Overactivity of the intestinal endocannabinoid system in celiac disease and in methotrexate-treated rats

Abstract

The endocannabinoid system is upregulated in both human inflammatory bowel diseases and experimental models of colitis. In this study, we investigated whether this upregulation is a marker also of celiac disease-induced atrophy. The levels of the cannabinoid CB(1) receptor, of the endocannabinoids, anandamide, and 2-arachidonoyl-glycerol (2-AG), and of the anti-inflammatory mediator palmitoylethanolamide (PEA) were analyzed in bioptic samples from the duodenal mucosa of celiac patients at first diagnosis assessed by the determination of antiendomysial antibodies and histological examination. Samples were analyzed during the active phase of atrophy and after remission and compared to control samples from non-celiac patients. The levels of anandamide and PEA were significantly elevated (approx. 2- and 1.8-fold, respectively) in active celiac patients and so were those of CB(1) receptors. Anandamide levels returned to normal after remission with a gluten-free diet. We also analyzed endocannabinoid and PEA levels in the jejunum of rats 2, 3, and 7 days after treatment with methotrexate, which causes inflammatory features (assessed by histopathological analyses and myeloperoxidase activity) similar to those of celiac patients. In both muscle/serosa and mucosa layers, the levels of anandamide, 2-AG, and PEA peaked 3 days after treatment and returned to basal levels at remission, 7 days after treatment. Thus, intestinal endocannabinoid levels peak with atrophy and regress with remission in both celiac patients and methotrexate-treated rats. The latter might be used as a model to study the role of the endocannabinoid system in celiac disease.

Abnormal anandamide metabolism in celiac disease

“…Nevertheless, there is still little evidence on the contribution of endocannabinoids in celiac disease, a chronic inflammation of the small bowel induced in genetically susceptible individuals by an environmental irritant, gluten, with the possible participation of other environmental cofactors [9]. In particular, there is only one study showing higher AEA levels in the duodenal mucosa of active celiac patients in comparison to treated celiac patients and controls [10]. In the present study, we aimed to explore AEA metabolism by investigating mRNA, protein and activity of enzymes responsible for the synthesis (N-acylphosphatidyl-ethanolamine specific phospholipase D, NAPE-PLD) [11] and degradation (fatty acid amide hydrolase, FAAH) [12] of AEA in the duodenal mucosa of untreated celiac patients, celiac patients on a gluten-free diet and control subjects.…”

Palmitoylethanolamide normalizes intestinal motility in a model of post‐inflammatory accelerated transit: involvement of CB1 receptors and TRPV1 channels

“…Additional and pharmacologically relevant targets of PEA action include PPARα (Lo Verme et al, 2005;O'Sullivan and Kendall, 2010) and transient receptor potential vanilloid type-1 (TRPV1) channels (De Petrocellis et al, 2001;Ambrosino et al, 2013; channel nomenclature follows Alexander et al, 2013b), which have been identified in peripheral nerves controlling intestinal motility (Boesmans et al, 2011;Holzer, 2011). PEA has been identified in the rodent Fu et al, 2007;Izzo et al, 2010;2012;Diep et al, 2011;Balvers et al, 2013) and human (Darmani et al, 2005;D'Argenio et al, 2007;Zhang et al, 2014) digestive tract. When given exogenously, PEA reduces gastrointestinal transit and displays anti-inflammatory effects in the gut (Di Paola et al, 2012;Petrosino et al, 2013;Esposito et al, 2014).…”

Endogenous Cannabinoid System and Its Role in Gastrointestinal Tract: Review

“…8 Çölyak hastalarında duodenumdan alınan biyopsilerde 2-AG düzeyi değişmez iken, AEA seviyesinin arttığı, glutensiz diyet tedavisi sonrası ise AEA seviyesinin normale döndüğü gözlen-miştir. 9 Kolon poliplerinde ve kolorektal kanser hastalarından alınan kolon biyopsilerinde hem 2-AG hem de AEA seviyelerinde anlamlı artış olduğu göz-lenmiştir. 10 Diğer bir çalışmada ise divertikülozis koli olan hastaların kolon dokusunda AEA seviyelerinin arttığı, 2-AG düzeyinin ise azaldığı saptanmıştır.…”