| Inflammatory bowel diseases (IBD) are chronic, immune-mediated disorders that are the result of inappropriate immune responses towards a subset of resident intestinal microbes in genetically susceptible individuals. Epidemiological studies have correlated dietary factors with increased risk for disease development, exacerbation and relapse in IBD patients. Iron is of particular interest because of the clinical concern of disease exacerbation upon oral iron supplementation in anemic IBD patients. Moreover, iron can selectively modulate the growth, physiology and function of numerous bacterial taxa, although the precise impact on specific resident intestinal bacteria remains largely unexplored. We therefore hypothesized that intestinal iron availability modulates the ecological structure and proinflammatory potential of the intestinal microbiota. To explore this hypothesis, we investigated how iron availability alters the composition of the intestinal microbiota and impacts the physiology and proinflammatory potential of adherent invasive Escherichia coli (AIEC), a distinct pathotype of enteric resident E. coli associated with IBD. In inflammation-resistant wild type mice, decreasing luminal iron concentrations during community assembly resulted in compositional changes consistent with a dysbiotic state, including a bloom in endogenous E. coli. Aggregation of the resident AIEC strain NC101, which is dependent on both cellulose production and iron availability, influenced subsequent interactions with macrophages. When monoassociated in germ free, inflammation-susceptible interleukin-10-deficient (Il10-/-) mice, abrogation of cellulose production in NC101 delayed onset of colitis, suggesting that cellulose may be a novel factor that enhances the proinflammatory potential of AIEC. Consistent with our in vivo observations, NC101 cellulose production corresponded with increased resistance against macrophage phagocytosis and enhanced macrophage proinflammatory responses when bacterial iron availability was restricted. When colonized with a complex microbiota, dietary iron supplementation also limited colitis development in Il10-/- mice. Taken together, these studies suggest that decreasing iron availability enhances the proinflammatory potential of the intestinal microbiota and highlight the complex interplay between host, microbial and environmental factors in the development of IBD. |
