The non-euphoric phytocannabinoid cannabidivarin counteracts intestinal inflammation in mice and cytokine expression in biopsies from UC pediatric patients
Graphical abstract
Introduction
Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn’s disease (CD), are relapsing and lifelong disorders characterized by chronic inflammation of the gastrointestinal tract. IBDs represent a global health burden that affects millions of people with rising incidence and prevalence worldwide [1,2]. IBD results from a complex interaction between environmental, genetic and epigenetic risk factors that cause an inappropriate mucosal immune response leading to intestinal inflammation. Additionally, recent evidence suggests that gut microbiota dysbiosis is strictly linked to initiation and progression of IBD, although it is still unclear whether this is a primary or secondary occurrence [3].
The plant Cannabis sativa contains over 100 terpenophenolic constituents, known as phytocannabinoids [4,5]. A number of surveys and small clinical trials suggest that patients with IBD use cannabis preparations to alleviate symptoms such as diarrhea, abdominal pain, and loss of appetite [[6], [7], [8], [9], [10], [11]]. Experimentally, single isolated cannabinoids such as delta-9-tetrahydrocannabinol [12], cannabidiol [[12], [13], [14], [15]], cannabigerol [16], and cannabichromene [17] have been shown to attenuate intestinal inflammation.
Cannabidivarin (CBDV) is a non-psychoactive phytocannabionid that was identified by Vollner and coworkers in 1969, although little information on its pharmacology and mode of action has been reported in the subsequent forty years [18]. More recently, pharmacodynamic studies have shown that CBDV shows very little affinity for cannabinoid receptors, but is a potent agonist of the transient receptor potential (TRP) ankyrin type-1 (TRPA1) [19]. TRPA1, a cation-permeable channel, is a member of the TRP superfamily with a pivotal role in intestinal inflammation [20]. Specifically, TRPA1 is expressed in sensory fibers innervating the gastrointestinal tract, mediates gastrointestinal hypersensitivity to mechanical stimuli, and modulates the release of pro-inflammatory peptides [21]. Currently, CBDV is under clinical investigation for epilepsy (NCT02369471) and Autism Spectrum Disorder in children (NCT03202303).
Here, we report that oral CBDV exerts, via TRPA1, anti-inflammatory effects and changes the composition of gut microbiota in the murine model of colitis induced by DNBS. Additionally, CBDV reduces colonic inflammation in biopsies from pediatric patients with IBD, a condition in which we found an unprecedented example of TRPA1 upregulation.
Section snippets
Drugs and reagents
2,4-dinitrobenzenesulfonic acid (DNBS) and myeloperoxidase (MPO) from human leucocytes, were purchased from Sigma Aldrich S.r.l. (Milan, Italy). CBDV [purity by high-performance liquid chromatography (HPLC), 99.0%], was kindly supplied by GW Research Ltd (Cambridge, UK). CBDV was dissolved in ethanol/Tween20/saline (1:1:8) for intraperitoneal (i.p.) injection (60 μl/mouse) and in carboxymethylcellulose (CMC 1%, 150 μl/mouse) for oral gavage administration. The vehicles had no significant
Preventive or curative CBDV (either oral or intraperitoneal) reduces colon weight/colon length ratio in experimental acute colitis
Intracolonic DNBS administration caused a number of signs of inflammation and disease, including increased colon weight/colon length ratio, neutrophil infiltration (as revealed by MPO activity), intestinal permeability, histological damage, up-regulation of pro-inflammatory cytokines and down-regulation of the anti-inflammatory cytokine IL-10 (Fig. 1, Fig. 2, Fig. 3). Intraperitoneal or oral CBDV (0.3–10 mg/kg), given before (preventive protocol, Fig. 1A,B and F) or after (curative protocol,
Discussion
Despite Cannabis treatment being used in the USA by IBD patients to reduce their IBD symptoms [33,34], our study represents the first evidence of CBDV intestinal anti-inflammatory effects. CBDV is the propyl analogue of cannabidiol, the main non-psychoactive cannabinoid isolated from Cannabis sativa [35]. Recently, CBDV has emerged among cannabinoids for its possible clinical use as an antiepileptic drug. In 2015, a Phase 2, double blind, randomized, placebo-controlled study has shown that CBDV
Contributors
E.P. was responsible for acquisition, analysis and interpretation of data; conception and design; and redaction of the manuscript. B.R., F.I., O.A.P., M.D.A., T.V., S.P., L.C., M.L., G.S., F.L., P.O. and R.C. carried out acquisition, analysis and interpretation of data. A.A.I. and V.D. were responsible for conception and design, analysis and interpretation of data, and critical reading of the manuscript. F.B. performed conception and design, analysis and interpretation of data, and redaction of
Funding
This work was supported by GW Research Ltd., UK.
Patient consent
Obtained.
Declaration of Competing Interest
AI, VD and FAI receive research grants from GW Research Ltd., UK.
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2022, International ImmunopharmacologyCitation Excerpt :These results suggested that DMB was a non-toxic candidate for the treatment of UC. Activated innate immune system is extremely common in the pathogenesis of UC [28], Correspondingly, hyperactivated inflammatory response promotes intestinal permeability and intestinal mucosal damage in patients with UC [29]. Our previous study indicated that DMB was a natural mitochondrion targeting antioxidant agent by cationic property [26], and alleviated UC in mice through regulating NF-κB signaling and T-helper cell homeostasis [28].
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