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. 2016 Feb;1(1):67-77.
doi: 10.1089/can.2016.0001. Epub 2016 Feb 24.

Endocannabinoids in the Gut

Nicholas V DiPatrizio

Endocannabinoids in the Gut

Nicholas V DiPatrizio. Cannabis Cannabinoid Res. 2016 Feb.

Abstract

Cannabis has been used medicinally for centuries to treat a variety of disorders, including those associated with the gastrointestinal tract. The discovery of our bodies' own "cannabis-like molecules" and associated receptors and metabolic machinery - collectively called the endocannabinoid system - enabled investigations into the physiological relevance for the system, and provided the field with evidence of a critical function for this endogenous signaling pathway in health and disease. Recent investigations yield insight into a significant participation for the endocannabinoid system in the normal physiology of gastrointestinal function, and its possible dysfunction in gastrointestinal pathology. Many gaps, however, remain in our understanding of the precise neural and molecular mechanisms across tissue departments that are under the regulatory control of the endocannabinoid system. This review highlights research that reveals an important - and at times surprising - role for the endocannabinoid system in the control of a variety of gastrointestinal functions, including motility, gut-brain mediated fat intake and hunger signaling, inflammation and gut permeability, and dynamic interactions with gut microbiota.

Keywords: cannabinoid receptor type 1 (CB1); endocannabinoid; enteric nervous system; gut-brain; microbiome; peristalsis; vagus nerve.

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Figures

<b>FIG. 1.</b>
FIG. 1.
The endocannabinoid system controls a variety of gastrointestinal functions. (A) The endocannabinoid system in the large intestine is proposed to interact with gut microbiota and regulate epithelial barrier permeability. For example, activating cannabinoid type 1 receptors (CB1Rs) in mice increased circulating levels of lipopolysaccharide (LPS)—which is an endotoxin released from Gram-negative bacteria—through a proposed mechanism that includes decreased expression of the tight junction proteins, occludin and zonula occludens-1, and resulting increases in permeability. It is suggested that CB1Rs located in the intestinal epithelium control these processes. (B) Endocannabinoid signaling in the jejunum mucosa of the small intestine is triggered by fasting and tasting dietary fats and is proposed to be a general hunger signal that acts at local CB1Rs to inhibit satiation., The evidence suggests that during fasting, cholinergic signaling (acetylcholine, ACh)—possibly by the efferent vagus nerve—activates muscarinic acetylcholine receptors (mAChRs) in the small intestine, which, in turn, drive the conversion of the 2-arachidonoyl-sn-glycerol (2-AG) precursor, 1-stearoyl-2-arachidonoyl-sn-glycerol (SAG), into 2-AG through the activity of diacylglycerol lipase (DGL). Inhibiting subtype m3 mAChRs locally in the rat intestine blocked fasting-induced production of 2-AG in the jejunum mucosa and inhibited refeeding after a 24-h fast to the same levels as when a peripherally restricted CB1R antagonist was administered. (C) Endocannabinoid activity at CB1Rs located on small intestinal enteroendocrine I cells—which produce and secrete the peptide, cholecystokinin (CCK)—is suggested to promote feeding during a fast and drive the intake of fat-rich foods by inhibiting the release of CCK, which normally binds CCK receptors on the sensory vagus nerve and induces satiation after a meal., Supporting this hypothesis, the expression of CB1R mRNA on CCK-containing enteroendocrine I cells in the mouse small intestine has been reported, which suggests that CB1Rs in the gut mucosa control feeding by inhibiting the release of CCK and therefore indirectly modifying the activity of the sensory vagus. (D) Many studies provide evidence that CB1Rs on enteric nerves control intestinal contractility by inhibiting the release of the excitatory neurotransmitter, ACh. Recent studies also suggest that contractility is controlled by a dynamic interplay between the retrograde messengers, the endocannabinoids, and purines (e.g., adenosine triphosphate, ATP), which act in an opposing manner. It is proposed that the excitatory actions on contractility for ATP are mediated through increases in ACh, which are inhibited by the activation of prejunctional CB1Rs on enteric nerves., Both systems may functionally interact to regulate synaptic strength in the enteric nervous system.
<b>FIG. 2.</b>
FIG. 2.
Fatty food intake is driven by gut–brain endocannabinoid signaling. Tasting dietary fat increases endocannabinoid levels within the rat jejunum. Inhibiting local endocannabinoid signaling at jejunal CB1Rs reduces fat intake and preferences for unsaturated dietary fats., Here, a rat prefers to eat fat-rich potato chips rather than a standard laboratory chow, which contains far lower quantities of dietary fat than chips. Thus, it is proposed for illustrative purposes that this rat's preference for the fat-rich food is driven by an enhancement of gut–brain endocannabinoid signaling (i.e., the body's natural “cannabis-like molecules”) that is triggered by tasting the fat contained in the chips.
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