Category Archives: Inflammatory Bowel Disease

Isoorientin Modulates Gut Microbes and Their Metabolites to Alleviate Caco-2 Cell Monolayer Inflammation by Reducing Intestinal Permeability via P-Gp/eCBs

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“Introduction: Isoorientin (ISO) is a naturally occurring flavonoid that studies have shown to have strong experimental antioxidant, anti-inflammatory, anti-diabetic and anti-obesity properties. It has been shown that ISO alleviates Dextran sodium sulfate (DSS) induced colitis in mice by modulating gut microbes and their metabolites. The aim of this study was to modulate gut microbes and their metabolism by ISO to investigate its anti-inflammatory effects and its specific molecular mechanisms in a lipopolysaccharide (LPS)-induced monolayer inflammation model in Caco-2 cells.

Methods: Feces from ISO-treated DSS colitis mice were collected and gut flora culture supernatants were prepared. Detection of the effect of intestinal flora supernatants on the monolayer barrier of Caco-2 cells by inoculation of Caco-2 cells into the Transwell transmembrane culture system to simulate the intestinal mucosal barrier.

Results: The results revealed that ISO-conditioned intestinal flora supernatant significantly increased TEER values, decreased intestinal epithelial FITC-dextran flux permeability, and restored LPS-induced occludin, ZO-1 protein expression in Caco-2 cells. Meanwhile, intestinal flora supernatant significantly ameliorated the LPS-induced inflammatory response. In addition, ISO further enhanced its protective effect on intestinal permeability by regulating the expression of P-glycoprotein (P-gp) and endogenous cannabinoid system (eCB)-related proteins, which may attenuate the inflammatory response by activating the P-gp/eCB signaling pathway.

Conclusion: The present study offers fresh perspectives into the application of ISO-conditioned intestinal flora supernatant as a potential anti-inflammatory agent and intestinal barrier protector in vitro. The unique regulation of the P-gp/eCBs pathway by ISO-conditioned intestinal flora supernatant was the novel mechanistic insights provided in this study.”

https://pubmed.ncbi.nlm.nih.gov/41126978/

“Overall, these findings could be instrumental in formulating treatment approaches involving ISO for managing inflammation-associated conditions in patients with IBD.”

https://www.dovepress.com/isoorientin-modulates-gut-microbes-and-their-metabolites-to-alleviate–peer-reviewed-fulltext-article-JIR

“Isoorientin is a flavonoid found in cannabis and hemp plants.”

  • “Hemp seed: Isoorientin has been detected in the seeds of Cannabis sativa (hemp) and shown to possess bioactivity, including neuroprotective effects.
  • Cannabis plant: The overall flavonoid content, including isoorientin, can vary depending on environmental factors like growing conditions.”

Efficacy of non-psychotropic Cannabis sativa L. standardized extracts in a model of intestinal inflammation

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“Background: The use of Cannabis sativa L. (Cannabis) was reported by observational studies on inflammatory bowel diseases (IBD) patients. However, this indication is poorly supported by clinical trials. Several pre-clinical studies demonstrated the anti-inflammatory activity of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and cannabidiol (CBD) at intestinal level. On the contrary, minor cannabinoids, such as cannabigerol (CBG), were less investigated. Moreover, several authors suggested that complex Cannabis extracts might display a higher efficacy in respect to pure cannabinoids against inflammatory disorders.

Methods: This study was aimed at investigating the role of Cannabis extracts, standardized in CBD and CBG content, in a model of in vitro-induced intestinal inflammation using CaCo-2 cells. Inflammatory mediators at transcriptional (PCR arrays) and protein level (ELISA assays) were investigated and correlated with enterocyte layer permeability. The two evaluated extracts, A and B, come from the mix of the same Cannabis varieties (Cannabis sativa L. Chemotype III and Chemotype IV), and are standardized in CBD and CBG at the same level, by changing the polarity of the primary extraction solvents.

Results: Pro-inflammatory cytokines involved in IBD, such as IL-1β and IFN-γ, induced the expression and the release of chemokines for lymphocytes (CXCL-9, CXCL-10, CCL20) in CaCo-2, while Cannabis extracts (100 µg/mL) or individual compounds (8 µM) showed inhibitory activity. After simulated digestion, extract A abrogated the release of CCL-20, while extract B abrogated the release of CXCL-9 and CXCL-10. The inhibition of CXCL-9 was demonstrated at transcriptional level also. The inhibitory activity paralleled with the content of CBD or CBG, acting at least in part through NF-κB impairment (-42% and – 66%, respectively). However, Cannabis extracts showed greater effect in the CaCo-2-THP-1 co-culture inflammation model compared to individual cannabinoids, thus partially recovering the epithelial barrier measured by transepithelial electrical resistance (TEER), and zonula occludens (ZO-1) expression.

Conclusions: Data collected within this study showed the importance of standardization and extraction method reproducibility through manufacturing and process control, besides demanding future investigations focusing on the effect of Cannabis extracts against intestinal inflammation, which show in this context effects higher than individual cannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/41053843/

“At the best of our knowledge, this is one of the few works in which the biological properties of standardized Cannabis extracts were compared with their major cannabinoids. More generally, the role of CBG in intestinal inflammation is matter of interest for its non-psychotropics nature, but it was investigated by few articles before. However, our data suggest that the use of Cannabis extracts against intestinal inflammation might be preferred in respect to single cannabinoids. Nevertheless, specific studies should be conducted with the aim to translate the evidence to in vivo models.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-025-00335-2

Orally Administered CBD/CBG Hemp Extract Reduces Severity of Ulcerative Colitis and Pain in a Murine Model

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“Background: Ulcerative colitis (UC) is an autoimmune disorder characterized by inflammation of the mucosa that gives rise to a disrupted epithelial morphology. Persistent or recurrent inflammation and the debilitating nature of the associated symptoms make treatment of UC challenging. Cannabinoids derived from Cannabis sativa L. have been used for treatment of gastrointestinal disorders due to the wide-ranging therapeutic benefits of these compounds. 

Methods: We evaluated a commercial hemp extract, high in cannabigerol (CBG) and cannabidiol (CBD), as a novel treatment for UC symptoms using the dextran sodium sulfate (DSS) model in mice. Hemp extract was administered via two different routes of administration, intraperitoneal (i.p) and oral (p.o). 

Results: Specifically, we observed that cannabinoid treatment reduced damage to the colonic epithelium. We also observed that CBG/CBD rich hemp extracts help reduce pain-related responses in these animals. 

Conclusions: Together, the data suggest that cannabinoid administration has the potential to be an effective alternate therapeutic option for UC management.”

https://pubmed.ncbi.nlm.nih.gov/40943856/

“Our current findings suggest that minor cannabinoids, particularly CBD and CBG, may prove to be useful, novel therapies for treating IBD. These findings are important because patients already report using cannabis and cannabinoid-based products for managing their symptoms, despite little clinical data to support the use of high-THC products for treating IBD.

In conclusion, our data suggest that HE enriched for CBD and CBG may offer therapeutic potential as a treatment for IBD patients.”

https://www.mdpi.com/2077-0383/14/17/6095

Cannabidiol Enhances the Therapeutic Efficacy of Olsalazine and Cyclosporine in a Murine Model of Colitis

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“Current therapies for inflammatory bowel disease (IBD), such as olsalazine and cyclosporine, often exhibit limited long-term efficacy and are associated with adverse effects. Cannabidiol (CBD), a non-psychoactive phytocannabinoid, shows promise for its anti-inflammatory properties, though its effectiveness as a monotherapy remains inconclusive.

This study investigates the therapeutic potential of combining low-dose CBD (10 mg/kg) with olsalazine (50 mg/kg) or cyclosporine (2.5, 5 mg/kg) in dextran sulphate sodium (DSS)-induced acute and chronic colitis models in mice.

Disease severity was assessed via disease activity index (DAI), colon morphology, cytokine and chemokine expression, myeloperoxidase (MPO) activity, systemic inflammatory markers, and glucagon-like peptide-1 (GLP-1) regulation. Safety evaluations included haematology and plasma biochemistry. DSS-treated mice showed elevated DAI scores, colon shortening, heightened inflammation, and organ enlargement. Combination therapies significantly ameliorated colitis, reducing DAI, MPO activity, and inflammatory cytokines, while restoring colon length and GLP-1 levels-without inducing liver or kidney toxicity.

These findings demonstrate that combining a low dose of CBD with standard IBD drugs enhances therapeutic efficacy while minimizing side effects, supporting its integration into future combination strategies for more effective and safer IBD management.”

https://pubmed.ncbi.nlm.nih.gov/40869234/

“Cannabidiol (CBD), a non-psychoactive phytocannabinoid derived from Cannabis sativa, has emerged as a promising therapeutic candidate for the treatment of inflammatory conditions, including IBD. CBD’s anti-inflammatory, antioxidant, and immunomodulatory effects are mediated through multiple pathways, including the modulation of cytokine production, inhibition of oxidative stress, and interaction with the endocannabinoidome (eCBome).”

“Collectively, our data provide a strong preclinical rationale for leveraging low-dose CBD to enhance the efficacy of existing IBD therapies. The reproducible synergistic effects observed in acute and chronic colitis models—spanning clinical, morphological, molecular, metabolic, and safety domains—underscore CBD’s potential as a safer adjunct agent. CBD co-therapy with CSA or olsalazine offers a multifaceted approach to IBD treatment—achieving superior disease suppression, preserving intestinal and systemic homeostasis, and maintaining an acceptable safety profile. This strategy holds promise for improving patient outcomes while potentially reducing the doses and side effects of conventional IBD drugs. Clinical trials will be essential to confirm safety and efficacy in human IBD patients.”

https://www.mdpi.com/1422-0067/26/16/7913

Inflammatory bowel disease patients believe cannabis and cannabidiol oil relieve symptoms

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“Background: Patients with Inflammatory bowel disease (IBD) often seek alternative therapies for symptom management. This study investigates the perceptions, consumption patterns, and reported outcomes of cannabis and cannabidiol (CBD) oil use among IBD patients and controls.

Methods: A 37-question survey was administered to 139 participants (IBD patients, n = 93; control/non-IBD participants, n = 33) to assess usage frequency and beliefs regarding cannabis and CBD oil as treatment for IBD. The survey also evaluated the impact of these substances on IBD symptoms, quality of life, and opioid use.

Results: Cannabis consumption was higher in IBD patients (57, 53.8%) than controls (15, 45.5%) with both groups strongly supporting medical cannabis use (IBD; 92, 86.8% vs. controls; 29, 84.9%). Most IBD patients believed cannabis (67, 63.2%), CBD oil (60, 56.6%), corticosteroids (77, 73.3%), and biologics/immunosuppressants (85, 81.0%) had a somewhat-extremely beneficial effect in relieving IBD symptoms. Over 50% of IBD cannabis users reported relief from abdominal pain, other pain, stress, anxiety, depression, and nausea/vomiting, with Crohn’s disease patients experiencing significantly more relief than ulcerative colitis patients for certain symptoms (p < 0.05). Notably, 19.4% of IBD patients reported decreased opioid use, and 14.5% reported induced remission with cannabis or CBD oil.

Conclusions: Consumption of cannabis and CBD oil was perceived as beneficial for relieving IBD, with many reporting significant symptom relief from using these substances. The strong support of cannabis and CBD oil as medical treatments and therapeutic effects highlights the potential for cannabis and CBD oil as treatments in IBD.”

https://pubmed.ncbi.nlm.nih.gov/40687272/

“Recent preclinical studies have suggested that cannabinoids, including CBD and THC, may reduce gastrointestinal inflammation and modulate intestinal motility. The presence of cannabinoid receptors in the gut, along with the anti-inflammatory effects of some cannabinoids, has led researchers to explore the potential for therapeutic applications of cannabis in the treatment of IBD.”

“Animal studies of the chemistry and physiology of cannabinoids have shown potential anti-inflammatory, antidiarrheal, and nociceptive-limiting effects, paralleling the growing interest in cannabis as a treatment option for IBD.

Human studies have also indicated that there may be a benefit in controlling IBD symptoms and improving quality of life. Additionally, anecdotal reports and observational studies have highlighted potential benefits in reducing disease activity and managing symptoms like abdominal pain, cramping, joint pain, and diarrhea.”

https://www.academia.edu/2994-435X/2/2/10.20935/AcadMed7773

Cannabidiol as an immune modulator: A comprehensive review

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“Cannabidiol (CBD), a non-psychoactive phytocannabinoid derived from Cannabis sativa, has emerged as a promising therapeutic agent due to its diverse pharmacological properties, including potent anti-inflammatory, neuroprotective, and immunomodulatory effects.

CBD modulates immune responses, including the regulation of T cell activity, induction of macrophage apoptosis, suppression of pro-inflammatory cytokines, and modulation of signaling pathways involved in inflammation and immune homeostasis. A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science databases to identify relevant preclinical and clinical studies on CBD’s immunomodulatory effects.

Preclinical and clinical studies demonstrate its efficacy in treating autoimmune diseases such as Type 1 diabetes, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease, along with its potential in neuropathic pain and cancer therapy.

Recent advancements in nanotechnology-based delivery systems have further enhanced CBD’s therapeutic potential by improving its solubility, bioavailability, and targeted delivery, enabling innovative approaches for wound healing, inflammation management, and cancer treatment. However, challenges such as variability in immune responses, limited long-term safety data, and potential drug-drug interactions persist.

This review comprehensively examines CBD’s pharmacokinetics, pharmacodynamics, and immunomodulatory mechanisms, highlighting its clinical potential, existing limitations, and future directions in advancing its integration into precision medicine and immune regulation.”

https://pubmed.ncbi.nlm.nih.gov/40407987/

“Given the multifaceted pharmacological properties of CBD, it holds significant promise as a therapeutic agent.”

https://link.springer.com/article/10.1007/s44446-025-00005-7

Targeting the Endocannabinoidome: A Novel Approach to Managing Extraintestinal Complications in Inflammatory Bowel Disease

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“Background: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder marked by persistent gastrointestinal inflammation and a spectrum of systemic effects, including extraintestinal manifestations (EIMs) that impact the joints, skin, liver, and eyes. Conventional therapies primarily target intestinal inflammation, yet they frequently fail to ameliorate these systemic complications. Recent investigations have highlighted the complex interplay among the immune system, gut, and nervous system in IBD pathogenesis, thereby underscoring the need for innovative therapeutic approaches. 

Methods: We conducted a comprehensive literature search using databases such as PubMed, Scopus, Web of Science, Science Direct, and Google Scholar. Keywords including “cannabinoids”, “endocannabinoid system”, “endocannabinoidome”, “inflammatory bowel disease”, and “extraintestinal manifestations” were used to identify peer-reviewed original research and review articles that explore the role of the endocannabinoidome (eCBome) in IBD. 

Results: Emerging evidence suggests that eCBome-a network comprising lipid mediators, receptors (e.g., CB1, CB2, GPR55, GPR35, PPARα, TRPV1), and metabolic enzymes-plays a critical role in modulating immune responses, maintaining gut barrier integrity, and regulating systemic inflammation. Targeting eCBome not only improves intestinal inflammation but also appears to mitigate metabolic, neurological, and extraintestinal complications such as arthritis, liver dysfunction, and dermatological disorders. 

Conclusions: Modulation of eCBome represents a promising strategy for comprehensive IBD management by addressing both local and systemic disease components. These findings advocate for further mechanistic studies to develop targeted interventions that leverage eCBome as a novel therapeutic avenue in IBD.”

https://pubmed.ncbi.nlm.nih.gov/40283915/

“Extraintestinal manifestations of IBD pose a significant and diverse array of clinical challenges, significantly impacting patients’ lives and healthcare utilization. While conventional therapies primarily target gut inflammation, the endocannabinoidome emerges as a promising and versatile target for managing inflammatory, metabolic, and extraintestinal complications of IBD. Preliminary evidence highlights its therapeutic potential, but further research is essential to optimize clinical applications and ensure safety.”

https://www.mdpi.com/1424-8247/18/4/478

The Endocannabinoid System: Implications in Gastrointestinal Physiology and Pathology

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“The endocannabinoid system (ECS), composed of receptors, endocannabinoids, and enzymes that regulate biosynthesis and degradation, plays a fundamental role in the physiology and pathology of the gastrointestinal tract, particularly in the small and large intestine and liver.

Specifically, cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 (CB2R), located principally in the nervous system and immune cells, orchestrate processes such as intestinal motility, intestinal and hepatic inflammation, and energy metabolism, respectively.

The main endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), influence appetite, body weight regulation, and inflammatory states and thus have implications in obesity, non-alcoholic fatty liver disease (NAFLD) and irritable bowel syndrome (IBS).

Recent studies have highlighted the therapeutic potential of targeting the ECS to modulate gastrointestinal and metabolic diseases. In particular, peripheral CB1R antagonists and CB2R agonists have shown efficacy in treating intestinal inflammation, reducing hepatic steatosis, and controlling IBS symptoms. Moreover, the ECS is emerging as a potential target for the treatment of colorectal cancer, acting on cell proliferation and apoptosis.

This review highlights the opportunity to exploit the endocannabinoid system in the search for innovative therapeutic strategies, emphasizing the importance of a targeted approach to optimize treatment efficacy and minimize side effects.”

https://pubmed.ncbi.nlm.nih.gov/39941074/

“In conclusion, these findings suggest that the ECS offers a versatile approach for modulating gastrointestinal physiological aspects and treating conditions such as obesity and its complications, IBS, and CRC. Future research should refine ECS-targeted therapies to maximize their efficacy and minimize adverse effects, unlocking new opportunities for innovative treatments of disordered metabolism, inflammation, and cancer.

Clinical studies show that medical cannabis could be a valuable adjunct to cancer and treatments for inflammation, providing symptom relief and improving patients’ overall quality of life. However, further research is needed to refine treatment protocols and explore their full therapeutic potential.”

https://www.mdpi.com/1422-0067/26/3/1306

Entourage effects of nonpsychotropic cannabinoids on visceral sensitivity in experimental colitis

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“Abdominal pain is the most disabling symptom of inflammatory bowel diseases, but current treatments are limited, leading patients to seek alternatives such as cannabis.

Cannabis contains over 100 cannabinoids which, unlike tetrahydrocannabinol, are biologically active compounds often without psychotropic effects (ie, nonpsychotropic cannabinoids [npCBs]). These npCBs have analgesic and anti-inflammatory properties and may show potentiating effects when administered in combination, referred to as the entourage effect.

Here, we investigated the analgesic effects of cannabichromene, cannabidiol (CBD), cannabidivarin, and cannabigerol (CBG), individually and in combination, using the mouse model of dextran sulfate sodium colitis-induced visceral hypersensitivity (VHS).

We then explored antinociceptive targets through patch-clamp electrophysiology on dorsal root ganglia neurons and recombinant channels. We found that a single injection of 10 mg/kg of either CBD or CBG reduced both VHS and c-Fos activation in the spinal dorsal horn. Moreover, a combination of npCBs consisting of 5 mg/kg CBD with 1 mg/kg of cannabichromene, cannabidivarin, and CBG-all at subtherapeutic dosages-reduced VHS, without altering colitis. Electrophysiological recordings revealed that the antinociceptive mixture of npCBs acts through voltage-gated sodium and calcium channels, particularly Cav2.2, but not Cav3.2 and Kv channels.

These results suggest that CBD, CBG, and a mixture of npCBs given at subtherapeutic doses may be beneficial in managing VHS associated with inflammatory bowel disease.

SIGNIFICANCE STATEMENT: Cannabis is increasingly used as an alternative treatment for managing pain associated with chronic conditions. Nonpsychotropic cannabinoids, such as cannabidiol, interact with ionotropic and voltage-gated ion channels. In our study, we demonstrated that cannabidiol, cannabigerol, and a combination of nonpsychotropic cannabinoids, administered at subtherapeutic doses, effectively alleviated visceral hypersensitivity associated with inflammatory bowel disease.”

https://pubmed.ncbi.nlm.nih.gov/39921943/

https://jpet.aspetjournals.org/article/S0022-3565(25)09725-3/abstract

Cannabis use in Crohn’s disease: a systematic review and meta-analysis of randomized controlled trials (RCTs)

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“Objective: This meta-analysis aims to systematically evaluate the efficacy and safety of cannabis in the management of Crohn’s disease (CD) by synthesizing evidence from randomized controlled trials (RCTs). By adhering to the 2020 PRISMA guidelines and registering the study protocol with PROSPERO, this research intends to offer robust, evidence-based recommendations for healthcare practitioners on the therapeutic potential and clinical implications of cannabis use in CD management.

Methods: A literature search encompassing PubMed, Google Scholar, and the Cochrane Library was conducted to identify relevant RCTs comparing cannabis to placebo or standard therapy in CD patients. Inclusion criteria focused on outcomes such as remission rates, C-reactive protein (CRP) levels, quality of life (QoL), and adverse events (AEs). Statistical analysis using RevMan 5.3 involved weighted mean differences (MD) and 95% confidence intervals to compare outcomes between the cannabis and control groups.

Results: The meta-analysis revealed significant findings regarding the impact of cannabis on CD management. The cannabis group exhibited significantly higher clinical remission rates at 8 weeks compared to the control group, with low heterogeneity [MD = – 67.98; 95% CI: (- 100.68, – 35.29)]. However, a statistically significant improvement in QoL was observed in the placebo group compared to the cannabis-treated group [MD = 19.62; 95% CI (14.24 to 25.00)]. There was a non-significant lowering in serum CRP levels compared to the placebo group [MD: – 0.51; 95% CI: (- 1.05, 0.02)].

Conclusion: The study concludes that cannabis shows promise as a therapeutic option for CD, demonstrating higher remission rates and potential benefits for disease management. However, it also highlights the need for larger, standardized research studies to solidify conclusions regarding efficacy, safety, and biomarker responses in CD patients.”

https://pubmed.ncbi.nlm.nih.gov/39821383/

https://link.springer.com/article/10.1007/s11845-024-03844-w