Autophagy-driven modulation of stem cell dynamics in <i>Helicobacter pylori</i> -induced gastric diseases in mice

Chronic <i>Helicobacter pylori</i> infection is a major contributor to gastric disease progression, with its involvement in autophagy and stem cell dynamics playing a critical role in disease mechanisms. This study investigated how <i>H</i>. <i>pylori</i>, particularly in combination with the carcinogen N-nitroso-N-methylurea (NMU), disrupted autophagy and stem cell function, driving gastric pathology. <i>H</i>. <i>pylori</i> infection significantly increased autophagy, promoted the epithelial-mesenchymal transition, suppressed <i>Tff2</i> and <i>Ghrelin</i> expression in mouse gastric organoids, and enhanced stem cell proliferation (organoid numbers increased 92% compared to control at 24 weeks, <i>p</i> < 0.001), while NMU caused milder autophagy, severe inflammation, glandular dilation, and reduced stemness markers (CD133 decreased 30% at 24 weeks, <i>p</i> < 0.05). Combined <i>H</i>. <i>pylori</i> and NMU exposure synergistically dysregulated <i>Tff2</i>/<i>Ghrelin</i> expression, exacerbated autophagic flux disruption, and impaired stem cell function, reducing organoid budding (decreased 43% vs. <i>H</i>. <i>pylori</i> alone at 36 weeks, <i>p</i> < 0.01) and dysregulating <i>CD133</i>, <i>CD44</i>, <i>Lgr5</i>, and <i>SOX2</i> expression. Pathologically, this combination led to severe gastric damage, including intestinal metaplasia and neutrophil infiltration. Chloroquine (CQ) treatment mitigates these effects by reversing autophagic dysfunction, restoring stem cell capacity (<i>Lgr5</i> increased 97% at 44 weeks, <i>p</i> < 0.05), differentially modulating <i>Tff2</i>/<i>Ghrelin</i>: potentiating <i>Tff2</i> and suppressing Ghrelin, normalizing organoid growth, attenuating the EMT, and reducing inflammation, particularly in the <i>H</i>. <i>pylori</i> + NMU group. These findings elucidate how <i>H</i>. <i>pylori</i> and NMU drive gastric pathology through autophagy-stem cell crosstalk and highlight CQ's potential as a targeted therapeutic strategy for infection-associated gastric damage.