The onset and progression of various disorders, including chronic urticaria, are associated with stress. The gut-brain-skin axis is used to describe correlations among the nervous system, gastrointestinal tract states and systemic and skin inflammation. We have summarized inflammatory and immune mechanisms underlying chronic urticaria and stress in the context of the gut-brain-skin axis. The study was aimed to show the relationships between substance P, the neurotransmitter, and diamine oxidase, the enzyme disrupting histamine in the gut of patients suffering from chronic urticaria. A total of 165 adults aged 18–68 were enrolled; 97 patients had chronic urticaria, the comparison group was formed of 68 nominally healthy individuals. ELISA (Cloud-Clone Corp; China) was used to simultaneously estimate serum levels of substance P, diamine oxidase, and histamine. We revealed a significant positive correlation (ρ = 0.5; p < 0.05) between substance P and diamine oxidase in patients with chronic urticaria and in the comparison group, which confirmed the existence of the gut-brain-skin axis. The paper provides theoretical background and new targets for treatment of chronic urticaria. The possibility of prevention and treatment of these disorders by modulation of gut microbiota is discussed, the place of diet and the lifestyle modification contributing to improvement of general health are determined.