the endocannabinoid system and gut health

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duke
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the endocannabinoid system and gut health

Post by duke »

link to source https://hempedification.wordpress.com/2 ... d-the-gut/

hi all i like many others suffer from poor gut health and food allergies i.b.s and the answer might have been staring me in the face quite literally for years,i had noticed on the odd times i use the cannabis oil i make for my tina and friends (cleaning the bowl with olive oil and use in food) the left over from evap in my pyrex dish i use to mix with olive oil or cold pressed rape seeds oil or coconut oil all work well.
on these times i notice less gut problems esp at night as broken sleep makes for a miserable duke!
so i checked out granny crows storm list here https://grannystormcrowslist.wordpress.com/the-list/
and found this quite recent article of great interest
THE ENDOCANNABINOID SYSTEM AND THE GUT
“The brain and the gut speak the same language”, Ethan Russo, MD, Cannabinoid Scientist

endocanabanoids

The Endocannabinoid System (ECS) is a network of receptors and enzymes spread throughout the body, which can interact with one’s own cannabinoids (endogenous or endocannabinoids) because of substances found in nature called phytocannabinoids. These are present in Cannabis sativa and in cannabimimetics, found in other plants, including Black Pepper (Piper nigrum), Clove (Syzgium aromaticum), Echinacea species, Hops (Humulus lupulus), Kava (Piper methysticum) and Maca (Lepidium meyenii). The ECS includes:

Two endogenous cannabinoids;
Anandamide (AEA)
2-Arachidonoyl glycerol (2-AG)Image result for endocannabinoids anandamide and 2ag
Two primary receptors;
Cannabinoid Receptor 1 (CB1)
Cannabinoid Receptor 2 (CB2)
Two synthesising enzymes;
Diacylglycerol lipase
N-acyl-phosphatidylethanolamine-phospholipase D
Two degrading enzymes;
Fatty acid amide hydrolase (FAAH), which breaks down Anandamide
Monoacylglycerol lipase (MAGL), which breaks down 2-AG


Endocannabinoid System and the Gut

A schematic overview of cannabinoid receptors, cannabinoid-responsive non-cannabinoid receptors, their ligands and degrading enzymes of the Endocannabinoid System. 2-AG, 2-arachidonoyl glycerol; AEA, Anandamide; CB, cannabinoid receptor; CBD, cannabidiol; FAAH, fatty acid amide hydrolase; GPR55, G protein-coupled receptor 55; NAAA, N-acylethanolamine-hydrolysing acid amidase; PEA, palmitoylethanolamide; PPARs, peroxisome proliferator-activated nuclear receptors; THC, Δ9-tetrahydrocannabinol; TRPV1, transient receptor potential of vanilloid-type 1.

Cannabis has been used medicinally for centuries in people suffering from disorders associated with the gastrointestinal (GI) tract, including abdominal pain, cramps, diarrhoea, nausea and vomiting. An extensive amount of research offers justification for the traditional use of phytocannabinoids for GI health. This research points to a strong connection between the ECS and various aspects of gut health. The gut-brain axis, which refers to the ability of intestinal function to alter various aspects of mental and cognitive health, has drawn considerable attention. Research indicates that actions of the gut-brain axis may be in part mediated by the ECS. It has long been known the ECS regulates many functions in the body including mental health and pain control and as knowledge is expanding, other components of the system are being discovered, mostly new receptors. Most compounds that interact with the ECS either act on a receptor or a degrading enzyme, though other mechanisms are possible. Receptors include GPR55, GPR18, TRPV1 (the vanilloid or capsaicin receptor) and a possible CB3 receptor.

Other endogenous ligands include Virodhamine, NADA (N-Arachidonoyl dopamine) and possibly Noladin (2-arachidonoyl glyceryl ether, 2AGE). High concentrations of 2-AG and Anandamide are observed in the colon along with significant FAAH activity, involved in the breakdown of Anandamide. The enteric nervous system (ENS) of the GI tract contains approximately 500 million nerve endings and the highest levels of immune cells in the body are found in the GI tract. Roughly 20% of the nerves are intrinsic primary afferent neurons which alert the brain when subtle changes occur. This communication occurs through the vagus nerve. Endocannabinoids may regulate neurotransmission in the gut, as indicated by the presence of the CB2 receptor on enteric neurons and its expression by immune and epithelial cells in the GI tract. Altering the activity of CB1 receptors can regulate sensory processing from the gut, brain integration of the brain-gut axis, extrinsic control of the gut and intrinsic control by the ENS.



Inflammatory GI Disorders
Cannabis compounds have been described in historical medical texts going back centuries as treatments for conditions like diarrhoea and cramping. Endocannabinoids and phytocannabinoids are involved in inflammatory regulation in the gut. Endocannabinoids help signal immune cell movement to intestinal inflammation sites. Due to its role in regulating gut inflammation, the ECS has been shown to modulate inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Human IBD tissue is characterised by increased epithelial CB2-receptor expression, suggesting CB2 receptors act in an immunomodulatory capacity in this disorder. This in turn affects mucosal immunity in the inflamed colon and interacts with the actions of CB1 receptors in the colonic lining to promote wound healing. CB1 receptors play an important role in gut health as evidenced by the increased incidence of diarrhoea in people administered CB1 receptor antagonists. Both CB1 and CB2 receptors help to modulate an inflammatory response when stimulated. If there is more active inflammation in the gut, the body seems to recruit more CB2 receptors to regulate pain, inflammatory response and motility.

The current body of evidence indicates the overall tone of the ECS is increased in the presence of chronic inflammation in the intestines. In addition to CB2 recruitment, expression of CB1 receptors and TRVP1 activity may also be increased. Studies of patients with ulcerative colitis, diverticulitis and coeliac disease have all shown elevated levels of Anandamide. Collectively, these mechanisms are theorised to be an attempt by the body to safeguard against inflammatory damage. Other evidence supporting the ECS’ role in modulating colonic inflammation was provided by rodent models showing suppressing FAAH lead to a rise in Anandamide levels which stops development of colitis. Inhibiting FAAH and the inflammatory enzyme cyclooxygenase (COX) in mice with colitis reduces severity of the disease by elevating Anandamide levels and acting on the CB1 receptor. Blocking FAAH and COX correlated with higher concentrations of the endocannabinoid palmitoylethanolamide (PEA) and oleoylethanolamide. In intestinal tissue from ulcerative colitis patients, PEA levels are 1.8-fold higher compared with healthy patients, likely a result of the PEA attempting to help heal the inflammation.

PEA has pronounced anti-inflammatory properties. Phytocannabinoids CBD, THC and cannabigerol (CBG) have significantly reduced intestinal inflammation in animal models. THC was most effective in rats with experimental colitis, although CBD enhanced effects of an ineffective THC dose to the point where the combination, CBD and lower-dose THC, was the equivalent of a higher THC-only dose. CBG also proved beneficial in rodent models of colitis. CBG inhibited colitis in mice and lowered the synthesis of reactive oxygen species in intestinal epithelial cells. CBG has shown promise in animal models of colitis. Beta-carophyllene, a sesquiterpenoid phytocannabinoid found in Cannabis but also in many other plants, is a selective CB2 agonist, being looked at in a variety of GI conditions from gastritis to colitis.

Human research using a CBD supplement corroborates potential benefits of modulating the ECS in IBD/IBS. In a 10-week study of patients with ulcerative colitis given a CBD-rich botanical extract, the primary endpoint of percentage of patients in remission after treatment was similar between the placebo and CBD group. However, the placebo group experienced more gastrointestinal-associated adverse effects. In human colonic cultures derived from ulcerative colitis patients, CBD suppressed enteric reactive gliosis and reduced inflammation, thus inhibiting intestinal damage. Researchers concluded, “Our results therefore indicate that CBD indeed unravels a new therapeutic strategy to treat inflammatory bowel diseases”. Clearly, as another group of researchers stated, the ECS “in the gut is a potential therapeutic target for IBS and other functional bowel disorders”.

WordPressECSStimulation
Gut Motility
Endocannabinoids are known to regulate gut motility, the time it takes for food to move through the intestines. Slow gut motility is commonly called constipation and fast gut motility, diarrhoea. Evidence indicates the ECS plays an important role in gut motility. The best understood mechanism is activation of the CB1 receptor. Many studies indicate CB1 receptor activation suppresses peristalsis and GI contraction. CB1 receptor activation leads to an inhibition of acetylcholine (ACH) release, leading to slowed peristalsis and reduced smooth muscle contraction and accounts for some of the better-known uses of THC (a strong CB1 agonist) for GI discomfort, including calming nausea, slowing emptying of the stomach and reducing stomach acid. The CB1 receptor is activated by THC, but because CBD does not directly affect the CB1 receptor, it may be less likely to produce constipation. CBD regulates activity of the enzyme FAAH, involved in GI motility through breaking down of Anandamide.

Several known phytocannabinoids can block FAAH and allow Anandamide to have a longer action which can enhance some of the positive benefits of CB1 activation in the gut in an indirect manner. Additional evidence shows inhibiting diacylglycerol lipase (DGL), the enzyme responsible for the synthesis of the endocannabinoid 2-AG, improves gut motility. If there is active inflammation in the gut, the body will recruit CB2 receptors to help regulate motility that might be out of balance due to inflammation. Conversely there is evidence substances which antagonise CB1 increase GI motility. This might make them useful agents in conditions such as gastroparesis or irritable bowel with constipation (IBS-C) where hypomotility is a dominant aspect of the pathology. Researchers have proposed there may be other, yet-to-be-identified mechanisms by which the ECS regulates motility. For example, PEA, not known to interact with CB1 or CB2, seems to have similar effects on GI motility to THC. It can slow motility in both the presence and absence of inflammation.

Psychological Stress
The ECS regulates abdominal pain (visceral hyperalgesia) caused by chronic stress and may explain, at least in part, the relationship between chronic stress and IBD/IBS. The ECS is a key player in the regulation of visceral pain and the means by which psychological stress impairs GI function may involve this system. Chronic stress reduces levels of the endocannabinoid Anandamide while elevating 2-AG in the brain and down-regulating CB1 receptors in sensory ganglia, which regulate visceral pain. During chronic psychological stress, CB1 receptor activity is altered through epigenetic pathways, which may explain the association between stress and abdominal pain. Epigenetics refers to the alteration of gene expression through pathways other than the genetic code. It refers to the changes that occur in our genes due to lifestyle or environmental factors. Through these epigenetic actions, chronic stress affects the CB1 gene promoter, leading to lower levels of CB1 in sensory neurons that innervate (supply with nerves) the colon and other pelvic organs.WordPressEpigenetics

Weight, Energy Balance and Metabolism
In the late 1990’s and early 2000’s one area of interest was energy balance and metabolism. It was already known cannabinoids acted to stimulate appetite, a very useful function for individuals with a medical condition that causes reduced appetite and unwanted weight loss. It was ultimately discovered CB1 receptors signal activity that regulates energy homoeostasis, particularly the release of Ghrelin and Neuropeptide Y – both potent stimulators of appetite and hunger. It was not long before researchers began asking, “What if we could create a drug that bound to the CB1 receptor and had the opposite effect? Wouldn’t that be great for weight loss?” So, they set out to make an “anti-munchies” drug – and rimonabant was born – an “inverse agonist” that created an opposing effect at the CB1 receptor and squelched appetite. But what happens when you purposefully disrupt the body’s ability to stimulate the ECS? Things go haywire. Those enrolled in a planned 33-month study did report lower overall appetite but demonstrated an increased risk of suicide, so pronounced the study was abandoned after a year and four suicides!

rimonabant1“Patients taking rimonabant reported feeling severely depressed and having serious thoughts about committing suicide”, Psychology Today reported. Many individuals in the trials had significant weight loss and reversal of metabolic and cardiometabolic disease, however, dropout rates were >50% as they also developed pain, anxiety, irritability, nausea and vomiting. In creating an opposite action at the CB1 receptor, rimonabant didn’t just suppress appetite, it suppressed all of the activities of this part of the ECS. The ECS’ role in food intake was shown in a study demonstrating increased endocannabinoid signalling occurs after hedonic eating (consuming food for pleasure). In both normal-weight and obese humans, thinking about eating or eating a highly palatable food such as chocolate, leads to circulating levels of endocannabinoids, higher compared with a nonpalatable control diet. The CB1 receptor is deeply involved in hedonics, thus when CB1 receptors were totally blocked, many people lost the joy that comes from eating, some so much so, it was fatal. CB1 also plays a role in the regulation of pain, inflammation and digestive function which is why blockade of the receptor produced pain, nausea and other symptoms of an ECS thrown completely out of balance.

Obesity can generally be characterised as a hyperactive, deranged ECS. Through pathways associated with the gut-brain axis, alterations in the ECS can result in obesity and accompanying inflammation. In addition to its substantial role in appetite, CB1 stimulation increases fatty acid synthesis and hepatic lipogenesis, while reducing lipolysis. It also decreases insulin sensitivity, both in the liver and peripherally, mediated by a down-regulation of adiponectin. Finally, it triggers increased production and storage of triglyceride. Couple all these actions with CB1 stimulation leading to amplified desire for indulgent foods and you have the makings of a vicious cycle, seen in metabolic syndrome with obesity as the disease progresses. While rimonabant was not the solution, it certainly pointed to the critical role of the ECS in weight and metabolic health. As for natural compounds, Tetrahydrocannabivarin (THCV) is notable in its ability to act as a negative modulator of the CB1 receptor. In animal models it has been shown to improve insulin sensitivity and obesity and also act to protect pancreatic islet cells.



Intestinal Permeability
The intestinal barrier represents a complex interface between self and non-self. As such the integrity of this barrier and how it is regulated is important to broad aspects of health from local gut health to metabolism and mental function. CB1 and CB2 are both expressed in the intestinal barrier and may play separate but related roles in its function. CB1 is thought to play a protective role at least in part through regulation of intestinal secretory IgA. In animal models where CB1 is blocked, IgA decreases, pro-inflammatory enzyme activity increases and there is observable increase in intestinal permeability. Similar findings can be seen with an acute stress exposure. In response to inflammation, CB1 expression is enhanced as is FAAH activity. This may be an effort by the body to slow motility, but this response also appears to be protective in other ways. CB2 receptors also play a role, but primarily after an insult has occurred to the intestinal barrier.

The expression of CB2 receptors has been shown to increase in conditions such as Crohn’s disease and ulcerative colitis where inflammation is a hallmark and intestinal permeability is disturbed. This is likely an effort by the body to bring inflammation under control due to the role of the CB2 receptor in decreasing the secretion of inflammatory cytokines. Animal models suggest an increased expression of CB2 receptors may reduce visceral pain sensation, suggesting a possible role for substances that interact with the CB2 receptor in managing both pain and inflammation. Beta-caryophyllene (BCP) has already shown promise in this area. Also notable is some probiotics such as Lactobacillus acidophillus NCFM are able to activate the CB2 receptor which may account for some of the efficacy of probiotics in treating conditions with increased intestinal permeability and inflammation.

Microbiota
Perhaps one of the most interesting aspects of the ECS’ role in gut health is its interaction with the gut microbiota. The gut microbiota can modulate intestinal endocannabinoid tone. A microbiota profile associated with obesity also correlates with an increased intestinal concentration of Anandamide, which leads to increased gut permeability (leaky gut). In fact, the link between the gut microbiota and obesity may be mediated by the ECS. The results of a study where the bacterium, Akkermansia muciniphila, was administered to obese and type 2 diabetic mice daily support this concept. In that study, the bacterium reversed diet‐caused obesity. It accomplished this by increasing intestinal levels of endocannabinoids that control inflammation, the gut barrier and gut peptide secretion. On the other end of the spectrum, endocannabinoids from adipose tissue can also modulate the composition of the gut microbiota. This indicates there is bidirectional communication between the microbiota and the ECS. Evidence of this cross-talk is reinforced by studies showing the beneficial effects of probiotic supplementation on gut health may in part involve this system.

Communication with the Brain
Many researchers now believe the “gut-brain connection” is the ECS. The ENS contains all the components of the ECS including CB1 and CB2 receptors, synthesising and degrading enzymes and endocannabinoids. The ECS regulates communication between the gut and the brain in a bi-directional manner. This means changes in the brain due to things like stress or pain can alter GI function and may be important in functional bowel health and health concerns like irritable bowel. Conversely, changes in the gut due to inflammation or infection are communicated back to the brain via the ECS. Deficiency of the ECS may be one reason that some chronic GI challenges can be hard to resolve. The ECS seems to underpin the relationship between stress and visceral pain, inflammation and alterations in motility. Chronic stress induces widespread changes to the ECS that include a decrease in AEA, an increase in 2-AG and reduction in the number of CB1 receptors. This corresponds with changes in the hypothalamic-pituitary-adrenal (HPA) axis. The result is a decrease in endocannabinoid-mediated analgesia and a lessened ability to dampen visceral pain signals. Decreased activity and number of CB1 receptors are likewise linked to increased intestinal motility, diarrhoea and nausea. This stress-induced ECS-HPA dysfunction, is thought to at least partially underlie the pathophysiology of IBS.



Perhaps some of the most exciting research on the ECS examines the regulation of the intestinal barrier and the interrelationship with the microbiome. In addition to the aforementioned interaction of some probiotics with ECS receptors, the ECS has now attracted attention as the missing link tying together the microbiome, intestinal barrier health and systemic disease. The ECS may provide the answer. What is proposed is that increases in intestinal permeability brought about obesity induced changes to the microbiometrigger an upregulation in CB1 activity – particularly in adipose tissue – that further drives obesity and metabolic derangement. This is thought to be facilitated by the rise in serum lipopolysaccharide (LPS) which directly stimulates ECS activity. Experimental models indicate addressing leaky gut with pre or probiotics may offer a valid intervention if intestinal permeability can be reversed resulting in a fall in LPS and normalisation of ECS balance.

An abundance of evidence is pointing to the conclusion the Endocannabinoid System is involved in gut health and may even be an important mediator of the actions of the gut-brain axis. Targeting this system by the use of phytocannabinoids may be one way to reduce colonic inflammation and reduce the effects of stress on the gut. The ECS exerts strong influences on digestive health. As we further understand the mechanisms of the ECS in the gut, we can leverage therapeutic interventions that directly target this influential system, allowing us to address a number of conditions that, while common, are often challenging to address in clinical practice.

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Adapted from The Endocannabinoid System’s Intriguing Role in Gut Health, The Endocannabinoid System and the Gut and Granny Storm Crow’s List
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