Iron deficiency accelerates Helicobacter pylori–induced carcinogenesis in rodents and humans

Abstract

Gastric adenocarcinoma is strongly associated with Helicobacter pylori infection; however, most infected persons never develop this malignancy. H. pylori strains harboring the cag pathogenicity island (cag + ), which encodes CagA and a type IV secretion system (T4SS), induce more severe disease outcomes. H. pylori infection is also associated with iron deficiency, which similarly augments gastric cancer risk. To define the influence of iron deficiency on microbial virulence in gastric carcinogenesis, Mongolian gerbils were maintained on iron-depleted diets and infected with an oncogenic H. pylori cag + strain. Iron depletion accelerated the development of H. pylori-induced premalignant and malignant lesions in a cagA-dependent manner. H. pylori strains harvested from iron-depleted gerbils or grown under iron-limiting conditions exhibited enhanced virulence and induction of inflammatory factors. Further, in a human population at high risk for gastric cancer, H. pylori strains isolated from patients with the lowest ferritin levels induced more robust proinflammatory responses compared with strains isolated from patients with the highest ferritin levels, irrespective of histologic status. These data demonstrate that iron deficiency enhances H. pylori virulence and represents a measurable biomarker to identify populations of infected persons at high risk for gastric cancer.

The gastric microbial community,Helicobacter pyloricolonization, and disease

“…To date the emphasis has been largely on bacterial virulence factors, host genetics, and environmental influences, particularly diet. [5][6][7] But with the recent recognition that the stomach is also colonized by other bacteria, another potential determinant of the outcome of H. pylori infection is the composition or structure of bacterial communities in the stomach, either at the time of exposure or over the course of infection (Fig. 1).…”

Antigenic Proteins of Helicobacter pylori of Potential Diagnostic Value

“…Thus, these antigens are regarded as prospective candidates that may serve as infection markers (Robinson et al, 2007). Various H. pylori antigens, such as CagA, VacA, HspB, FlaA, FlaB and urease subunits (UreA, UreB), have been employed as diagnostic markers of infection (Widmer et al, 1999;Cremonini et al, 2004;Schumann et al, 2006;Zhang et al, 2012;Flores-Luna et al, 2013;Noto et al, 2013). Although several studies tried to establish an association between well-known virulence markers and clinical outcomes, the results were not conclusive.…”

Dynamic Expression of the BabA Adhesin and Its BabB Paralog during Helicobacter pylori Infection in Rhesus Macaques

“…Understanding how H. pylori sometimes leads to clinical disease versus asymptomatic infection, or perhaps even mutualism (2), is one of the leading challenges in the field. Emerging evidence suggests the importance of host and bacterial genetics (1), and their interaction (3), as well as dietary (4,5) and other environmental variables, including the gastric microbiota (6). Among the bacterial virulence factors found more commonly in strains isolated from patients with clinical disease, the best studied is the cytotoxin-associated gene pathogenicity island (cagPAI), which encodes a type IV secretion system (T4SS) that is essential for injection of the CagA bacterial oncoprotein (7,8).…”