Abstract
Inflammatory bowel disease is a group of conditions with rising incidence caused by genetic and environmental factors including diet. The chelator ethylenediaminetetraacetate (EDTA) is widely used by the food and pharmaceutical industry among numerous other applications, leading to a considerable environmental exposure. Numerous safety studies in healthy animals have revealed no relevant toxicity by EDTA. Here we show that, in the presence of intestinal inflammation, EDTA is surprisingly capable of massively exacerbating inflammation and even inducing colorectal carcinogenesis at doses that are presumed to be safe. This toxicity is evident in two biologically different mouse models of inflammatory bowel disease, the AOM/DSS and the IL10−/− model. The mechanism of this effect may be attributed to disruption of intercellular contacts as demonstrated by in vivo confocal endomicroscopy, electron microscopy and cell culture studies. Our findings add EDTA to the list of food additives that might be detrimental in the presence of intestinal inflammation, but the toxicity of which may have been missed by regulatory safety testing procedures that utilize only healthy models. We conclude that the current use of EDTA especially in food and pharmaceuticals should be reconsidered. Moreover, we suggest that intestinal inflammatory models should be implemented in the testing of food additives to account for the exposure of this primary organ to environmental and dietary stress.
Highlights
Western diet and modern highly processed foods are believed to play a key role for the growing incidence of IBD and especially Crohn’s d isease[1,2,3], the identification of specific noxious agents remains a challenge
We examined the effect of oral iron compounds with different chemical properties on clinical and histological inflammation as well as on tumorigenesis in the azoxymethane—dextran sodium sulfate (AOM/DSS) mouse model[15,16], as well as the interleukin 10-knockout (IL10−/−) mouse[17]
We were surprised to find that only Fe-EDTA exacerbated colitis and massively increased tumour burden, while the other iron compounds did not differ from the control (Fig. 1, Supplementary Fig. S1)
Summary
Western diet and modern highly processed foods are believed to play a key role for the growing incidence of IBD and especially Crohn’s d isease[1,2,3], the identification of specific noxious agents remains a challenge. EDTA is the most commonly used chelator worldwide, with annual production exceeding 50,000 tons just in the European U nion[4]. It finds application in the agriculture, chemical, textile and paper industry, as well as in cosmetics, household chemicals and medications. We show that EDTA compounds aggravate intestinal inflammation and colitis-associated carcinogenesis in two mechanistically different mouse models, at doses that are expected to be non-toxic according to current regulations and recommendations. Our results add EDTA to the growing list of food additives that may constitute an environmental factor for IBD and colitis-associated carcinogenesis
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