Diet-Induced Obesity Exacerbates Helicobacter pylori -Associated Precancerous Phenotypes

Stomach infection with the bacterium Helicobacter pylori ( Hp ) can cause chronic gastric inflammation, metaplasia (transdifferentiation of mature cell types), dysplasia (abnormal cells), and finally cancer. Obesity can also increase gastric cancer risk. However, host- Hp interactions during obesity are poorly understood. Here we investigated the impact of diet-induced obesity in two mouse models of Hp -associated disease. To model chronic gastric inflammation, we used C57BL/6 mice, and to model more severe disease, we used transgenic mice in which tamoxifen induces gastric expression of a constitutively active Kras allele, leading to metaplasia. We fed mice a high-fat diet (60% kilocalories from fat) to induce obesity, or a matched control diet (10% kilocalories from fat), then infected them with Hp or mock-infected them. In mock-infected C57BL/6 mice, high-fat diet had a minimal impact on gastric pathology and gene expression. In Hp -infected C57BL/6 mice, high-fat diet increased inflammation at the junction between the glandular stomach and non-glandular forestomach, a squamous epithelium similar to the human esophagus, and increased gastric expression of the cancer-associated genes Cldn7 and Reg3g . In KRAS+ mice with or without Hp infection, the impact of diet-induced obesity was more apparent, with increased metaplasia and dysplasia (abnormal cells). As well, high-fat diet caused an expansion of metaplastic pit cells, a lineage we previously found to be associated with Hp -driven inflammation. Thus, in these mouse models, diet-induced obesity does not directly drive gastric immunopathology, but enhances the development of pre-cancerous changes under susceptible conditions.