The GBA encompasses bidirectional communication between the central and the enteric nervous systems , linking emotional and cognitive centers of the brain with intestinal functions . The autonomic nervous system, the ENS, and the hypothalamic pituitary adrenal axis mediate the communication of the GBA. Enteroendocrine signaling through enteroendocrine hormones activates neuronal pathways, including extrinsic afferent neurons, sending messages to the CNS. These pathways mediate not only behaviors associated with food intake but also cognition and mood. Cannabis has been associated with significant increases in ghrelin and leptin, and decreases in PYY, consistent with the modulation of appetite hormones mediated through endocannabinoid receptors.61The endocannabinoid system encompasses a key interface between the gut microbiota, the immune system, and homeostasis of the human host. Two main endogenous cannabinoids, or endocannabinoids, are the brain-derived arachidonoyl ethanolamide, known as anandamide , and 2-arachidonoylglycerol derived from lipid precursors, such as arachidonic acid, that are synthesized on demand. 2-AG has been isolated from both gut and brain Thissue. Endocannabinoids in the postsynaptic neuron are released into the synaptic cleft and travel retrograde to the presynaptic neuron, where they inhibit neurotransmitter release; then they are rapidly metabolized by lipoxygenase, cyclooxygenase, and epoxygenases, enzymes involved in eicosanoid metabolism. AEA and 2-AG can also be degraded by hydrolysis into arachidonic acid and glycerol/ethanolamine by serine esterases. The cannabinoid receptors type-1 and -2 are located throughout the periphery and are concentrated in the GI tract.
CB1 receptors are most abundant in the brain, grow tray stand where they function in neurotransmision. The CB1 receptors are predominantly located in the nociceptive areas of the CNS, the cerebellum, hippocampus, limbic system, and the basal ganglia. These receptors have a limited concentration in the substantia nigra and periaqueductal gray matter, but are not observed in the medullary respiratory centers. CB1 receptors can also be expressed on immune, cardiac, and testicular cells. In the GI tract, CB1 agonists are involved in feeding behavior, GI motility, satiety signaling, and energy balance. CB1 peripheral activity includes lipogenesis and inhibition of adiponectin found at elevated levels in obese and diabetic individuals. CB1 signaling has been linked to increased levels of free fatty acids, low HDL, high triglycerides, and insulin resistance. CB2 receptors are expressed mainly on membranes of immune and hematopoietic cells in the periphery. CB2 receptors are densely located in immune Thissue and organs, expressed by diverse cell types, including macrophages, splenocytes, microglial, monocytes, and T cells resident in the thymus, spleen, and bone marrow and tonsils. CB2 receptors located in the periphery have an immunomodulatory function playing an important role in pain reduction, inflammation, and physiological immune defense. CB2 activation mediates a regulatory or suppressive anti-inflammatory effect but in some cases stimulation of CB2 stimulates Thissue destruction and apoptosis, such as in cancer cells. Agonists of this receptor do not have psychoactive properties and are effective in mediating immunosuppression, preventing fibrosis or other organ scarring or in certain diseases triggering Thissue damage.
Antagonistic ligands for the endocannabinoid receptor signaling in the gut have an anti-inflammatory effect with an attenuation of inflammatory cytokines, an increase in Akkermansia muciniphila, and decreases in Lachnospiraceae and Erysipelotrichaceae diversity in the gut. CB1 signaling is TLR4 dependent and known to be influenced by at least A. muciniphila. In one study, A. muciniphila administration increased the intestinal levels of endocannabinoids that control in- flammation, the gut barrier, and gut peptide secretion. CB1 activation is anti-inflammatory in the gut. The dysbiotic gut environment and GALT are set up for an augmented cycle of inflammation and increased permeability of the gut epithelial barrier. The gut microbiota sends signals to the brain while affecting many functions through several pathways that comprise the GBA, including emotion and cognition . HIV infection may, therefore, lead to the destabilization of the GBA through alterations of the immune system and gut, a possible consequence of ongoing gut epithelial barrier abnormalities and viral replication in the GALT persisting despite ART effectiveness in suppressing peripheral virus. HIV infection and associated gut inflammation disrupt the gut-endocannabinoid-brain interface, and these disturbances adversely affect brain function. While interactions between the gut microbiota and the endocannabinoid system are complex, there are likely to be opportunities to develop therapeutics targeting this axis. Binding of the plant-based cannabinoid THC to presynaptic cannabinoid receptors, in the CNS, principally CB1, mimics the biological properties of AEA, acting like a mood enhancer and stimulant of joy and happiness or euphoria.
Cannabis administration is associated with significant increases in ghrelin and leptin and decreases in hormones that modulate appetite mediated through endogenous cannabinoid receptors. Medicinal and recreational cannabis comes in at least two species, Cannabis indica and Cannabis sativa, and in a variety of cultivars and formulations with different reported efficacies for treatment of various conditions. ‘‘Cultivar’’ is short for ‘‘cultivated variety’’ and represents not a taxonomic category, but a horticultural one, describing different plants that have been bred and selected by humans . Examples of cultivars include Acapulco Gold and Charlotte’s Web. Acapulco Gold is a golden-leafed C. sativa strain originally from the Acapulco area of southwest Mexico. Charlotte’s Web is a high-CBD, low-THC cannabis variety and extract marketed as a dietary supplement under federal law of the United States. More than 2,000 cultivars are available to consumers, but their chemical constituents and consistency have not been systematically characterized. This highlights the importance of providing consumers with consistent product information. CBD/THC extracts are reported to be more effective at treating pain compared to THC alone both in rodents and in human cancer-related pain. Species and cultivar differences in effects on the microbiome have not been studied. There is also the chemovar referring to the different chemical varieties rather than the strain. Each of the chemovars will have variations in the cannabinoids isolated from the strain in various concentrations of CBD, THC, cannabivarins, CBN, cannabigerol, and other chemicals such as terpenes. Each of them has specific functions and is able to elicit unique pharmacological actions and effects. Modes of administration are also important with respect to effect of cannabis and its therapeutic uses. Whether mode of administration differentially influences the gut microbiome is unknown. For example, one might expect orally administered cannabis to have more potent effects on the gut microbiome given high local concentrations than inhaled cannabis. But this has not been studied. Modes of administration will vary in time to onset of effects. Inhaled versions have a rapid onset of effect based on inhalations, whereas ingestion has a longer time to onset due to the transit to digestive processing and absorption. Finally, it is difficult to ascertain the dosing due to individual effects on physiology and tolerance. The low systemic bio-availability of orally administered cannabinoids has led to exploration of other routes, including intranasal, transdermal, and transmucosal. These are possible because of the highly lipophilic nature of cannabinoids. Additional approaches to formulation that may influence bioavailability include salt formation , co-solvency , micellization , –emulsification, complexation , hydroponic racks and encapsulation in lipid-based formulations and nanoparticles. The U.S. Federal Drug Administration has approved three synthetic cannabinoids and one plant-derived cannabinoid. Marinol is approved for anorexia and nausea related to HIV and chemotherapy; Cesamet is approved to treat chemotherapyinduced nausea and chronic pain; and Epidiolex is a plant-derived CBD indicated for the treatment of seizures associated with Lennox–Gastaut syndrome or Dravet syndrome in patients 2 years of age and older.Emerging findings suggest that cannabinoids can modulate the gut microbiota and inflammatory states by stabilizing blood–brain barrier function and reducing neuroinflammation. Neuroinflammation related to chronic immune activation, oxidative stress, and microbial translocation by a leaky gut barrier could affect the CNS through enteroendocrine signaling and the vagus nerve.
These routes may interact with the better understood link between LPS translocation and chronic in- flammation in the CNS due to microglial activation. Since inflammation and immune activation are believed to contribute to neurocognitive impairment in HIV, the antioxidant and anti-inflammatory properties and possible effects on gut barrier integrity of cannabinoids may favorably impact neurocognitive function. When THC and other exogenous cannabinoids interact with the endocannabinoid system, they can relieve pain as a result of neuromodulatory actions on both afferent pain signals and brain processing of pain. Several other potential therapeutic interventions have not been rigorously studied in randomized, controlled clinical trials. There is substantial evidence that THC stimulates appetite and reduces nausea. CBD is not psychoactive, acting as a serotonin 5-HT1A receptor agonist, and also has antioxidant and anti-inflammatory properties. In addition, although CBD has a low binding affinity for CB1 and CB2 receptors, it modulates several noncannabinoid receptors and ion channels and delays the ‘‘reuptake’’ of endogenous neurotransmitters such as anandamide and adenosine, by altering the binding of ligands to certain G-protein coupled receptors.Reports suggest that CBD may be effective for managing multiple anxiety based disorders, such as panic attacks, post-traumatic stress disorder, generalized anxiety, obsessive–compulsive disorders, and some cancers. Endocannabinoid signaling is known to influence gut barrier integrity, providing a highly relevant context for the study of the effects of cannabis. The endocannabinoid system in the large intestine interacts with the gut microbiota to regulate epithelial barrier permeability. The endogenous cannabinoid AEA, acting through CB1 and CB2 receptors, plays a pivotal role in maintaining immunological homeostasis and health in the gut. AEA contributes to the process by which the gut immune system actively tolerates microbial antigens. The bioactive lipid agonists and antagonists of cannabinoid receptors are known to have a direct effect on gut barrier function. Some CB1 and CB2 ligands are considered ‘‘gate openers,’’ promoting inflammation due to increased permeability of food antigens and pathogen-associated molecular patterns . Other CB1 and CB2 ligands promote increased barrier function and reduce inflammation. Enteroendocrine L cells are innervated by enteric glial cells and afferent neurons. Enteroendocrine L cells express endocannabinoid receptors . SIV infection was associated with gut epithelial barrier disruption, markers of increased inflammation/ immune activation , disrupting the translational control of IRAK1, and facilitating persistent GI inflammation. Previously published animal model studies support our focus on gut barrier permeability in the context of HIV and cannabis. One study demonstrated that chronic THC was associated with anti-inflammatory Th2 cytokine expression and reduced apoptosis among animals infected with SIV with markers of increased in- flammation and immune activation in epithelial crypt cells. These THC-mediated gut alterations were associated with reduced neuroinflammation measured as lower levels of TNFa, IL1b, IL6, and MCP1 in the striatum of SIV-infected rhesus macaques. These results may possibly translate to PWH; however, there were notable sex-specific differences in THC outcomes in SIV infected macaques. While THC mediated clinical differences in male rhesus macaques, reducing morbidity and mortality, as well as attenuation of SIV disease progression, female macaques did not demonstrate those protective benefits at similar doses. Male rhesus macaques had a reduction in plasma viral levels, decreased expression of Thissue pro-inflammatory cytokines, and a decrease in intestinal apoptosis. Female macaques did not have protective benefits with alterations in SIV viral load and CD4 + /CD8 + ratio, with chronic daily THC administration. These contrasting effects may be due to endocrine hormonal differences, requiring more research to investigate the mechanisms for differences. Given these findings and the numerous studies reviewed and cohorts, the field of HIV-related gut dysbiosis is biased toward males and particularly MSM. Future studies should consider of purposively including adequate sampling of HIV-infected cis-females especially in examining the effects of phytocannabinoids. Recently, studies have determined that cannabis is associated with reduced markers of immune activation and inflammation in CSF. This reduction was based on previous research demonstrating that selective stimulation of CB2 receptor leads to neuroinflammation and microglial activation. Thirty-six PWH and 21 HIV negative participants underwent lumbar puncture and provided estimated days since their last cannabis use . More recent use of cannabis was associated with significantly lower CSF levels of IL-16 and C-reactive protein . These findings are consistent with the notion that CNS anti-inflammatory effects of cannabinoids may be mediated directly through the microglial CB2 receptors or indirectly, for example, through cannabis-mediated alterations in gut microbiota composition, improved gut barrier function, or reduced translocation of proinflammatory bacterial products .Over time, internal and external factors such as prolonged stress, environmental factors, poor nutrition, and overuse of cannabis may influence the ability to produce endocannabinoids. Clinical endocannabinoid defi- ciency syndrome has been linked to migraines, neuromuscular pain, and GI disorders. Specific symptoms and symptom clusters have been linked to a defi- ciency in the endocannabinoids, AEA and 2-AG.