brain gut connection

The gut-brain connection

Effects of Diet on Brain Plasticity

Autism's Gut-Brain Connection

Gut–brain link grabs neuroscientists

Endocannabinoid system acts as a regulator of immune homeostasis in the gut

Endogenous cannabinoids (endocannabinoids) are small molecules biosynthesized from membrane glycerophospholipid.

The endocannabinoid system (ECS) is highly conserved in evolution dating back to at least 600 million years.

It consists of:

(i) lipid endocannabinoids;

(ii) their receptors such as the Gprotein-coupled receptors, cannabinoid receptor 1 (CB1), cannabinoid receptor 2 (CB2), and a ligand-gated cation channel vanilloidreceptor 1 (i.e., TRPV1);

(iii) the enzymes such as fatty acidamide hydrolyase (FAAH) that regulate the levels of endocannabinoids in vivo.

The ECS impacts several aspects of mammalianphysiology, particularly in the gut.

Endogenous cannabinoids such as anandamide (AEA) belong to theN-acylethanolamine family.

Anandamide (AEA) is an endogenous intestinal cannabinoid that controls appetite and energy balance by engagement of the enteric nervous system through cannabinoid receptors.

Here, we uncover a role for AEA and its receptor, CB2, in the regulation of immune tolerance in the gut and the pancreas.

The pungent molecule capsaicin (CP) has a similar effect as AEA; however, CP acts by engagement of the vanilloid receptor TRPV1, causing local production of AEA, which acts through CB2.

We show that the engagement of the cannabinoid/vanilloid receptors augments the number and immune suppressive function of the regulatory CX3CR1hi macrophages (Mf), which express the highest levels of such receptors among the gut immune cells.

Gut Bacteria's Vital Role in Prefrontal Cortex

Your Gut Bacteria Affects Your Brain Function

Mounting Research Shows Gut-Brain Connection

The Gut-Brain Connection, Mental Illness, and Disease

Manipulating the Human Microbiome to Manage Disease

Manipulating the Human Microbiome for Precision Public Health

Manipulating Bacterial Communities: Microbiome Engineering

Manipulating the microbiota to improve human health

Alterations of the Gut Microbiota in Patients:
Coronavirus Disease 2019 or H1N1 Influenza

The Microbiome Make Us "Supra Human"

The human genome, regardless of race, holds an informational blueprint capable of producing 17 different carbohydrate active enzymes (CAzymes1).

These CAzymes evolved primarily to digest terrestrial plants, and took millions of years to develop.

The average human microbiome, on the other hand, is far more dynamic, and contains many orders of magnitude more CAzymes than the generically shared human genome is capable of producing itself.

One study estimated there are about 16,000 different CAzymes in the human gut microbiome.

The human digestive symbiont Bacteroides thetaiotaomicron3, alone, contains 261 carbohydrate digesting enzymes known as glycoside hydrolases and polysaccharide lyases

Mechanisms of altered brain function from gut dysbiosis

The human body hosts an enormous abundance and diversity of microbes, which perform a range of essential and beneficial functions.

Appreciation of the importance of these microbial communities to many aspects of human physiology has grown dramatically in recent years.

Achieving a better understanding of the contribution of the microbiome to mental health will require further development of analytical methods.

Developmental pathways must also take into consideration points of interaction with our resident microbiota.

Refining these models based on empirical data now represents a key challenge in understanding the processes behind altered brain function and mental illness.

Stress and the brain-gut axis in functional and chronic-inflammatory gastrointestinal diseases

Microbes make us who we are

Gut feelings about the endocannabinoid system

Cannabinoid signalling regulates inflammation and energy balance

Cannabinoids and the gut: new developments and emerging concepts

Acute Δ9-tetrahydrocannabinol blocks gastric hemorrhages

The endocannabinoid system and gut-brain signalling

gastrointestinal system

chronic liver disease

kidney fibrosis




Endocannabinoids and the gastrointestinal tract

In the past centuries, different preparations of marijuana have been used for the treatment of gastrointestinal (GI) disorders, such as GI pain, gastroenteritis and diarrhea.

Δ9tetrahydrocannabinol, as well as endogenous and synthetic cannabinoids, exert their biological functions on the gastrointestinal tract by activating two types of cannabinoid receptors, CB1 receptor and CB2 receptor.

While CB1 receptors are located in the enteric nervous system and in sensory terminals of vagal and spinal neurons and regulate neurotransmitter release, CB2 receptors are mostly distributed in the immune system, with a role presently still difficult to establish.

Under pathophysiological conditions, the endocannabinoid system conveys protection to the GI tract, eg from inflammation and abnormally high gastric and enteric secretion.

Anti-inflammatory cannabinoids in diet

Anandamide and 2-AG have been shown to inhibit the inflammatory processes triggered upon activation of the toll-like receptor complex CD14/TLR4/MD2 (i.e., LPS and carrageenan stimulation).

The same effect has also been reported for other CB2 receptor agonists like JWH133,12 HU-308,13 and N-alkylamides.

Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid-type CB2 receptor

Cannabinoids have already been shown to suppress several macrophage functions, including phagocytosis, cytolysis and cytokine secretion.

Identification of the mRNA for the CB1 receptor in human neuroblastoma SH-SY5Y cells, and the mRNA and protein for the CB2 receptor in human microglia and THP-1 cells.

THP-1 cells appear generally to be a good model for human macrophages having a range of properties similar to microglia and other mononuclear phagocytes, including release of such products as superoxide anion, TNF-α, IL-1ß, prostaglandin E2.

Endogenous cannabinoid system protects against colonic inflammation

Conclusion: The endogenous cannabinoid system is physiologically involved in the protection against excessive inflammation in the colon, both by dampening smooth muscular irritation caused by inflammation and by controlling cellular pathways leading to inflammatory responses. These results strongly suggest that modulation of the physiological activity of the endogenous cannabinoid system during colonic inflammation might be a promising therapeutic tool for the treatment of several diseases characterized by inflammation of the gastrointestinal tract.

Cannabinoids in intestinal inflammation and cancer.

Conclusion: Pharmacological eg● endocannabinoid levels may be a promising strategy to counteract intestinal inflammation and colon cancer.

Members of the endocannabinoid system are distinctly regulated in inflammatory bowel disease and colorectal cancer

The two forms of IBD, ulcerative colitis (UC) and Crohn's disease (CD) have rapidly increased in the past years in Western countries ranging at a prevalence of more than 200 cases per 100,000 inhabitants.

Differential Expression of Cannabinoid Receptors in the Human Colon: Cannabinoids Promote Epithelial Wound Healing

Initially, restitution is achieved by epithelial dedifferentiation and migration, followed by proliferation, and, finally, differentiation and maturation. LPA has been shown to enhance intestinal epithelial wound healing through increased epithelial cell migration.

gastric cancer

Effect of a synthetic cannabinoid agonist on the proliferation and invasion of gastric cancer cells.

Conclusion: Cannabinoids as a new gastric cancer therapy.

Pharmacological synergism between cannabinoids and paclitaxel in gastric cancer cell lines

Conclusion: Cannabinoids as a good palliative agent for cancer patients receiving paclitaxel.

Cannabidiol promotes apoptosis via regulation of XIAP/Smac in gastric cancer

Conclusion: Our study showed that CBD induces apoptotic cell death in gastric cancer cells, which is triggered by ER stress generation and subsequent XIAP inhibition by Smac. Taken together, our results suggest the potential of CBD in novel treatments against gastric cancer.

Cannabidiol Induces Cell Cycle Arrest and Cell Apoptosis in Human Gastric Cancer SGC-7901 Cells

To study the effect of CBD on gastric cancer in vitro, we treated the gastric cancer SGC-7901 cells with different concentrations of CBD for 24 and 48 h. These results indicated that CBD could effectively induce cell cycle arrest at the G0–G1 phase by inhibiting CDK2 and cyclin E expression. We found that as the concentration of CBD increased, the percentage of apoptotic cells in the SGC-7901 population increased. These results indicated that CBD effectively induced apoptosis in SGC-7901 cells.

chronic liver disease

Use of cannabidiol in the treatment of autoimmune hepatitis

The role of the endocannabinoid system in liver diseases

Conclusion: The EC system is strongly up-regulated during chronic liver diseases. Until now it has been implicated in the pathogenesis of fatty liver disease associated with obesity, alcohol abuse, and hepatitis C, in the progression of fibrosis to cirrhosis, and in the development of portal hypertension, hyperdynamic circulatory syndrome and its complications, and cirrhotic cardiomyopathy. Furthermore, the EC system can participate in the pathogenesis of acute liver injury by modulating the mechanisms responsible for cell injury and inflammatory response. Thus, targeting the CB1 and CB2 receptors represents a potential therapeutic goal for the treatment of liver diseases.

Cannabinoid receptors as new targets of antifibrosing strategies during chronic liver diseases

Conclusion: Endocannabinoid-based therapies, combining CB2 agonists and CB1 antagonists may open novel therapeutic perspectives for the treatment of chronic liver diseases.

The endocannabinoid system as a key mediator during liver diseases

Conclusion: CB1 receptors have been implicated in the pathogenesis of several lesions such as liver fibrogenesis, alcoholic and metabolic steatosis, or circulatory failure associated with cirrhosis. In contrast, stimulation of hepatic CB2 receptors is emerging as an overall protective pathway with antifibrogenic properties and beneficial effects on liver inflammation, alcoholic fatty liver and hepatocyte survival and regeneration.

Beneficial paracrine effects of cannabinoid receptor 2 on liver injury and regeneration

The present study shows that activation of CB2 receptors alleviates CCl4-induced hepatitis and accelerates liver regeneration, therefore identifying CB2 agonists as potential beneficial hepatoprotective agents.

Conclusion: CB2 receptors reduce liver injury and promote liver regeneration following acute insult, via distinct paracrine mechanisms involving hepatic myofibroblasts.

CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis

Conclusion: Our study shows that CB1 receptor antagonists hold promise for the treatment of liver fibrosis.

Cannabidiol protects liver from binge alcohol-induced steatosis

Conclusion: CBD can alleviate lipid accumulation in both an in vitro HepG2 cell model and an in vivo binge alcohol treatment model by multiple mechanisms.

Cannabinoid CB2 receptors protect against alcoholic liver disease by regulating Kupffer cell polarization

Conclusion: These findings demonstrate that CB2 receptors display beneficial effects on alcohol-induced inflammation by regulating M1/M2 balance in Kupffer cells, thereby reducing hepatocyte steatosis via paracrine interactions between Kupffer cells and hepatocytes.

Two non-psychoactive cannabinoids reduce intra-cellular lipid levels and inhibit hepatosteatosis

Conclusion: Our results suggest that THCV and CBD might be used as new therapeutic agents for the pharmacological treatment of obesity- and metabolic syndrome-related NAFLD/hepatosteatosis

Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy

Δ9-THC- and JWH-015-induced autophagy and apoptosis relies on CB2 receptor activation
Δ9-THC and JWH-015 inhibit the growth of the human HCC lines HepG2 and HuH-7 via autophagy stimulation
AMPK activation and TRB3 upregulation involved Δ9-THC- and JWH-015-induced autophagy and apoptosis of HCC cells
AMPK and TRB3 regulate cannabinoid-induced autophagy of HCC cells through different mechanisms
Activation of AMPK by cannabinoids relies on CAMKK


Regulation of nausea and vomiting by cannabinoids

Considerable evidence demonstrates that manipulation of the endocannabinoid system regulates nausea and vomiting in humans and other animals. The anti-emetic effect of cannabinoids has been shown across a wide variety of animals that are capable of vomiting in response to a toxic challenge. CB1 agonism suppresses vomiting, which is reversed by CB1 antagonism, and CB1 inverse agonism promotes vomiting.

Regulation of nausea and vomiting by the endocannabinoid system

One of the oldest pharmacological remedies for nausea and vomiting is the plant cannabis. In clinical trials, cannabis-based medicines have been found to be effective anti-emetics and even surpass some modern treatments in their potential to alleviate nausea.

Cannabinoids suppress acute and anticipatory nausea

Conclusion: Cannabinoids have great promise as treatments for nausea and that their anti-nausea effects may be mediated by the interoceptive insular cortex.

Regulation of nausea and vomiting by cannabinoids

Conclusion: This model may be a useful tool for elucidating the neurobiology of nausea and the role that the endocannabinoid system plays in the regulation of this distressing condition.

Regulation of nausea and vomiting by cannabinoids

Conclusion: Future efforts aimed at developing new endocannabinoid-based anti-nausea and anti-emetic therapies are clearly warranted.

kidney fibrosis

Expression of cannabinoid receptors in human kidney

Conclusion: Our data suggest a possible implication of the endocannabinoid system in the physiology and development of the human kidney.

Cannabinoid receptor 1 is a major mediator of renal fibrosis

Conclusion: CB1 has a major role in the activation of myofibroblasts and may be a new target for treating chronic kidney disease.

Cannabinoid-2 receptor activation ameliorates hepatorenal syndrome


Cannabinoids Alleviate Experimentally Induced Intestinal Inflammation by Acting at Central and Peripheral Receptors

In conclusion, in the present study we showed that the CB receptor agonists AM841 and CB 13 displayed protective and therapeutic effects on colitis in mice. Most importantly, we demonstrated that the anti-inflammatory action of the cannabinoids was mediated through CB1 and CB2 receptors localized centrally and possibly to a lesser extent - peripherally. To the best of our knowledge, this is the first evidence showing the involvement of central CB receptors in development and treatment of colitis. These results are crucial for our understanding of the pharmacology of CB ligands in GI inflammation and may have potential applications in the development of future treatment strategies for IBD in humans.

Cannabidiol, a safe and non-psychotropic ingredient of the marijuana plant Cannabis sativa, is protective in a murine model of colitis

Cannabidiol, a safe and non-psychotropic ingredient of marijuana, exerts pharmacological effects (e.g., antioxidant) and mechanisms (e.g., inhibition of endocannabinoids enzymatic degradation) potentially beneficial for the inflamed gut.


Cannabis for inflammatory bowel disease

The endocannabinoid system is involved in almost all major immune events.

In murine colitis, cannabinoids decrease histologic and microscopic inflammation.

In humans, cannabis has been used to treat a plethora of gastrointestinal problems, including anorexia, emesis, abdominal pain, diarrhea, and diabetic gastroparesis.

In an observational study in 30 patients with Crohn's disease (CD), we found that medical cannabis was associated with improvement in disease activity and reduction in the use of other medications.

In a more recent placebo-controlled study in 21 chronic CD patients, we showed a decrease in the CD activity index >100 in 10 of 11 subjects on cannabis compared to 4 of 10 on placebo.

Complete remission was achieved in 5 of 11 subjects in the cannabis group and 1 of 10 in the placebo group.

Cannabis induces a clinical response in patients with Crohn's disease

Conclusion: A short course (8 weeks) of THC-rich cannabis produced significant clinical, steroid-free benefits to 10 of 11 patients with active Crohn's disease, compared with placebo, without side effects.

Treatment of Crohn's Disease with Cannabis


The Expanded Endocannabinoid System/Endocannabinoidome as a Potential Target for Treating Diabetes Mellitus

As with the eCB system, many eCBome members regulate several physiological processes, including energy intake and storage, glucose and lipid metabolism and pancreatic health, which contribute to the development of type 2 diabetes (T2D). Preclinical studies increasingly support the notion that targeting the eCBome may beneficially affect T2D. The eCBome is implicated in T2D at several levels and in a variety of tissues, making this complex lipid signaling system a potential source of many potential therapeutics for the treatments for T2D.

Activation of the Peripheral Endocannabinoid System in Human Obesity

Activation of CB-1 receptors in the gastrointestinal tract may also be relevant for the pathogenesis of obesity. The response of circulating ghrelin to fasting was diminished with rimonabant, suggesting that CB-1 receptors are involved in ghrelin secretion

unique library index

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