Systemic iron reduction by venesection alters the gut microbiome in patients with haemochromatosis

Abstract

Background & aims: Iron reduction by venesection has been the cornerstone of treatment for haemochromatosis for decades, and its reported health benefits are many. Repeated phlebotomy can lead to a compensatory increase in intestinal iron absorption, reducing intestinal iron availability. Given that most gut bacteria are highly dependent on iron for survival, we postulated that, by reducing gut iron levels, venesection could alter the gut microbiota.

Methods: Clinical parameters, faecal bacterial composition and metabolomes were assessed before and during treatment in a group of patients with haemochromatosis undergoing iron reduction therapy.

Results: Systemic iron reduction was associated with an alteration of the gut microbiome, with changes evident in those who experienced reduced faecal iron availability with venesection. For example, levels of Faecalibacterium prausnitzii, a bacterium associated with improved colonic health, were increased in response to faecal iron reduction. Similarly, metabolomic changes were seen in association with reduced faecal iron levels.

Conclusion: These findings highlight a significant shift in the gut microbiome of patients who experience reduced colonic iron during venesection. Targeted depletion of faecal iron could represent a novel therapy for metabolic and inflammatory diseases, meriting further investigation.

Lay summary: Iron depletion by repeated venesection is the mainstay of treatment for haemochromatosis, an iron-overload disorder. Venesection has been associated with several health benefits, including improvements in liver function tests, reversal of liver scarring, and reduced risk of liver cancer. During iron depletion, iron absorption from the gastrointestinal (GI) tract increases to compensate for iron lost with treatment. Iron availability is limited in the GI tract and is crucial to the growth and function of many gut bacteria. In this study we show that reduced iron availability in the colon following venesection treatment leads to a change in the composition of the gut bacteria, a finding that, to date, has not been studied in patients with haemochromatosis.

Keywords: ALT, alanine aminotransferase; CRP, C-reactive protein; FAAS, flame atomic absorption spectrophotometry; GI, gastrointestinal; HFE, hyperferritinaemia; HH, hereditary haemachromatosis; Haemochromatosis; Iron; LDA, linear discriminant analysis; LEfSe, linear discriminant analysis effect size; Microbiome; TSP, 3-(trimethylsilyl)-propionate-d4; Venesection; WCC, white cell count.

Graphical abstract

Fig. 1

Iron and biochemical changes at baseline and after treatment. (A) Patients with iron overload had significantly higher faecal free iron levels compared with healthy controls. Significant reductions in serum (B) ferritin and (C) ALT were seen in paired samples on treatment (note that one ALT data point is missing in the treatment group). Free faecal iron fell significantly with treatment (D). Of these, 6 individuals had a significant reduction in faecal free iron (group A; reduced faecal iron), while 5 did not (group B; unchanged faecal iron) (E). Group A had significantly more iron removed by venesection compared with group B (F). Graphs are presented as mean ± SEM. ∗p <0.05 ∗∗p <0.005. Differences between groups were assessed using Mann-Whitney U test or Wilcoxon tests as appropriate. ALT, alanine transferase.

Fig. 2

Changes in bacterial composition with iron reduction. LEfSe analysis of faecal samples stratified by response to venesection. LEfSe identified taxa with differential relative abundance between categories (p <0.05). Data indicate LDA showing an effect size greater than log LDA = 2, which were deemed statistically significant. Baseline faecal samples of patients stratified according to eventual response to venesection (A) and differentially abundant taxa in faecal samples after venesection (B). Significant changes in 3 bacterial species were evident in those with reduced faecal free iron following venesection [Group A, ∗p <0.05 (C–E)]. Graphs are presented as mean ± SEM. Differences between groups were assessed using Wilcoxon test. LDA, linear discriminant analysis; LEfSe, linear discriminant analysis effect size.