"Dysregulated Polyamine Metabolism in H. pylori-associated Gastric Inflammation and Disease Progression"

Stomach diseases are very frequent in Veterans. Helicobacter pylori is the most common bacterial pathogen in humans, and stomach infection is common in VA patients, especially due to deployment related acquisition. H. pylori causes chronic gastritis, peptic ulcer disease, and in 1-3% of patients, progression to gastric cancer, the fourth leading cause of cancer deaths worldwide. In this Merit Review program, we have focused on the role of polyamines in gastric disease. We reported during the current award that 1) gastric epithelial cell (GEC)-specific deletion of ornithine decarboxylase, the rate-limiting enzyme for polyamine synthesis, protects mice from H. pylori-induced gastric inflammation, GEC proliferation, and immune dysregulation; and 2) total deletion of spermine oxidase (SMOX), which back-converts the polyamine spermine (Spm) to spermidine, prevents gastric inflammation and carcinogenesis, immune dysfunction, and blocks DNA damage and carcinogenic signaling. We now show that GECs exposed to H. pylori produce acrolein, a highly damaging reactive aldehyde, and that this is generated by SMOX. Acrolein can also cause generation of other electrophiles by causing lipid peroxidation. Data from our current CSRD endoscopic study in VATVHS patients show increased acrolein and other electrophile adducts in gastric tissues and organoids from VA patients infected with H. pylori. We also reported that scavengers of electrophiles, including 2-hydroxybenzylamine (2-HOBA), which has been safely tested in humans, markedly attenuate gastric carcinoma in our models. The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), encoded by the gene Nfe2l2, enhances detoxification of reactive aldehydes and our data show that its activation is increased in VA gastritis tissues and in mice with dysplasia and carcinoma. Importantly, we have isolated VA patient H. pylori strains that cause a high frequency of gastric carcinoma in our INS-GAS mouse model. We hypothesize that SMOX-generated electrophiles increase gastric inflammation and carcinogenesis, and this process is regulated by NRF2, making NRF2 activators and electrophile scavengers new potential therapeutics. Our Aims are: Aim 1) To determine the cell-specific roles of SMOX-derived electrophiles; we will use C57BL/6 and INS-GAS mice with specific deletion of Smox in A) GECs and B) myeloid cells. These mice will be infected with highly pathogenic H. pylori strains from VA patients, and treated ± Spm, the SMOX substrate. We will study electrophile adducts, inflammation, dysplasia, and carcinoma. Aim 2) To determine if NRF2 reduces SMOX-derived electrophiles. We will use mice with specific deletion of Nfe2l2 in A) GECs and B) myeloid cells. These mice will be infected with VA H. pylori, and we will assess electrophile adducts, inflammation, and markers of advanced lesions, and test if Spm increases disease and if 2-HOBA reduces disease in Nfe2l2-deficient mice. In 2C, we will use INS-GAS mice infected with VA H. pylori and determine effects of NRF2 activators, sulforaphane and dimethyl fumarate, on electrophile production, inflammation, and carcinogenesis. Aim 3) To determine if electrophiles and NRF2 are targets for prevention of carcinogenesis in Veterans. We will enroll 80 patients at the VATVHS undergoing clinically indicated upper endoscopy, across the histologic disease spectrum that includes normal, gastritis with and without H. pylori infection, and advanced lesions of atrophic gastritis and intestinal metaplasia. In A) we will determine if gastric levels of adducts of reactive aldehydes/electrophiles are inversely correlated with NRF2 activity, and if plasma electrophiles are biomarkers of gastric disease. In B) we will directly test molecular and cellular effects of electrophile production using VA patient-derived gastric organoids stimulated with VA H. pylori ± 2-HOBA ± NRF2 agonists. We will assess electrophile adducts, DNA damage, and inflammatory/carcinogenic Project Number: 2I01CX002171-06 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Keith Wilson | Institution: VETERANS HEALTH ADMINISTRATION, NASHVILLE, TN | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 GAST-L (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11045486