Abstract
BACKGROUND & AIMS: Gastric cancer is the fifth most common cancer worldwide. Men are disproportionately affected by gastric cancer, which ranks as the fourth most common cancer in men compared with eighth in women. Chronic inflammation driven by Helicobacter pylori infection remains the leading gastric cancer risk factor. Evidence suggests that sex hormones shape sex differences in infection outcomes and cancer susceptibility. This study investigates how androgens influence the gastric inflammatory response to Helicobacter infection and contribute to sex disparities in pre-dysplastic disease progression. METHODS: Male and female mice were colonized with Helicobacter felis. Androgen levels were manipulated by bilateral castration in males and dihydrotestosterone (DHT) treatment in females. Single-cell RNA sequencing was used to identify androgen-responsive leukocyte populations and to establish cell communication networks between leukocyte clusters. The functional roles of these cells were further defined using type 2 innate lymphoid cell (ILC2)- and T cell-deficient mouse models. RESULTS: Infected female mice developed significantly more severe gastric inflammation, atrophy, and metaplasia infection compared with males. Androgen depletion by castration increased gastric inflammation and accelerated preneoplastic lesion development, whereas these pathological features were reduced by DHT treatment. Androgen-responsive ILC2s were key initiators of gastric inflammation, and ILC2 depletion abolished the sex differences in H felis pathogenesis. CONCLUSIONS: This study reveals that androgens protect from Helicobacter-induced gastric inflammation by modulating ILC2 activation. These findings indicate that ILC2s serve as master regulators of Helicobacter-driven gastric inflammation and highlight their role in directing sex differences in the progression of pre-dysplastic disease.