Category Archives: Inflammatory Bowel Disease

Dietary Cannabidiol Activates PKA/AMPK Signaling and Attenuates Chronic Inflammation and Leaky Gut in DSS-Induced Colitis Mice

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“Scope: Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the gut, accompanied by impaired epithelial integrity, increased macrophage infiltration, and enhanced colon cancer risk.

Methods and results: Cannabidiol (CBD), a phytocannabinoid isolated from cannabis plants, is supplemented into mice diet, and its beneficial effects against dextran sulfate sodium (DSS)-induced experimental colitis is evaluated. Eight-week-old mice were fed a standard diet supplemented with or without CBD (200 mg kg-1 ) for 5 weeks. In the 4th week of dietary treatment, mice were subjected to 2.5% DSS induction for 7 days, followed by 7 days of recovery, to induce colitis. CBD supplementation reduced body weight loss, gross bleeding, fecal consistency, and disease activity index. In addition, CBD supplementation protected the colonic structure, promoted tissue recovery, and ameliorated macrophage infiltration in the colonic tissue, which was associated with the activation of cyclic AMP-protein kinase A, extracellular signal-regulated kinase ½, and AMP-activated protein kinase signaling pathways. CBD supplementation also suppressed NLRP3 inflammasome activation and related pro-inflammatory marker secretion. Consistently, CBD feeding reduced tight junction protein claudin2 and myosin light chain kinase in DSS-treated mice.

Conclusion: Dietary CBD protects against inflammation and colitis symptoms induced by DSS, providing an alternative approach to IBD management.”

https://pubmed.ncbi.nlm.nih.gov/38175840/

https://onlinelibrary.wiley.com/doi/10.1002/mnfr.202300446

Phytocannabinoids Reduce Inflammation of Primed Macrophages and Enteric Glial Cells: An In Vitro Study

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“Intestinal inflammation is mediated by a subset of cells populating the intestine, such as enteric glial cells (EGC) and macrophages. Different studies indicate that phytocannabinoids could play a possible role in the treatment of inflammatory bowel disease (IBD) by relieving the symptoms involved in the disease.

Phytocannabinoids act through the endocannabinoid system, which is distributed throughout the mammalian body in the cells of the immune system and in the intestinal cells. Our in vitro study analyzed the putative anti-inflammatory effect of nine selected pure cannabinoids in J774A1 macrophage cells and EGCs triggered to undergo inflammation with lipopolysaccharide (LPS). The anti-inflammatory effect of several phytocannabinoids was measured by their ability to reduce TNFα transcription and translation in J774A1 macrophages and to diminish S100B and GFAP secretion and transcription in EGCs.

Our results demonstrate that THC at the lower concentrations tested exerted the most effective anti-inflammatory effect in both J774A1 macrophages and EGCs compared to the other phytocannabinoids tested herein.

We then performed RNA-seq analysis of EGCs exposed to LPS in the presence or absence of THC or THC-COOH. Transcriptomic analysis of these EGCs revealed 23 differentially expressed genes (DEG) compared to the treatment with only LPS. Pretreatment with THC resulted in 26 DEG, and pretreatment with THC-COOH resulted in 25 DEG. To evaluate which biological pathways were affected by the different phytocannabinoid treatments, we used the Ingenuity platform. We show that THC treatment affects the mTOR and RAR signaling pathway, while THC-COOH mainly affects the IL6 signaling pathway.”

https://pubmed.ncbi.nlm.nih.gov/37834076/

https://www.mdpi.com/1422-0067/24/19/14628

Cannabidiol attenuates inflammatory impairment of intestinal cells expanding biomaterial-based therapeutic approaches

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“Cannabis-based biomaterials have the potential to deliver anti-inflammatory therapeutics specifically to desired cells, tissues, and organs, enhancing drug delivery and the effectiveness of anti-inflammatory treatment while minimizing toxicity. As a major component of Cannabis, Cannabidiol (CBD) has gained major attention in recent years because of its potential therapeutic properties, e.g., for restoring a disturbed barrier resulting from inflammatory conditions. The aim of this study was to test the hypothesis that CBD has beneficial effects under normal and inflammatory conditions in the established non-transformed intestinal epithelial cell model IPEC-J2. CBD induced a significant increase in transepithelial electrical resistance (TER) values and a decrease in the paracellular permeability of [³H]-D-Mannitol, indicating a strengthening effect on the barrier. Under inflammatory conditions induced by tumor necrosis factor alpha (TNFα), CBD stabilized the TER and mitigated the increase in paracellular permeability. Additionally, CBD prevented the barrier-disrupting effects of TNFα on the distribution and localization of sealing TJ proteins. CBD also affected the expression of TNF receptors. These findings demonstrate the potential of CBD as a component of Cannabis-based biomaterials used in the development of novel therapeutic approaches against inflammatory pathogenesis.”

https://pubmed.ncbi.nlm.nih.gov/37779918/

“Overall, these findings suggest that CBD will be a promising component in biomaterial-based therapeutic approaches for the treatment of inflammatory pathomechanisms.”

https://www.sciencedirect.com/science/article/pii/S2590006423002685?via%3Dihub

Cannabinoids and the GI Tract

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“The synthesis and degradation of endocannabinoids, location of cannabinoid (CB) receptors, and cannabinoid mechanisms of action on immune/inflammatory, neuromuscular, and sensory functions in digestive organs are well documented. CB2 mechanisms are particularly relevant in immune and sensory functions. Increasing use of cannabinoids in the USA is impacted by social determinants of health including racial discrimination which is associated with tobacco and cannabis co-use, and combined use disorders. Several conditions associated with emesis are related to cannabinoid use, including cannabinoid hyperemesis or withdrawal, cyclic vomiting syndrome, nausea and vomiting of pregnancy. Cannabinoids generally inhibit gastrointestinal motor function; yet they relieve symptoms in patients with gastroparesis and diverse nausea syndromes. Cannabinoid effects on inflammatory mechanisms have shown promise in relatively small placebo-controlled studies in reducing disease activity and abdominal pain in patients with inflammatory bowel disease (IBD). Cannabinoids have been studied in disorders of motility, pain, and disorders of gut brain interaction. The CB2 receptor agonist, cannabidiol, reduced total Gastroparesis Cardinal Symptom Index and increased ability to tolerate a meal in patients with gastroparesis appraised over 4 weeks of treatment. In contrast, predominant-pain endpoints in functional dyspepsia with normal gastric emptying were not significantly improved with cannabidiol. The CB2 agonist, olorinab, reduced abdominal pain in IBD in an open-label trial and in constipation-predominant irritable bowel syndrome in a placebo-controlled trial. Cannabinoid mechanisms alter inflammation in pancreatic and liver diseases. In conclusion, cannabinoids, particularly agents affecting CB2 mechanisms, have potential for inflammatory, gastroparesis, and pain disorders; however, the trials require replication and further understanding of risk-benefit to enhance use of cannabinoids in gastrointestinal diseases.”

https://pubmed.ncbi.nlm.nih.gov/37678488/

Cannabidiol acts as molecular switch in innate immune cells to promote the biosynthesis of inflammation-resolving lipid mediators

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“Cannabinoids are phytochemicals from cannabis with anti-inflammatory actions in immune cells. Lipid mediators (LM), produced from polyunsaturated fatty acids (PUFA), are potent regulators of the immune response and impact all stages of inflammation. How cannabinoids influence LM biosynthetic networks is unknown. Here, we reveal cannabidiol (CBD) as a potent LM class-switching agent that stimulates the production of specialized pro-resolving mediators (SPMs) but suppresses pro-inflammatory eicosanoid biosynthesis. Detailed metabololipidomics analysis in human monocyte-derived macrophages showed that CBD (i) upregulates exotoxin-stimulated generation of SPMs, (ii) suppresses 5-lipoxygenase (LOX)-mediated leukotriene production, and (iii) strongly induces SPM and 12/15-LOX product formation in resting cells by stimulation of phospholipase A2-dependent PUFA release and through Ca2+-independent, allosteric 15-LOX-1 activation. Finally, in zymosan-induced murine peritonitis, CBD increased SPM and 12/15-LOX products and suppressed pro-inflammatory eicosanoid levels in vivo. Switching eicosanoid to SPM production is a plausible mode of action of CBD and a promising inflammation-resolving strategy.”

https://pubmed.ncbi.nlm.nih.gov/37647900/

https://www.cell.com/cell-chemical-biology/fulltext/S2451-9456(23)00249-0?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2451945623002490%3Fshowall%3Dtrue

Role of Gut Microbiota in Cannabinoid-Mediated Suppression of Inflammation

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“Cannabinoids and the endocannabinoid system have been well established to play a crucial role in the regulation of the immune response. Also, emerging data from numerous investigations unravel the imperative role of gut microbiota and their metabolites in the maintenance of immune homeostasis and gut barrier integrity. In this review, we concisely report the immunosuppressive mechanisms triggered by cannabinoids, and how they are closely associated with the alterations in the gut microbiome and metabolome following exposure to endogenous or exogenous cannabinoids. We discuss how cannabinoid-mediated induction of microbial secondary bile acids, short chain fatty acids, and indole metabolites, produced in the gut, can suppress inflammation even in distal organs. While clearly, more clinical studies are necessary to establish the cross talk between exo- or endocannabinoid system with the gut microbiome and the immune system, the current evidence opens a new avenue of cannabinoid-gut-microbiota-based therapeutics to regulate immunological disorders.”

https://pubmed.ncbi.nlm.nih.gov/36776218/

“The microbiome-eCB signaling modulation exploiting exo- or endogenous cannabinoids opens a new avenue of cannabinoid-gut microbiota-based therapeutics to curb metabolic and immune-oriented conditions.”

https://www.frontierspartnerships.org/articles/10.3389/adar.2022.10550/full

Impact of Cannabis Use on Inpatient Inflammatory Bowel Disease Outcomes in 2 States Legalizing Recreational Cannabis

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“Background: We evaluated the impact of recreational cannabis legalization on use and inpatient outcomes of patients with inflammatory bowel disease (IBD).

Methods: Hospitalized adult patients in Colorado and Washington before (2011) and after (2015) recreational cannabis legalization were compared by chi-square tests for categorical variables and t-tests for continuous variables. Multivariable regression models adjusting for demographic data were fit to assess the association of cannabis use with hospital outcomes.

Results: Reported cannabis use increased after legalization (1.2% vs 4.2%, P < .001). On multivariable analysis, in 2011, cannabis users were less likely to need total parenteral nutrition (odds ratio 0.12, P = .038), and in 2015 had less hospital charges ($-8418, P = .024).

Conclusions: The impact of cannabis legalization and use on IBD is difficult to analyze but may have implications on inpatient IBD outcomes as described in this retrospective analysis. Large, prospective studies are needed to evaluate other IBD outcomes based on cannabis legalization and use.”

https://pubmed.ncbi.nlm.nih.gov/36777043/

“Lay Summary

Colorado and Washington inpatient databases were analyzed before (2011) and after (2015) recreational cannabis legalization assessing use and inflammatory bowel disease outcomes. Cannabis use increased after legalization. In 2011, cannabis users were less likely to need total parenteral nutrition, and in 2015 had less hospital charges.”

https://academic.oup.com/crohnscolitis360/article/4/2/otac015/6576191?login=false


The effect of medical cannabis in inflammatory bowel disease: analysis from the UK Medical Cannabis Registry

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“Objectives: Cannabis-based medicinal products (CBMPs) have shown promising preclinical activity in inflammatory bowel disease. However, clinical trials have not demonstrated significant effects on active inflammation. This study aims to analyze changes in health-related quality of life (HRQoL) and adverse events in IBD patients prescribed CBMPs.

Methods: A case series from the UK Medical Cannabis Registry was performed. Primary outcomes included changes from baseline in the Short Inflammatory Bowel Disease Questionnaire (SIBDQ), Generalized Anxiety Disorder-7 (GAD-7), Single-Item Sleep Quality Scale (SQS), and EQ-5D-5L Index score at 1 and 3 months. Statistical significance was defined using p<0.050. Secondary outcomes included incidence of adverse events.

Results: Seventy-six patients with Crohn’s disease (n=51; 67.11%) and ulcerative colitis (n=25; 32.89%) were included. The median baseline SIBDQ score improved at 1 and 3 months. EQ-5D-5L index values, GAD-7 and SQS also improved after 3 months (p<0.050). Sixteen (21.05%) patients reported adverse events with the majority being classified as mild to moderate in severity. No life-threatening AEs were reported.

Conclusion: Patients treated with CBMPs for refractory symptoms of Crohn’s disease and ulcerative colitis demonstrated a short-term improvement in IBD-specific and general HRQoL. Prior cannabis consumers reported greater improvement compared to cannabis-naïve individuals.”

https://pubmed.ncbi.nlm.nih.gov/36562418/

https://www.tandfonline.com/doi/abs/10.1080/17474124.2022.2161046?journalCode=ierh20

Phytocannabinoids Act Synergistically with Non-Steroidal Anti-Inflammatory Drugs Reducing Inflammation in 2D and 3D In Vitro Models

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“Lung inflammation is associated with elevated pro-inflammatory cytokines and chemokines. Treatment with FCBD:std (standard mix of cannabidiol [CBD], cannabigerol [CBG] and tetrahydrocannabivarin [THCV]) leads to a marked reduction in the inflammation of alveolar epithelial cells, but not in macrophages.

In the present study, the combined anti-inflammatory effect of FCBD:std with two corticosteroids (dexamethasone and budesonide) and two non-steroidal anti-inflammatory drugs (NSAID; ibuprofen and diclofenac), was examined. Enzyme-linked immunosorbent assay (ELISA) was used to determine protein levels. Gene expression was determined by quantitative real-time PCR. Inhibition of cyclo-oxygenase (COX) activity was determined in vitro.

FCBD:std and diclofenac act synergistically, reducing IL-8 levels in macrophages and lung epithelial cells. FCBD:std plus diclofenac also reduced IL-6, IL-8 and CCL2 expression levels in co-cultures of macrophages and lung epithelial cells, in 2D and 3D models. Treatment by FCBD:std and/or NSAID reduced COX-1 and COX-2 gene expression but not their enzymatic activity. FCBD:std and diclofenac exhibit synergistic anti-inflammatory effects on macrophages and lung epithelial cells, yet this combined activity needs to be examined in pre-clinical studies and clinical trials.”

https://pubmed.ncbi.nlm.nih.gov/36559009/

“We have shown that FCBD:std and diclofenac have synergistic anti-inflammatory effects on macrophages and lung epithelial cells, which involve the reduction of COX and CCL2 gene expression and IL levels. FCBD:std, when combined with diclofenac, can have considerably increased anti-inflammatory activity by several fold, suggesting that in an effective cannabis-diclofenac combined treatment, the level of NSAIDs may be reduced without compromising anti-inflammatory effectivity.”

https://www.mdpi.com/1424-8247/15/12/1559

Cannabinoid Therapeutic Effects in Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

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“Introduction: Inflammatory Bowel Disease (IBD) patients may benefit from cannabinoid administration supplementary therapy; currently no consensus on its effect has been reached.

Methods: a systematic review of RCTs on cannabinoid supplementation therapy in IBD has been conducted; data sources were MEDLINE, Scopus, ClinicalTrials.

Results: out of 974 papers found with electronic search, six studies have been included into the systematic review, and five of them, for a grand total of 208 patients, were included into the meta-analysis.

Conclusions: cannabinoid supplementation as adjuvant therapy may increase the chances of success for standard therapy of Crohn’s Disease during the induction period; no statement on its potential usage during maintenance period can be derived from retrieved evidence. Its usage in Ulcerative Colitis is not to be recommended. If ever, low-dose treatment may be more effective than higher dosage. Mean CDAI reduction was found stronger in patients treated with cannabinoids (mean CDAI reduction = 36.63, CI 95% 12.27-61.19) than placebo. In future studies, it is advisable to include disease activity levels, as well as patient-level information such as genetic and behavioral patterns.”

https://pubmed.ncbi.nlm.nih.gov/36289701/

https://www.mdpi.com/2227-9059/10/10/2439/htm