<i>Helicobacter mastomyrinus</i> Cytolethal Distending Toxin Induces Calcium Dyshomeostasis and Liver Injury via Endoplasmic Reticulum Stress

Helicobacter mastomyrinus (H.m), a Helicobacter species colonizing rodent liver and intestine, produces cytolethal distending toxin (CDT), which induces host cell damage. While the active CdtB subunit is linked to various diseases, the pathogenic mechanisms of H.m in the liver and the precise actions of CdtB remain incompletely defined. This study generated a CdtB-deficient strain (H.m ΔCdtB) and compared it with the wild-type H.m (H.m WT). Male BALB/c mice were orally infected via gavage. The impacts of CdtB on liver injury, inflammation, oxidative stress, endoplasmic reticulum (ER) stress, and calcium homeostasis were systematically evaluated. Infection with H.m for 12 and 24 weeks induced significant hepatic inflammation and necrosis and a significant increase in hepatocyte proliferation. CdtB deficiency did not impair H.m colonization but markedly reduced inflammatory severity. CdtB facilitated the secretion of proinflammatory cytokines (IL-1β, IL-6, MCP-1, TNF-α), driving chronic liver inflammation. Mechanistically, H.m infection upregulated ER stress-related genes and proteins, increased calcium ion levels, whereas H.m ΔCdtB infection showed no significant effects. Notably, pharmacological inhibition of ER stress by 4-phenylbutyric acid alleviated calcium imbalance and attenuated liver injury. These findings indicate that H.m CdtB induces ER stress, disrupting intracellular calcium homeostasis and exacerbating liver injury in male BALB/c mice.