Gastric coinfection with thiopeptide-positive
Cutibacterium acnes
decreases FOXM1 and pro-inflammatory biomarker expression in a murine model of
Helicobacter pylori
-induced gastric cancer
Authors: Lunger Courtney , Shen Zeli , Holcombe Hilda , Mannion Anthony J. , Dzink-Fox JoAnn , Kurnick Susanna , Feng Yan , Muthupalani Sureshkumar , Carrasco Sebastian E. , Wilson Keith T. , Peek Richard M. , Piazuelo M. Blanca , Morgan Douglas R. , Armijo Amanda L. , Mammoliti Melissa , Wang Timothy C. , Fox James G. 
Published: November 2023

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 reduced
H. pylori
gastric colonization. These data show that thiopeptide-positive
C. acnes
exhibited anti-inflammatory and anti-FOXM1 properties in the context of
H. pylori
gastritis.

IMPORTANCE

H. pylori
infects half of the world population and is the leading cause of gastric cancer. We previously demonstrated that gastric cancer risk is associated with gastric microbiota. Specifically, gastric urease-positive
Staphylococcus epidermidis
and
Streptococcus salivarius
had contrasting effects on
H. pylori
-associated gastric pathology and immune responses in germ-free INS-GAS mice. As gastritis progresses to gastric cancer, the oncogenic transcription factor
Foxm1
becomes increasingly expressed. In this study, we evaluated the gastric commensal
C. acnes
, certain strains of which produce thiopeptides that directly inhibit FOXM1. Thiopeptide-positive
C. acnes
was isolated from Nicaraguan patient gastric biopsies and inoculated into germ-free INS-GAS mice with
H. pylori
. We, therefore, asked whether coinfection with
C. acnes
expressing thiopeptide and
H. pylori
would decrease gastric
Foxm1
expression and pro-inflammatory cytokine mRNA and protein levels. Our study supports the growing literature that specific non-
H
.
pylori
gastric bacteria affect inflammatory and cancer biomarkers in
H. pylori
pathogenesis.