**2. The Gut-Lung-Skin Barrier**

The gut-lung-skin barrier is a virtual structure encompassing the epithelium of the digestive tract, the pulmonary system and the cutaneous layer. More and more often, studies cite similarities and interactions in the immune response regulated in these structures [4–6]. The recently described T helper 17 (Th17) subset of cells and their regulatory pathway provide further evidence validating the unity of the immune response and regulation in the gut-lung-skin barrier [7]. These cells are capable of producing various cytokines such as granulocyte colony-stimulating factor (G-CSF) and interleukins (ILs) -8 and -22, and trigger the synthesis of effectors producing IL-17 and interferon-gamma (IFN-γ) [8]. Furthermore, Th17 cells are involved in the interactions between the microbiota of the specific tissue and the host, regulating the immune response [8]. The most prominent cytokines involved in the protection against microbial infection are IL-17 and IL-22, which increase the release of antimicrobial peptides, neutrophil recruitment and granulopoiesis while maintaining the integrity of the epithelial layer in boundary tissues [9]. When IL-17 fails due to insufficient expression, a large variety of cutaneous, pulmonary and gastrointestinal infections may occur, accompanied by significant inflammation [10–12]. Some infectious agents such as *Staphylococcus aureus* are capable of stimulating its expression [13]. IL-22 also contributes to the immune response against various infectious diseases of the gut-lung-skin barrier and exhibits pro-inflammatory roles by enhancing the effects of tumor necrosis factor-alpha (TNF-α), and by activating various other cytokines [9,14].

However, the gut-lung-skin barrier cross-talk in inflammation is not limited to the activity of Th17 cells. The epithelial cells produce thymic stromal lymphopoietin (TSLP), a cytokine similar to IL-7, which is involved in the allergic response and is a key factor in the onset of allergic inflammation in the skin, lungs and gastrointestinal tract [15]. TSLP is considered to be a biomarker for disruptions of the epithelial integrity, and was cited as a determining and aggravating factor in a variety of allergy models, including ovalbumin (OVA)-induced asthma, atopic dermatitis and allergic diarrhea [16].

Sustained inflammatory processes in the gut-lung-skin barrier develop similar complications, regardless of the initial location of the inflammation. Among the common comorbidities are metabolic syndrome, cardiovascular events and bone loss [5,17,18]. These may be explained by the increased production of TNF-α, which is an essential mediator of chronic inflammation and is usually accompanied by IL-4, IL-6 and IL-17, increasing the risk of the aforementioned complications, as well as favoring the appearance of other metabolic conditions [5,19,20].

Because inflammation is the cornerstone of many pathological conditions, including cancer, the possible connections and interferences between inflammatory processes in different organs and systems have substantial implications. Inflammatory conditions, regardless of their substrate or location, benefit from relatively specific management, which includes one or several anti-inflammatory drugs. However, due to adverse effects and interactions, there is a growing interest in medicinal-grade natural compounds that have demonstrated their effectiveness and usually act through dedicated receptors that are widely distributed in the human body. These substances have been labeled 'phytochemicals', and some examples include capsaicin, curcumin, resveratrol and cannabinoids [21–24]. Curcumin, resveratrol, gingerol, and ginsenoside have demonstrated antioxidant and antiinflammatory effects by modulating the MAP and NF-κB pathways, making them excellent candidates in the treatment of atopic dermatitis [25]. Multiple in vivo and in vitro studies have outlined the chemopreventive properties of whole-fruit substances in skin carcinogenesis, where carotenoids, polyphenols, flavonoids and anthocyanins have demonstrated pro-apoptotic, antiproliferative, and ROS-reducing effects in basal and squamous cell carcinoma models [26–29]. Capsaicin's effects on chemonociception were fundamental in cutaneous pathophysiology research, but its applications have extended from skin pain modulation to various local and system-wide pathologies, including malignancies [30–32]. Cannabinoids, in particular, show great promise due to the mediation of their actions by the dedicated cannabinoid receptors, which serve the activity of the endocannabinoid system but also respond to the administration of natural or synthetic cannabinoids.
