Obesity acceleratesHelicobacter felis-induced gastric carcinogenesis by enhancing immature myeloid cell trafficking and T_H17 response

Abstract

Objective To investigate the role of obesity-associated inflammation and immune modulation in gastric carcinogenesis during Helicobacter-induced chronic gastric inflammation. Design C57BL/6 male mice were infected with H felis and placed on a high-fat diet (45% calories from fat). Study animals were analysed for gastric and adipose pathology, inflammatory markers in serum, stomach and adipose tissue, and immune responses in blood, spleen, stomach and adipose tissue. Results H felis-induced gastric carcinogenesis was accelerated in diet-induced obese mice compared with lean controls. Obesity increased bone marrow-derived immature myeloid cells in blood and gastric tissue of H felis-infected mice. Obesity also led to elevations in CD4 T cells, IL-17A, granulocyte macrophage colony-stimulating factor, phosphorylated STAT3 and prosurvival gene expression in gastric tissue of H felis-infected mice. Conversely, in adipose tissue of obese mice, H felis infection increased macrophage accumulation and expression of IL-6, C-C motif ligand 7 (CCL7) and leptin. Finally, the combination of obesity and gastric inflammation synergistically increased serum proinflammatory cytokines, including IL-6. Conclusions Here, we have established a model to study the molecular mechanism by which obesity predisposes individuals to gastric cancer. In H felis-infected mice, obesity increased proinflammatory immune responses and accelerated gastric carcinogenesis. Interestingly, gastric inflammation augmented obesity-induced adipose inflammation and production of adipose-derived factors in obese, but not lean, mice. Our findings suggest that obesity accelerates Helicobacter-associated gastric cancer through cytokine-mediated cross-talk between inflamed gastric and adipose tissues, augmenting immune responses at both tissue sites, and thereby contributing to a protumorigenic gastric microenvironment.

The homing receptor CD44 is involved in the progression of precancerous gastric lesions in patients infected with Helicobacter pylori and in development of mucous metaplasia in mice

“…However, in addition to neutrophils other cells including dendritic cells, and myeloid suppressor monocytes also express Gr1[63;65;66]. Recent studies have shown that myeloid–derived suppressor cells (MDSCs) contribute to H. pylori -related inflammation and carcinogenesis [67–69], as well as modulation of IFN-γ responses [70]. To determine whether the levels of Gr1 expression in the gastric mucosa of wild type and CD44−/− infected mice differed, we conducted IHC for Gr1 and found that WT mice infected with H. pylori had a high number of Gr1+ cells infiltrating their gastric mucosa (>30 per high power field) both in the corpus and in the antrum (Figure 6A and B, respectively).…”

Bifidobacterium pseudocatenulatum CECT 7765 Reduces Obesity-Associated Inflammation by Restoring the Lymphocyte-Macrophage Balance and Gut Microbiota Structure in High-Fat Diet-Fed Mice

“…reuteri ATCC 6475 administration reduced the levels of this cytokine, presumably by restoring Foxp3+ Treg/Th17 balance [ 37 ]. In our study, the increased serum leptin concentration could also contribute to the enhanced Th17 response, suggested by the increased serum IL-17A levels in obese mice [ 38 ]. However, this effect could not be attributed to cytokines involved in Th17 cell differentiation and maintenance, such as IL-6 and IL-1β [ 38 ], because their concentrations were not significantly increased in serum of our obese mice.…”

Leptin receptor signaling is required for high-fat diet-induced atrophic gastritis in mice

“…The involvement of gastric leptin in diet-induced obesity-associated gastric atrophy has not previously been investigated, although the elevation of serum leptin contributes to tumorigenesis in the stomach of obese mice infected with H. felis [ 66 ]. In the current study, we showed rapid (1 week) mucosal morphological changes in the gastric cardia (Fig.…”