Oral and Intravenous Iron Therapy Differentially Alter the On- and Off-Tumor Microbiota in Anemic Colorectal Cancer Patients

SIMPLE SUMMARY: Anemia is commonly associated with colorectal cancer and often requires intervention with therapeutic iron. However, iron is required for growth by the majority of colonic bacteria, leading to competition for free luminal iron. Hence, this leaves the potential for the route of iron administration to lead to differential gut bacterial populations. This study aimed to investigate the differences in on- and off-tumor bacterial populations following oral and intravenous therapy in anemic colorectal cancer patients. The following iron therapies were shown to be differential to bacterial diversity, microbial populations, and predictive metagenomics, inferring that oral iron-treated patients may have a potentially more procarcinogenic microbiota compared to intravenous iron-treated patients. Overall, this suggests that intravenous iron may be a more beneficial treatment for anemia in colorectal cancer, in order to limit microbial perturbations associated with oral iron. ABSTRACT: Iron deficiency anemia is a common complication of colorectal cancer and may require iron therapy. Oral iron can increase the iron available to gut bacteria and may alter the colonic microbiota. We performed an intervention study to compare oral and intravenous iron therapy on the colonic tumor-associated (on-tumor) and paired non-tumor-associated adjacent (off-tumor) microbiota. Anemic patients with colorectal adenocarcinoma received either oral ferrous sulphate (n = 16) or intravenous ferric carboxymaltose (n = 24). On- and off-tumor biopsies were obtained post-surgery and microbial profiling was performed using 16S ribosomal RNA analysis. Off-tumor α- and β-diversity were significantly different between iron treatment groups. No differences in on-tumor diversity were observed. Off-tumor microbiota of oral iron-treated patients showed higher abundances of the orders Clostridiales, Cytophagales, and Anaeroplasmatales compared to intravenous iron-treated patients. The on-tumor microbiota was enriched with the orders Lactobacillales and Alteromonadales in the oral and intravenous iron groups, respectively. The on- and off-tumor microbiota associated with intravenous iron-treated patients infers increased abundances of enzymes involved in iron sequestration and anti-inflammatory/oncogenic metabolite production, compared to oral iron-treated patients. Collectively, this suggests that intravenous iron may be a more appropriate therapy to limit adverse microbial outcomes compared to oral iron.