_applied sciences_  
_Article_  
Endogenous Cannabinoids in Crohn's Disease  
[PERSON] 1,1\({}^{\dagger}\)2, [PERSON] 1,1\({}^{\dagger}\)2, [PERSON] 2\({}^{\copyright}\) and [PERSON] 3,*\({}^{\copyright}\)  
in highly developed countries, especially in Europe and North America [2]. Although the peak incidence occurs in the second and third decade of life, CD in children and adolescents accounts for approximately one-fourth of all cases [3]. The first symptoms of CD are often atypical and include abdominal pain and diarrhea [4]. Patients may also suffer from abdominal pain of various locations and intensity, and chronic diarrhea. The latter may result in developmental disorders in children and nutritional deficiencies [5]. All these symptoms might significantly reduce the quality of life of CD patients. Several theories exist as to the cause of the disease, but the most current theory on the pathogenesis of IBD suggests a loss of tolerance to the intestinal microbiota and abnormal bacteria-host interactions that induce an autoimmune response and promote inflammation in the gut [6; 7; 8]. The endocannabinoid system (ECS) consists of three main parts: receptors, endogenous agonists, and cannabinoid-degrading enzymes. There are two classical types of G protein-coupled metabotropic receptors, type 1 and 2 [9; 10]. The type 1 cannabinoid receptor (CB1) is mainly present on the cells of the central nervous system (CNS) but can also be found in other parts of the body, such as the gastrointestinal tract (GI tract) and vascular endothelium [11]. Type 2 cannabinoid receptor (CB2) is expressed mostly on cells and organs of the immune system, such as macrophages, leukocytes, spleen, tonsils, and thymus. CB2 seems to be highly inducible, with its concentration in the CNS increasing many times during inflammation, although it is not clear whether this increase is due to CB2-expressing immune cell migration or to increased expression of the receptor on CNS cells [9]. Both receptors are also common in the gastrointestinal tract, especially in enteric nerves and enteroendocrine cells [12; 13]. The effects of CB1 and CB2 stimulation are complex and often overlapping; primarily, CB1 stimulation increases reactive oxygen species (ROS) and tumor necrosis factor \(\alpha\) (TNF-\(\alpha\)) production and induces M1 macrophage (classically activated by IFN-\(\gamma\) or lipopolysaccharide) polarization. CB2 enhances macrophage polarization toward the M2 form (alternatively activated by cytokines) and reduces proinflammatory cytokine secretion from T-cells [14]. Apart from said receptors, there are also several poorly understood orphan receptors, such as GPR3, GPR55, and GPR84. Endogenous cannabinoids (eCBs) are derivatives (esters and amides) of long-chain polyunsaturated fatty acids and they act through described specific receptors. The two most important among them are 2-arachidonovglycerol (2-AG) and anandamide (AEA). They are synthesized by enzymes: diacylglycerol lipase (DAGL) and N-acyl-phosphatidylethanolamine phospholipase (NAPE-PLD), respectively [15]. 2-AG has a high affinity toward both CB1 and CB2 receptors, while AEA binds preferably to the CB1 receptor and has a low affinity for CB2 [14]. AEA can also inhibit neutrophil recruitment and thus reduce inflammation [16]. Two main enzymes responsible for endocannabinoid degradation are monoacylglycerol- Carol lipase (MAGL) and fatty acid amide hydrolase (FAAH). 2-AG is primarily metabolized by MAGL, which hydrolyses about 85% of 2-AG in the brain, thus being the most important 2-AG-degrading enzyme in the CNS [17]. The FAAH enzyme metabolizes AEA but is also capable of breaking down 2-AG to some extent. According to research, exposure to chronic stress impacts the homeostasis of the endocannabinoid system. The release of corticotropin-releasing hormone (CRH) by the pituitary gland changes the activity of the FAAH enzyme, resulting in a decrease in AEA levels. It has been discovered that the rise of 2-AG is linked to an increase in cortisol levels.