In recent decades, the role of hydrogen sulfide (H2S), a gas mediator and signaling agent, has been studied in the regulation of intercellular signaling and intracellular signal transduction pathways with various physiological and pathophysiological effects in cells and tissues. These cellular pathways are responsible for changes in metabolism, epigenetic, and cellular behavior. There are enzymatic and non-enzymatic pathways of endogenous hydrogen sulfide biosynthesis. Numerous studies have shown the diverse effects of H2S on the physiological processes of neurotransmission in the brain, vascular smooth muscle relaxation in synergy with nitric oxide (NO), apoptosis, autophagy, angiogenesis, aging, inflammation, redox system, manifestations of oxidative stress, protein, as well as bioenergetic effects and systemic bioregulatory effects, including ANS. Recently, it was shown that H2S signaling is often dysregulated in different dysfunctions. The effect of H2S on insulin secretion and protection of the heart, kidneys, and brain from ischemic damage, and hypoxia is known. The availability of H2S as a bioregulator has led to changes in cytoprotection, scavenger’s function, and antiinflammatory activities in the digestive system, as well as it could be a molecular target for the creating new safe hybrid compounds, esp., H2S-realized nonsteroidal anti-inflammatory drugs. Our recent research has shown a cytoprotective effect on the mucous membrane of the esophagus and stomach. Thiosulfate sulfurtransferase (TST, EC 2.8.1.1)-derived H2S plays an important role in maintaining redox balance but its effects on mesenteric integrity in aspects of age-related changes and during stress response or high-carbohydrate diet are still limited.