Gastric coinfection with thiopeptide-positive Cutibacterium acnes decreases FOXM1 and pro-inflammatory biomarker expression in a murine model of Helicobacter pylori -induced gastric cancer

作者：Courtney Lunger, Zeli Shen, Hilda Holcombe, Anthony Mannion, JoAnn Dzink-Fox, Susanna Kurnick, Yan Feng, Sureshkumar Muthupalani, Sebastian E. Carrasco, Keith T. Wilson, Richard M. Peek, M. Blanca Piazuelo, Douglas R. Morgan, Amanda L. Armijo, Melissa Mammoliti, Timothy C. Wang, James G. Fox · 发表于：Microbiology Spectrum · 年份：2023 · DOI：10.1128/spectrum.03450-23 · 被引用次数：10 · 研究领域：Helicobacter pylori-related gastroenterology studies、Galectins and Cancer Biology、Genetic factors in colorectal cancer

ABSTRACT Helicobacter pylori ( H. pylori ) causes a cascade from gastritis to gastric neoplasia. During the chronic stages, the oncogenic transcription factor forkhead box protein M1 ( FOXM1 ) becomes increasingly expressed. Given certain strains of the gastric commensal Cutibacterium acnes ( C. acnes ) produce thiopeptides that directly inhibit FOXM1, we hypothesized that coinfection with thiopeptide-positive C. acnes would decrease Foxm1 expression and alter H. pylori -induced pathogenesis. C. acnes was isolated from 31% of gastric biopsies from Nicaraguan patients, and thiopeptide-positive strains were identified by whole genome sequencing. Germ-free INS-GAS mice were inoculated with thiopeptide-positive C. acnes , H. pylori SS1, H. pylori 1 week before C. acnes , C. acnes 2 weeks before H. pylori , or no bacteria. At 17 weeks post-infection, males dosed with C. acnes followed by H. pylori exhibited increased inflammation scores by histopathology; however, males dosed with H. pylori followed by C. acnes exhibited reduced gastric Foxm1 , pro-inflammatory cytokine ( Il-1β , Ifn-γ , Tnf-α , Il-17a , and iNOS ), regulatory cytokine ( Foxp3 ) gene expression, pro-inflammatory IgG2a antibodies, and gastric lymph node RORγT expression compared to H. pylori- monoinfected mice. Male mice coinfected with C. acnes followed by H. pylori exhibited reduced gastric inflammatory markers (IL-17, IL-10, GM-CSF, M-CSF, MCP-1, MIP-1α, MIP-2, RANTES, and VEGF) by cytokine array analysis and re...