Figure 4.

Overview of the endocannabinoid system in the gut. Endocannabinoids in the intestine are produced primarily by enteric neurons and by subpopulations of extrinsic neurons. Some epithelial subtypes, including goblet and Paneth cells, may also produce endocannabinoids, based on the presence of synthetic enzymes identified in single cell expression studies. The main endocannabinoids are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Other N-acylethanolamides and acylglycerols act to regulate gut functions. Endocannabinoids act at CB₁ and CB₂ receptors to regulate various functions in the gut. Various immune cells express CB₂ receptors, which function primarily to dampen immune responses. Enteric neurons express CB₁ receptors, which modulate enteric neural control of various gastrointestinal functions. Various epithelial subtypes express CB₁ receptor under physiological conditions, which acts to suppress secretory responses. CB₁ activation also decreases epithelial permeability by altering tight junction protein expression and localization. Endocannabinoids have a reciprocal relationship with the gut microbiota; endocannabinoids can affect the composition of the microbiota, and different commensals (bacteria, fungi) can alter the endocannabinoid system. 2-OG, 2-oleoylglycerol; 2-PG, 2-palmitoylglycerol; LEA, N-linoleoylethanolamide; OEA, N-oleoylethanolamide; PEA, N-palmitoylenthanolamide; SEA, N-stearoylethanolamide. Figure created with BioRender.com.