Chronic atrophic gastritis: molecular pathogenesis and therapeutic targets

Chronic atrophic gastritis (CAG) is one of the most common gastrointestinal diseases characterized by decreased thickness of the gastric mucosa, reduced number of gastric glands and moderate inflammation. The etiology of CAG is related to the adverse effects of two major factors, Helicobacter infection and autoimmune aggression. The leading initial role in the damage to the gastric mucosa, leading to long-term consequences in the form of atrophy, belongs to H. pylori. As atrophic gastritis progresses, other bacterial species (Fusobacterium nucleatum, Streptococcus anginosus) appear in the gastric lumen and may cause additional damage and/or provoke carcinogenesis. Damage to the gastric epithelium is accompanied by two response patterns, superficial and glandular. In the context of CAG pathogenesis, the glandular response is of great importance, characterized by slow development and changes in the structure of the fundal glands. The most sensitive to damage are the lining cells, the death of which can be carried out by apoptosis, autophagy, pyroptosis and ferroptosis. The death of cladding cells triggers paligenosis - the process of stepwise transformation of the main cells into metaplastic SPEM-cells, which at the final stage due to the activation of mTOR pathway acquire the ability to divide, and repeated cycles of their de/redifferentiation contribute to the accumulation of oncogenic mutations. With continued exposure to unfavorable factors, gastric mucosal atrophy progresses to the next stage of the Correa cascade - pyloric metaplasia, then to intestinal metaplasia and dysplasia. Modern research methods, including sequencing of individual cells, molecular imaging, and the use of organoids allow us to identify the main molecular targets responsible for regenerative processes in the gastric mucosa. Stimulation of these mechanisms in the nearest future may become the basis for pathogenetic treatment of CAG, aimed not only at elimination of the main etiologic factors and cessation of inflammation, but also at regeneration of gastric glands and restoration of secretory function.

chronic atrophic gastritis, Helicobacter pylori, autoimmune gastritis, atrophy, pyloric metaplasia, intestinal metaplasia, reparative regeneration, paligenosis

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