Oral versus intravenous iron replacement therapy distinctly alters the gut microbiota and metabolome in patients with IBD

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Abstract

Objective

Iron deficiency is a common complication in patients with IBD and oral iron therapy is suggested to exacerbate IBD symptoms. We performed an open-labelled clinical trial to compare the effects of per oral (PO) versus intravenous (IV) iron replacement therapy (IRT).

Design

The study population included patients with Crohn's disease (CD; N=31), UC (N=22) and control subjects with iron deficiency (non-inflamed, NI=19). After randomisation, participants received iron sulfate (PO) or iron sucrose (IV) over 3 months. Clinical parameters, faecal bacterial communities and metabolomes were assessed before and after intervention.

Results

Both PO and IV treatments ameliorated iron deficiency, but higher ferritin levels were observed with IV. Changes in disease activity were independent of iron treatment types. Faecal samples in IBD were characterised by marked interindividual differences, lower phylotype richness and proportions of Clostridiales. Metabolite analysis also showed separation of both UC and CD from control anaemic participants. Major shifts in bacterial diversity occurred in approximately half of all participants after IRT, but patients with CD were most susceptible. Despite individual-specific changes in phylotypes due to IRT, PO treatment was associated with decreased abundances of operational taxonomic units assigned to the species Faecalibacterium prausnitzii, Ruminococcus bromii, Dorea sp. and Collinsella aerofaciens. Clear IV-specific and PO-specific fingerprints were evident at the level of metabolomes, with changes affecting cholesterol-derived host substrates.

Conclusions

Shifts in gut bacterial diversity and composition associated with iron treatment are pronounced in IBD participants. Despite similar clinical outcome, oral administration differentially affects bacterial phylotypes and faecal metabolites compared with IV therapy.

Trial registration number

clinicaltrial.gov (NCT01067547).

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Most cited references 44

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Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases.

Henri Duboc, Sylvie Rajca, Dominique Rainteau … (2013)

Gut microbiota metabolises bile acids (BA). As dysbiosis has been reported in inflammatory bowel diseases (IBD), we aim to investigate the impact of IBD-associated dysbiosis on BA metabolism and its influence on the epithelial cell inflammation response. Faecal and serum BA rates, expressed as a proportion of total BA, were assessed by high-performance liquid chromatography tandem mass spectrometry in colonic IBD patients (42) and healthy subjects (29). The faecal microbiota composition was assessed by quantitative real-time PCR. Using BA profiles and microbiota composition, cluster formation between groups was generated by ranking models. The faecal BA profiles in germ-free and conventional mice were compared. Direct enzymatic activities of BA biotransformation were measured in faeces. The impact of BA on the inflammatory response was investigated in vitro using Caco-2 cells stimulated by IL-1β. IBD-associated dysbiosis was characterised by a decrease in the ratio between Faecalibacterium prausntizii and Escherichia coli. Faecal-conjugated BA rates were significantly higher in active IBD, whereas, secondary BA rates were significantly lower. Interestingly, active IBD patients exhibited higher levels of faecal 3-OH-sulphated BA. The deconjugation, transformation and desulphation activities of the microbiota were impaired in IBD patients. In vitro, secondary BA exerted anti-inflammatory effects, but sulphation of secondary BAs abolished their anti-inflammatory properties. Impaired microbiota enzymatic activity observed in IBD-associated dysbiosis leads to modifications in the luminal BA pool composition. Altered BA transformation in the gut lumen can erase the anti-inflammatory effects of some BA species on gut epithelial cells and could participate in the chronic inflammation loop of IBD.

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High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease

Alan W. Walker, Jeremy Sanderson, Carol Churcher … (2011)

Background The gut microbiota is thought to play a key role in the development of the inflammatory bowel diseases Crohn's disease (CD) and ulcerative colitis (UC). Shifts in the composition of resident bacteria have been postulated to drive the chronic inflammation seen in both diseases (the "dysbiosis" hypothesis). We therefore specifically sought to compare the mucosa-associated microbiota from both inflamed and non-inflamed sites of the colon in CD and UC patients to that from non-IBD controls and to detect disease-specific profiles. Results Paired mucosal biopsies of inflamed and non-inflamed intestinal tissue from 6 CD (n = 12) and 6 UC (n = 12) patients were compared to biopsies from 5 healthy controls (n = 5) by in-depth sequencing of over 10,000 near full-length bacterial 16S rRNA genes. The results indicate that mucosal microbial diversity is reduced in IBD, particularly in CD, and that the species composition is disturbed. Firmicutes were reduced in IBD samples and there were concurrent increases in Bacteroidetes, and in CD only, Enterobacteriaceae. There were also significant differences in microbial community structure between inflamed and non-inflamed mucosal sites. However, these differences varied greatly between individuals, meaning there was no obvious bacterial signature that was positively associated with the inflamed gut. Conclusions These results may support the hypothesis that the overall dysbiosis observed in inflammatory bowel disease patients relative to non-IBD controls might to some extent be a result of the disturbed gut environment rather than the direct cause of disease. Nonetheless, the observed shifts in microbiota composition may be important factors in disease maintenance and severity.

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Ferrous Sulfate Supplementation Causes Significant Gastrointestinal Side-Effects in Adults: A Systematic Review and Meta-Analysis

Zoe Tolkien, Lynne Stecher, Adrian P Mander … (2015)

Background The tolerability of oral iron supplementation for the treatment of iron deficiency anemia is disputed. Objective Our aim was to quantify the odds of GI side-effects in adults related to current gold standard oral iron therapy, namely ferrous sulfate. Methods Systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating GI side-effects that included ferrous sulfate and a comparator that was either placebo or intravenous (IV) iron. Random effects meta-analysis modelling was undertaken and study heterogeneity was summarised using I2 statistics. Results Forty three trials comprising 6831 adult participants were included. Twenty trials (n = 3168) had a placebo arm and twenty three trials (n = 3663) had an active comparator arm of IV iron. Ferrous sulfate supplementation significantly increased risk of GI side-effects versus placebo with an odds ratio (OR) of 2.32 [95% CI 1.74–3.08, p<0.0001, I2 = 53.6%] and versus IV iron with an OR of 3.05 [95% CI 2.07-4.48, p<0.0001, I2 = 41.6%]. Subgroup analysis in IBD patients showed a similar effect versus IV iron (OR = 3.14, 95% CI 1.34-7.36, p = 0.008, I2 = 0%). Likewise, subgroup analysis of pooled data from 7 RCTs in pregnant women (n = 1028) showed a statistically significant increased risk of GI side-effects for ferrous sulfate although there was marked heterogeneity in the data (OR = 3.33, 95% CI 1.19-9.28, p = 0.02, I2 = 66.1%). Meta-regression did not provide significant evidence of an association between the study OR and the iron dose. Conclusions Our meta-analysis confirms that ferrous sulfate is associated with a significant increase in gastrointestinal-specific side-effects but does not find a relationship with dose.

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Author and article information

Journal

Journal ID (nlm-ta): Gut

Journal ID (iso-abbrev): Gut

Journal ID (hwp): gutjnl

Journal ID (publisher-id): gut

Title: Gut

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Print): 0017-5749

ISSN (Electronic): 1468-3288

Publication date (Print): May 2017

Publication date (Electronic): 4 February 2016

Volume: 66

Issue: 5

Pages: 863-871

Affiliations

[1 ]Division of Gastroenterology, Department of Medicine, University of Alberta , Edmonton, Canada

[2 ]Department of Gastroenterology, Wollongong Hospital, Wollongong , NSW, Australia

[3 ]ZIEL Institute for Food and Health, Technische Universität München , Freising, Germany

[4 ]Research Unit Analytical BioGeoChemistry, German Research Center for Environmental Health , Neuherberg, Germany

[5 ]Chair of Nutrition and Immunology, Technische Universität München , Freising, Germany

Author notes

[Correspondence to ] Professor Dirk Haller, Chair of Nutrition and Immunology, Technische Universität München, Gregor-Mendel-Str. 2, Freising 85354, Germany; dirk.haller@ 123456tum.de

TL, TC and KS contributed equally and share first authorship. RF and DH contributed equally and share last authorship.

Article

Publisher ID: gutjnl-2015-309940

DOI: 10.1136/gutjnl-2015-309940

PMC ID: 5531225

PubMed ID: 26848182

SO-VID: 73ca1b91-56d3-4918-9eba-4c6518014545

Copyright © Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

License:

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

History

Date received : 9 May 2015

Date revision received : 2 December 2015

Date accepted : 21 December 2015

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ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: ibd clinical,inflammatory bowel disease,intestinal bacteria,iron deficiency,anemia

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ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: ibd clinical, inflammatory bowel disease, intestinal bacteria, iron deficiency, anemia

Oral versus intravenous iron replacement therapy distinctly alters the gut microbiota and metabolome in patients with IBD

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Karger: Gastroenterology

Most cited references 44

Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases.

High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease

Ferrous Sulfate Supplementation Causes Significant Gastrointestinal Side-Effects in Adults: A Systematic Review and Meta-Analysis

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