Cellular and molecular gastroenterology and hepatology · 2025
Endogenous Glucocorticoids Moderate the Gastric Inflammatory Response to Helicobacter Infection and Protect from Autoimmunity.
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Druffner Sara R, Duncan Benjamin C, Morris Maeve T, Pascoe Jordan L, Abner Tyler M, Hussain Salik, Piazuelo M Blanca, Peek Richard M, Zhang Melody, DiPaolo Richard J, Busada Jonathan T
Аннотация
BACKGROUND & AIMS: Immune responses to infection must balance pathogen clearance with minimizing tissue damage and autoimmunity. Chronic gastric inflammation caused by Heliobactor pylori damages the gastric mucosa and promotes carcinogenesis. Glucocorticoids are immunoregulatory hormones that limit immune activation in the stomach. This study aimed to determine how endogenous glucocorticoids regulate the gastric immune response to Helicobacter infection and their impact on preneoplastic lesion development.
METHODS: We examined the role of endogenous glucocorticoids in shaping the gastric immune response to Helicobacter felis colonization. Gastric immune cell infiltration, atrophy, metaplasia, and preneoplastic lesion development were evaluated in adrenal-intact and adrenalectomized (ADX) mice. Auto-reactive immunoglobulin G antibodies were assessed using a mouse self-antigen array and by measuring their binding to healthy gastric tissue.
RESULTS: Loss of endogenous glucocorticoids led to significantly increased Hfelis-induced gastric T cell infiltration and proinflammatory cytokine expression compared with intact-infected controls. Although all intact mice maintained chronic infection for up to 12 months post-colonization, nearly all ADX mice eradicated Hfelis within 2 to 3 weeks. Despite bacterial clearance, ADX mice continued to exhibit chronic gastric inflammation and developed dysplasia. Autoantibody profiling showed that both intact and ADX groups generated self-reactive immunoglobulin G during active infection. However, only ADX mice sustained autoantibody production following bacterial eradication.
CONCLUSIONS: Endogenous glucocorticoids attenuate gastric inflammation during Helicobacter infection, supporting bacterial persistence while maintaining immune tolerance. These findings suggest that heightened immune responses to Hpylori may trigger autoimmune gastritis development, which can persist after Hpylori clearance and continue to drive gastric cancer risk.
METHODS: We examined the role of endogenous glucocorticoids in shaping the gastric immune response to Helicobacter felis colonization. Gastric immune cell infiltration, atrophy, metaplasia, and preneoplastic lesion development were evaluated in adrenal-intact and adrenalectomized (ADX) mice. Auto-reactive immunoglobulin G antibodies were assessed using a mouse self-antigen array and by measuring their binding to healthy gastric tissue.
RESULTS: Loss of endogenous glucocorticoids led to significantly increased Hfelis-induced gastric T cell infiltration and proinflammatory cytokine expression compared with intact-infected controls. Although all intact mice maintained chronic infection for up to 12 months post-colonization, nearly all ADX mice eradicated Hfelis within 2 to 3 weeks. Despite bacterial clearance, ADX mice continued to exhibit chronic gastric inflammation and developed dysplasia. Autoantibody profiling showed that both intact and ADX groups generated self-reactive immunoglobulin G during active infection. However, only ADX mice sustained autoantibody production following bacterial eradication.
CONCLUSIONS: Endogenous glucocorticoids attenuate gastric inflammation during Helicobacter infection, supporting bacterial persistence while maintaining immune tolerance. These findings suggest that heightened immune responses to Hpylori may trigger autoimmune gastritis development, which can persist after Hpylori clearance and continue to drive gastric cancer risk.