Multi-targeting inulin-based nanoparticles with cannabidiol for effective prevention of ulcerative colitis

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“The pathogenesis of ulcerative colitis (UC) is closely related to severe inflammation, damaged colonic mucosal barrier, increased oxidative stress and intestinal ecological imbalance. However, due to the nonspecific distribution and poor bioavailability of drugs, UC treatment is still a serious challenge. Here, a mitochondria/colon dual targeted nanoparticles based on redox response was developed to effectively alleviate UC.

Cannabidiol nanoparticles (CBD NPs) with a particle size of 143.2 ± 3.11 nm were prepared by self-assembly using polymers (TPP-IN-LA) obtained by modifying inulin with (5-carboxypentyl) triphenyl phosphonium bromide (TPP) and α-lipoic acid (α-LA). Excitingly, the constructed CBD NPs showed excellent mitochondrial targeting, with a Pearson correlation coefficient of 0.76 at 12 h.

The results of animal imaging in vivo showed that CBD NPs could be effectively accumulated in colon tissue. Not only that, CBD showed significant glutathione stimulated release in the presence of 10 mM glutathione at pH 7.4.

The results of in vivo animal experiments showed that CBD NPs significantly ameliorated DSS-induced colonic inflammation by modulating the TLR4-NF-κB signaling pathway. Moreover, CBD NPs significantly improved the histological damage of colon in UC mice, increased the expression level of tight junction protein ZO-1, and effectively restored the intestinal mucosal barrier function and intestinal mucosal permeability.

More importantly, CBD NPs significantly improved the species composition, abundance and amount of short chain fatty acids of intestinal flora in UC mice, thus effectively maintaining the balance of intestinal flora. The dual-targeted and glutathione-responsive nanoparticles prepared in this study provide a promising idea for achieving targeted delivery of CBD for effective treatment of UC.”

Medical Cannabis Increases Appetite but Not Body Weight in Patients with Inflammatory Bowel Diseases

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“We aimed to elucidate the effect of Medical Cannabis (MC) on appetite and nutritional status among patients with inflammatory bowel disease (IBD). A case series of patients with IBD were initiating treatment with MC for disease-related symptoms, at the IBD clinic of a tertiary referral medical center. Patients’ demographics, anthropometrics, medical history and treatment and MC use were systematically recorded. An appetite and food frequency questionnaire (SNAQ and FFQ) were filled before, and at 3 and 6 months of treatment. Patients with IBD initiating MC were enrolled (n = 149, age 39.0 ± 14.1 years, 42.3% female), and 33.6% (n = 50) were treated for improvement of nutritional status. A modest increase in appetite after 3 months was detected among all patients enrolled (Pv = 0.08), but there were no significant differences in energy or macronutrient intake, and in patients’ body mass index (BMI). A significant appetite improvement after 3 months was detected among 34.0% (n = 17) of patients, but this was not associated with increased caloric intake or BMI at 3 or 6 months. Among patients without increased appetite after 3 months of MC therapy, BMI decreased at 6 months (24.1 ± 3.7 vs. 23.4 ± 3.6, Pv = 0.010). MC may be a potential strategy to improve appetite among some patients with IBD, but not caloric intake or BMI.”

“MC may be a potential strategy to increase appetite among some patients with IBD, which may prevent further weight loss, but is not associated with a significant increase in caloric intake or in BMI.”

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.”

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.”

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.”

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

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.”

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.”

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.”

“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.”

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.”

“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.”

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.”