The food additive EDTA aggravates colitis and colon carcinogenesis in mouse models Original paper

What was studied?

This study tested whether dietary EDTA aggravates colitis-microbiome effects in the setting of intestinal inflammation, and whether EDTA (a common chelator used in foods and pharmaceuticals) can worsen colitis and promote colitis-associated colorectal cancer at doses considered safe. Using two mechanistically distinct murine inflammatory bowel disease (IBD) models—azoxymethane/dextran sodium sulfate (AOM/DSS) and IL10−/− colitis—the authors compared iron formulations (including Fe-EDTA) and then directly compared multiple EDTA salts (Fe-EDTA, Ca-EDTA, Na-EDTA) at a rodent NOAEL-equivalent dose (173 mg/kg body weight) and a human acceptable daily intake–modeled dose (21 mg/kg). They also probed the mechanism by assessing epithelial junctional integrity, permeability (in vitro and in vivo), and gut microbiome shifts by 16S rRNA sequencing.

Who was studied?

The primary subjects were 6-week-old male and female mice: conventional C57BL/6 mice for the AOM/DSS colitis-associated carcinogenesis model and C57BL/6 IL10−/− mice for genetically driven chronic enterocolitis, both widely used preclinical proxies for human IBD biology. Animals received defined diets containing EDTA compounds and underwent standardized colitis induction (DSS cycles in AOM/DSS; piroxicam synchronization in IL10−/−), with clinical disease activity (DAI), histologic activity (HAI), and tumor burden quantified at sacrifice. Complementary mechanistic work used human intestinal epithelial T84 cell monolayers to model barrier disruption with EDTA exposure, including cytokine pretreatment (TNFα/IFNγ) to mimic inflammatory conditions.

Most important findings

Across both mouse models, EDTA exposure markedly increased colitis severity and tumor burden compared with controls; notably, Fe-EDTA uniquely worsened outcomes among tested iron compounds, and follow-up experiments confirmed the effect was attributable to EDTA itself rather than iron. Mechanistically, EDTA increased epithelial permeability and disrupted intercellular contacts, with additive barrier damage under inflammatory cytokines; in vivo topical Na-EDTA rapidly increased fluorescein leakage and produced ultrastructural gaps consistent with adherens junction disruption. Microbiome profiling showed EDTA groups separated clearly from controls and exhibited reduced diversity, with a striking >10-fold increase in Akkermansia muciniphila and a smaller rise in Peptostreptococcaceae (including taxa linked in prior work to procarcinogenic activity). These findings define a plausible microbiome-and-barrier axis whereby EDTA promotes dysbiosis, mucin degradation, and bacterial translocation that can perpetuate inflammation and accelerate carcinogenesis in susceptible hosts.

Key implications

For clinicians and microbiome-signature efforts, this paper highlights EDTA as a “conditional toxin”: largely tolerated in healthy models yet strongly detrimental when mucosal inflammation is present, amplifying both disease activity and colitis-associated tumorigenesis. The consistent EDTA-linked signature of reduced diversity with enrichment of Akkermansia and Peptostreptococcaceae provides candidate database markers of additive-driven dysbiosis in IBD-like states, while the barrier-disruption data support a clinically relevant pathway (chelation of Ca/Mg destabilizing junctions) that could interact with existing epithelial fragility in IBD. The work argues for revisiting safety testing frameworks to include inflammatory gut models and suggests caution around EDTA-containing foods, supplements, and pharmaceuticals in patients with active IBD or impaired barrier function.

Citation

Evstatiev R, Cervenka A, Austerlitz T, et al. The food additive EDTA aggravates colitis and colon carcinogenesis in mouse models. Sci Rep. 2021;11:5188. doi:10.1038/s41598-021-84571-5