Impact of different gastric acid suppressants on chronic unpredictable mild stress-induced cognitive impairment in rats: A possible involvement of gut dysbiosis.

Recently, clinical evidence indicates that gastric acid suppressants are associated with an increased risk of the development of cognitive impairment and dementia, especially in elderly patients and those with mild cognitive impairment. Therefore, the aim of this research was to explore the impact of different gastric acid suppressants use, famotidine (Famo), esomeprazole (Esome) and vonoprazan (Vono) in the absence or the presence of chronic unpredictable mild stress (CUMS) on several memory tasks with examination of the role of gut dysbiosis. In the present study, rats received famotidine (3.7 mg/kg/day, p.o.) or esomeprazole (3.7 mg/kg/day, p.o.) or vonoprazan (1.85 mg/kg/day, p.o.) for 7 weeks with or without exposure to CUMS. Remarkably, CUMS with different acid suppressants caused a significant decrease in all memory tasks in late CUMS in the current investigation. CUMS with acid suppressants also revealed a marked alteration in the fecal Firmicutes/Bacteroidetes ratio compared to CUMS alone. This gut microbiome alteration was associated with an alteration in gut membrane integrity, as revealed by colonic histopathology and an elevation of systemic inflammatory markers. Besides, upregulation of hippocampal amyloid β and p-tau proteins and modification of brain histopathology were noticed. Our findings support the detrimental effect of gastric acid suppressants, especially proton pump inhibitors, on cognitive impairment in the presence of stress, with the possible involvement of gut dysbiosis.