Académie royale de Médecine de Belgique


Vidéo et résumé de Vincenzo Di Marzo

Lighting and extinguishing the fire: the endocannabinoidome and its emerging relationship with the gut microbiome in inflammation

par  Vincenzo DI MARZO        

Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis and its Impact on Metabolic Health, Faculty of Medicine and Faculty of Agricultural and Food Sciences, Université Laval, Québec, Canada; Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.

The endocannabinoid (eCB) system is an endogenous signaling apparatus composed of: 1) the receptors for cannabis psychotropic principle, Δ9-tetrahydrocannabinol, known as cannabinoid receptor of type-1 (CB1) and type-2 (CB2); 2) the lipid endogenous ligands of these receptors, N-arachidonoyl-ethanolamide (anandamide) and 2-arachidonoyl-glycerol (2-AG), known collectively as endocannabinoids (eCBs); and 3) the anabolic and catabolic enzymes for eCB tissue level regulation. The eCBs are local autocrine and paracrine mediators, and the eCB system is activated “on demand”, usually following elevation of intracellular calcium concentrations, to restore the homeostasis of cannabinoid receptor-expressing cells. By acting in a coordinated manner in several cells, it also regulates the homeostasis of tissues, organs and the organism in general. For example, immediately following the onset of inflammation, eCB levels are usually elevated, and the expression of CB2 receptors increased, in immune cells, to coordinate the inflammatory response in a manner that it can be resolved when no longer necessary. Under physiological conditions, eCB pro-homeostatic function is tightly regulated, in order to be exerted in a site- and time-specific manner, but this specificity, particularly in the case of eCB action at CB1 receptors, can be compromised during several chronic pathological conditions, especially those that follow from the failure of resolution of inflammation. Possibly also for this reason, agents that either activate CB2 receptors or antagonize CB1 receptors have been proposed as new therapeutics for (neuro)-inflammatory disorders, and particularly for those in which fibrosis follows unresolved inflammation (as in the liver, kidneys and lungs). Very recently, the realization that eCBs share metabolic routes and receptors with several other bioactive long chain fatty acid derivatives, which have also other molecular targets and metabolic enzymes, led to the concept of the “endocannabinoidome” (eCBome), an expanded eCB system, including more than 50 enzymes and receptors and more than 100 lipid mediators. Proteins previously identified to play a role in inflammation as either effectors or controllers (or both), like the transient receptor potential (TRP) cation channels, the orphan G protein-coupled receptors GPR18 and GPR55, the nuclear peroxisome proliferator-activated receptors (PPAR) ∝ and ϒ, and prostanoid receptors, are among the known targets of eCBome mediators or of some of their oxidation products. The study of this complex “super-system” and its relationship with inflammation requires the use of several “omic” technologies at once.

The inflammatory response is closely related to changes in the intestinal microbiome, a true additional and symbiotic “organ” that contributes to regulate metabolism and the immune response. Pathological alterations in the composition of intestinal microorganisms, collectively indicated as “dysbiosis”, are being increasingly associated with chronic low- or high-grade systemic inflammation contributing to several disorders of either peripheral organs (IBDs, diabetes, atherosclerosis, etc.) or the brain (Alzheimer’s, multiple sclerosis, etc.), and to their long-lasting and often irreversible consequences. The host eCB system and eCBome are emerging as being both targets and effectors of the gut microbiome through several molecular mechanisms. As with other physiological and pathological conditions, different eCBome receptors, and different eCBome mediators sometimes hitting more than one such receptors, play different roles in, and are regulated in different ways by, dysbiosis. This complexity makes the study of the relationships between the eCBome and gut microbiome in inflammation both challenging and, eventually, rewarding. In my lecture, I will describe such complexity and provide examples of how the gut microbiome and eCBome communicate and this axis becomes dysregulated in inflammation, and with what consequences and clinical implications.