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.

Gut-brain signaling controls food intake and energy homeostasis, and its activity is thought to be dysregulated in obesity. We will explore new studies that suggest the endocannabinoid (eCB) system in the upper gastrointestinal tract plays an important role in controlling gut-brain neurotransmission carried by the vagus nerve and the intake of palatable food and other reinforcers. A focus will be on studies that reveal both indirect and direct interactions between eCB signaling and vagal afferent neurons. These investigations identify (i) an indirect mechanism that controls nutrient-induced release of peptides from the gut epithelium that directly interact with corresponding receptors on vagal afferent neurons, and (ii) a direct mechanism via interactions between eCBs and cannabinoid receptors expressed on vagal afferent neurons. Moreover, the impact of diet-induced obesity on these pathways will be considered.

Gut-brain signaling controls feeding behavior and energy homeostasis; however, the underlying molecular mechanisms and impact of diet-induced obesity (DIO) on these pathways are poorly defined. We tested the hypothesis that elevated endocannabinoid activity at cannabinoid CB₁ receptor (CB₁Rs) in the gut of mice rendered DIO by chronic access to a high fat and sucrose diet for 60 days inhibits nutrient-induced release of satiation peptides and promotes overeating. Immunoreactivity for CB₁Rs was present in enteroendocrine cells in the mouse’s upper small-intestinal epithelium that produce and secrete the satiation peptide, cholecystokinin (CCK), and expression of mRNA for CB₁Rs was greater in these cells when compared to non-CCK producing cells. Oral gavage of corn oil increased levels of bioactive CCK (CCK-8) in plasma from mice fed a low fat no-sucrose diet. Pretreatment with the cannabinoid receptor agonist, WIN55,212-2, blocked this response, which was reversed by co-administration with the peripherally-restricted CB₁R neutral antagonist, AM6545. Furthermore, monoacylglycerol metabolic enzyme function was dysregulated in the upper small-intestinal epithelium from DIO mice, which was met with increased levels of a variety of monoacylglycerols including the endocannabinoid, 2-arachidonoyl-sn-glycerol. Corn oil failed to affect levels of CCK in DIO mouse plasma; however, pretreatment with AM6545 restored the ability for corn oil to stimulate increases in levels of CCK, which suggests that elevated endocannabinoid signaling at small intestinal CB₁Rs in DIO mice inhibits nutrient-induced CCK release. Moreover, the hypophagic effect of AM6545 in DIO mice was reversed by co-administration with the CCK_A receptor antagonist, devazepide. Collectively, these results provide evidence that hyperphagia associated with DIO is driven by a mechanism that includes CB₁R-mediated inhibition of gut-brain satiation signaling.

Agricultural workers, especially those who work in swine confinement facilities, are at increased risk for developing pulmonary diseases including asthma, chronic obstructive pulmonary disease, and chronic bronchitis due to exposures to fumes, vapors, and organic dust. Repetitive exposure to agricultural dust leads to unresolved inflammation, a common underlying mechanism that worsens lung disease. Besides occupational exposure to dusts, diet also significantly contributes to inflammation and disease progression. Since DHA (docosahexaenoic acid), a polyunsaturated omega-3 fatty acid and its bioactive metabolites have key roles in inflammation resolution, we rationalized that individuals chronically exposed to organic dusts can benefit from dietary modifications. Here, we evaluated the role of DHA in modifying airway inflammation in a murine model of repetitive exposure to an aqueous extract of agricultural dust (three-week exposure to swine confinement dust extract, HDE) and after a one-week resolution/recovery period. We found that mice fed a high DHA diet had significantly increased bronchoalveolar lavage fluid (BALF) levels of DHA-derived resolvins and lower TNFα along with altered plasma levels of endocannabinoids and related lipid mediators. Following the one-week recovery we identified significantly reduced BALF cellularity and cytokine/chemokine release along with increased BALF amphiregulin and resolvins in DHA diet-fed versus control diet-fed mice challenged with HDE. We further report observations on the effects of repetitive HDE exposure on lung Ym1+ and Arg-1+ macrophages. Overall, our findings support a protective role for DHA and identify DHA-derived resolvins and endocannabinoids among the potential mediators of DHA in altering airway inflammation in chronic agricultural dust exposure.

Helminths have co-evolved with their hosts resulting in the development of specialized host immune mechanisms and parasite-specific regulatory products. Identification of new pathways that regulate helminth infection could provide a better understanding of host-helminth interaction and may identify new therapeutic targets for helminth infection. Here we identify the endocannabinoid system as a new mechanism that influences host immunity to helminths. Endocannabinoids are lipid-derived signaling molecules that control important physiologic processes such as feeding behavior and metabolism. Following murine infection with Nippostrongylus brasiliensisis (Nb), an intestinal nematode with a similar life cycle to hookworms, we observed increased levels of endocannabinoids (2-AG, AEA) and the endocannabinoid-like molecule OEA in the infected lung and intestine. To investigate endocannabinoid function in helminth infection, we employed pharmacological inhibitors of cannabinoid subtype receptor 1 and 2 (CB₁R and CB₂R). Compared to vehicle-treated mice, inhibition of CB₁R but not CB₂R resulted in increased Nb worm burden and egg output, associated with significantly decreased expression of T helper type 2 cytokine IL-5 in intestinal tissue and splenocyte cultures. Strikingly, bioinformatic analysis of genomic and RNA-seq datasets identified putative genes encoding endocannabinoid biosynthetic and degradative enzymes in many parasitic nematodes. To test the novel hypothesis that helminth parasites produce their own endocannabinoids, we measured endocannabinoid levels in Nb by mass spectrometry and quantitative PCR and found that Nb parasites produced endocannabinoids, especially at the infectious larval stage. To our knowledge, this is the first report of helminth and host-derived endocannabinoids that promote host immune responses and reduce parasite burden.