## 6 Therapeutic Potential of Cannabinoids in Gut Diseases
### Endocannabinoids
#### 6.1.2 Endocannabinoids and Intestinal Inflammation  
Endocannabinoid concentrations and levels of CB1R expression may act as an indicator for celiac disease. This was suggested by a study of thirteen celiac patients in the phase of villous atrophy, seven in complete remission, and a control group of eleven who had never experienced the disease. Anandamide and PEA concentrations in duodenal biopsies from the study group with active disease were remarkably elevated compared to the non-eclica control group. An increase in the concentration of 2-AG was also noted, but not as significant as in the case of the two previous compounds. In this case, the results also turned out to be highly variable between individuals. One of the most significant and important observations in this study was that after switching celiac patients to a gluten-free diet and reduction in villous atrophy, more than half of the patients (7 out of 14) had their anandamide levels return to those found in non-eclica patients. PEA concentrations remained at the same level before and after dietary treatment. Patients in the active phase of the disease had increased CB1R immunofluorescence compared to the results from non-eclica patients and those in remission. This means that the increased expression of CB1R, the elevated concentrations of endocannabinoids and PEA, as well as their changes could serve as indicators of the course of the disease and treatment. Moreover, this study reinforced the idea that endocannabinoids most likely play a protective and homeostatic role during intestinal inflammations of different types, including celiac disease [104].  
Within the same study, an animal model of celiac disease was developed. Intestinal villous atrophy was induced in male Wistar rats with a single dose of methotrexate. Rats with induced intestinal inflammation had elevated levels of endocannabinoids in the jejunum. Anandamide, 2-AG, and PEA levels peaked on day three of treatment in the muscle/serosa layer and returned to the basal values on the seventh day alongside recovery. In mucosal samples, the levels of PEA and 2-AG were significantly higher than those in the control group, while the concentration of anandamide did not differ significantly [104].  
An experiment conducted on human explant colitis models suggested that CB2 receptor activation may reduce cytokine-evoked mucosal damage in the intestines. The results of the study showed that anandamide reduced induced tissue destruction and lowered the number of lymphocytes in the mucosa of human explants. Moreover, JTE-907, the CB2 receptor inverse agonist, caused loss of epithelial integrity, which strongly suggested that it was through this receptor that the protective effects of anandamide had occurred. However, not all endocannabinoid impact was completely reversed during CB2R blockade, suggesting an alternative route of tissue protection. Further testing with a target-specific CB1R agonist did not have the expected effect, and the expression of the receptor itself in the human tissues used in this study was found to be relatively low; the role of other receptors or mechanisms should be therefore suspected and examined [96]. The same study examined the impact of anandamide, CBD, and the CB1 and CB2 receptor agonists ACEA and JWH-015 on Caco-2 monolayer permeability, finding no significant effects on TEER. The substances also did not reverse the fall in TEER caused by cytokine-induced damage to the Caco-2 cells [96].  
Endocannabinoids have a high potential for repairing cytokine-evoked damage in the case of colitis and, most likely, other inflammation within the GIT. As stated before, the mechanism itself has not been fully investigated, but it is certain that the range of action and possibilities of these substances is quite wide.