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

Oliver Phipps,Edward A Dickson,Jonathan Segal,Aditi Kumar,Austin G Acheson,Hafid O Al-Hassi,Andrew D Beggs,Matthew J Brookes,Mohammed N Quraishi,Helen Steed

doi:10.3390/cancers13061341

Abstract

Simple SummaryAnemia 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.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.

Highlights

Perturbations in gut bacterial populations are characteristic of colorectal cancer, with the presence of pathogenic indigenous bacterial species at the expense of protective probiotic species [1]
Comparison of α-diversity metrics shows that patients treated with oral iron have a significantly higher bacterial diversity (Shannon diversity and Faith’s phylogenetic diversity), richness, and abundance (Chao1 and abundancebased coverage estimator (ACE)) within their off-tumor microbiota, relative to those treated with intravenous iron therapy (Figure 1; p < 0.05)
The colonic iron concentration was not assessed within this study; previous studies have shown that oral iron administration leads to significantly greater fecal iron concentration compared to intravenous iron administration, supporting this proposed mechanism [26]

Summary

Introduction

Perturbations in gut bacterial populations are characteristic of colorectal cancer, with the presence of pathogenic indigenous bacterial species at the expense of protective probiotic species [1]. Driver bacteria are involved in the initiation of colorectal cancer These driver bacteria are gradually outcompeted by opportunistic passenger bacteria, which have a selective advantage within the newly defined tumor-microenvironment. These passenger bacteria can potentially either promote or hinder tumor progression, depending on whether pathogenic or probiotic bacterial populations flourish [2,3]. The gut microbiota has been shown to be altered in response to many commonly used orally administered non-antibiotic drugs [4] This allows the potential for the route of iron administration in anemic colorectal cancer patients to lead to differential gut microbial populations. Depending upon which bacterial populations thrive, the route of iron administration may support colorectal cancer progression [2,5]

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