets in the CNS, have been extensively studied.
The endogenous cannabinoid system (ECS) includes endogenously produced cannabinoids and their receptors, along with synthesis and breakdown enzymes. This system is also represented at several levels along the gastrointestinal tract (GIT) putting it on the frontline during oral intake of exogenous cannabinoids. It is an important player in visceral physiology with essential roles on GIT motility, sensitivity, intestinal permeability, and inflammatory processes along with an apparent function in gut-brain communication (i.e. CB1 expression on vagus nerve afferents, modulation by mental states). These features contributed to making the ECS an attractive target for GI disorders’ treatment, such as inflammatory bowel disease (IBD), and gut-brain axis-linked pathophysiology (e.g. irritable bowel syndrome). Several cannabinoid receptor ligands were suggested as effective in ameliorating IBD symptoms in animal models, however, these results did not translate into successful clinical outcomes. Side effects, presumably emanating from central structures altering brain and energy balance, accounted as major drawbacks, highlighting the need to develop compounds that act peripherally.
While these synthetic drugs are being developed, unraveling the cellular and molecular mechanisms underlying cannabis-derived compounds’ impact along the GIT, is crucial to refining our understanding of their therapeutic potentials and limitations. New research exposing the promiscuous interactions of phytocannabinoids, such as CBD, with receptors and proteins (GPR18, GPR55, TrpV1R, 5-HT1AR, PPAR, etc.) beyond the ECS, and the potential cross-talks between ECS and the systems these receptors engage, opens to conceptualizing a more complex network at play. Meanwhile, the growing availability of minor phytocannabinoids (e.g. CBG, CBN, CBA) is fueling more investigations into the synergies amongst phytocannabinoids, a phenomenon known as the “entourage effect”. Ongoing research into these interactions is expanding this concept to other chemicals present in hemp, and other plants, as well those produced endogenously (e.g. Terpenes, phenolic acids, N-acylethanolamines, N-acyl-neurotransmitters, etc.), known to have functional properties of their own.
A better understanding of the pharmacological, biochemical, and functional interactions of these compounds along the GIT should provide promising grounds to improve current therapeutics by leveraging these synergies. Just as important as understanding these molecular interactions, are studies shedding light onto the genetic, epigenetic, circadian, dietary, microbiotic, and age-related factors, susceptible to modulate these therapeutic effects through the ECS. Understanding the interplays between these factors, systems and cellular pathways along the gut-brain axis could set the stage for more robust, personalized, and precise interventions.
This Research Topic aims to collect the latest molecular, cellular, and pre-clinical research outputs on the impact of cannabis-derived compounds derived from cannabis or other sources on the gut-brain axis fostering hope for new therapeutic outcomes. We welcome authors to address the following topics:
- Mechanistic interactions between diet-microbiota and the ECS.
- Hemp-derived compounds (Cannabinoids, terpenes, phenolic acids etc.) interactions and functional properties along the GIT.
- Experimental evidence supporting the cross-talk between the ECS and other systems (i.e. serotoninergic) throughout the digestive tract.
- Pre-clinical and clinical-based evidence supporting therapeutic applications of drugs leveraging synergies for the treatment of gut-brain axis-linked pathologies.
We hope to contribute to our understanding of the mechanisms underlying the potential contribution of hemp-derived compounds to improving pathologies along the gut-brain axis while pointing out current hurdles and gaps in our knowledge. We anticipate it will spur emerging and future research as we try to close the gap between pre-clinical and clinical outcomes.
Dr. Francesca Borrelli received research grants from GW pharmaceuticals to perform preclinical studies on phytocannabinoids and intestinal diseases. She holds patents on phytocannabinoids and colorectal cancer and inflammatory bowel diseases. The other Topics Editors declare no conflicts of interest with regard to their Research Topic.
