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Review

Oral Iron Supplementation—Gastrointestinal Side Effects and the Impact on the Gut Microbiota

by
Sarah R. Bloor
1,2,3,*,
Rudolph Schutte
1 and
Anthony R. Hobson
2,3
1
Faculty of Health, Education, Medicine and Social Care, Anglia Ruskin University, Chelmsford CM1 1SQ, UK
2
Functional Gut Diagnostics, Manchester M2 4NG, UK
3
The Functional Gut Clinic, London W1G 6NB, UK
*
Author to whom correspondence should be addressed.
Microbiol. Res. 2021, 12(2), 491-502; https://doi.org/10.3390/microbiolres12020033
Submission received: 12 May 2021 / Revised: 3 June 2021 / Accepted: 8 June 2021 / Published: 12 June 2021
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Abstract

:
Iron deficiency anaemia (IDA) is a worldwide healthcare problem affecting approximately 25% of the global population. The most common IDA treatment is oral iron supplementation, which has been associated with gastrointestinal (GI) side effects such as constipation and bloating. These can result in treatment non-adherence and the persistence of IDA. Intravenous iron does not cause GI side effects, which may be due to the lack of exposure to the intestinal lumen. Luminal iron can cause changes to the gut microbiota, aiding the promotion of pathogenic species and decreasing beneficial protective species. Iron is vital for methanogenic archaea, which rely on iron for growth and metabolism. Increased intestinal methane has been associated with slowing of intestinal transit, constipation, and bloating. Here we explore the literature to understand a potential link between iron and methanogenesis as a novel way to understand the mechanism of oral iron supplementation induced GI side effects.

1. Introduction

Iron deficiency anaemia (IDA) affects up to 25% of the worldwide population [1], or approximately 2 billion people [2]. Annually, in the U.K., IDA costs the NHS £55.48 million and causes 57,000 hospital admissions [3]. Some of the main causes of iron deficiency include dietary insufficiency, blood loss, malabsorption, pregnancy, infections, inflammation, and inflammatory bowel disease (IBD). It is estimated that IDA will occur in 60–80% of IBD patients [3], with it being the most common extraintestinal complication of IBD [4]. The high prevalence of IDA in the IBD community is likely to be multifactorial, including inflammation, poor iron absorption, intestinal bleeding and a restricted diet [3].
Iron supplementation is heavily prescribed to a wide range of patients to prevent and treat iron deficiency (ID) and IDA. Intravenous and oral iron therapy restores iron levels. However, an important unexplained clinical limitation of oral iron therapy is that it often causes significant gastrointestinal (GI) side effects such as constipation, abdominal pain, nausea, and bloating [5,6,7]. Oral iron is the most common treatment for ID and IDA due to its low cost, high bioavailability and effectiveness [5,6]. There are many different types of oral iron supplements available (Table 1), but the most commonly prescribed oral iron is ferrous sulphate [7]. Ferrous iron supplements are effective; however, they have a high frequency of side effects in comparison to ferric iron sources [8]. First-line treatment is recommended to be ferrous sulphate two or three times per day, totalling a daily maximum elemental iron dosage of 195 mg [9,10].
Intravenous (IV) iron is administered directly into the bloodstream and therefore bypasses the GI lumen. When first developed, IV iron was toxic and not well tolerated causing anaphylaxis and hypersensitivity reactions [11]. Subsequently, IV iron preparations have gone through numerous iterations to develop a safer and better-tolerated formulation. An example of this is ferric carboxymaltose, which is non-dextran and deemed to be safe and significantly better than oral iron at replenishing haemoglobin levels with a single dose of 750 mg. Very few adverse effects have been found with ferric carboxymaltose with minor side effects and no discontinuation of treatment needed [12].
Intravenous iron does seem to have several benefits over oral iron. Gastrointestinal side effects are not as frequently reported [9], and compliance is much greater, resulting in the quicker restoration of haemoglobin and resolution of iron deficiency [10]. In addition, in adult IBD patients, IV iron is more effective and well tolerated [4]. Many studies also report quicker replenishment of iron stores in the body [13] due to the high cellular uptake of intravenous iron in comparison to oral supplements, where unabsorbed iron is lost in the faeces [14,15]. However, IV iron is significantly more costly, being over 60 times more expensive than oral iron [16]. Despite this, cost-effectiveness analysis for the treatment of IDA in IBD patients identified ferric carboxymaltose as the most cost-effective treatment due to suitable adherence to treatment, the high number of patients that respond to the treatment, improvements in hospitalisation rates, and patient quality of life [17].
Up to 60% of people taking oral iron supplements report gastrointestinal side effects [10]. These GI complaints cause up to 50% of oral iron receiving patients to not follow their treatment plan, meaning their IDA persists [9]. However, patients that receive IV iron infusions report a lower occurrence of these side effects [10] such as nausea (1.6% vs. 4.9%), vomiting (1.0% vs. 6.8%), abdominal pain (1.3% vs. 7.9%), and diarrhoea (0.9% vs. 8.3%) [4]. As IV iron bypasses the gastrointestinal lumen, it is thought that GI side effects observed are mainly driven by the direct interaction of iron with the gastrointestinal milieu from oral iron administration.
Despite millions of patients taking oral iron, the mechanisms by which GI side effects are mediated are poorly understood. Numerous theories as to the cause of iron-induced side effects have been proposed, including via hydroxyl radicals, lipid peroxidation, cellular damage and microbiota changes [18]. Understanding the mechanism to improve the side effect profile could have significant benefits in terms of patient outcome and healthcare economics.

2. Iron Absorption and Dosing of Iron Therapy

Iron is absorbed in the duodenum and proximal jejunum. Heme and non-heme iron have different mechanisms of absorption (Figure 1). For heme iron, heme carrier protein 1 (HCP-1) transports iron into the enterocyte lumen, where the ferrous (Fe2+) iron is released from the protoporphyrin XI ring by heme oxygenase [19]. Non-heme iron is first converted from ferric (Fe3+) to Fe2+ iron by the reductase enzyme duodenal cytochrome B (DCYTB). Then divalent metal transporter-1 (DMT-1) on the apical surface of duodenal enterocytes actively transports the reduced iron into the enterocyte cytoplasm [19]. Iron is regulated at the level of intestinal absorption to prevent iron overload as there is a lack of an iron excretory pathway. Hepcidin is the main regulator for the accumulation of iron in the body. When iron stores and circulating iron in transferrin are at saturation point, liver hepatocytes produce hepcidin. This triggers the degradation of ferroportin, a transmembrane protein involved in iron efflux, preventing further iron absorption [20].
The typical adult diet should contain between 8 and 15 mg of iron per day, with an average of 1–2 mg absorbed daily to balance losses from the body [21,22]. However, a maximum of 25 mg elemental iron per day can be absorbed, but this amount is only under extreme iron deficiency conditions [23]. Despite this, clinical guidance recommends iron deficiency anaemia is treated with oral ferrous sulphate 200 mg tablet, with two or three tablets taken daily to replenish iron levels [24,25]. Each ferrous sulphate tablet contains 65 mg of elemental iron; therefore, patients could be receiving up to 195 mg of elemental iron daily, which is significantly more than is capable of being absorbed. This unabsorbed iron will pass through the gastrointestinal tract interacting with the milieu before being excreted in faeces.
Over the years, many iron supplements have been developed with the aim of decreasing GI side effects. This has been trialled by iron in a modified-release tablet or liquid form. In vitro model experiments of conventional release tablets of ferrous sulphate, ferrous fumarate and ferrous gluconate were compared to controlled-release ferrous sulphate with ascorbic acid tablets and sustained-release capsules of ferrous fumarate. Absorption of iron was significantly greater from conventional release ferrous sulphate, whilst both modified-release tablets showed low absorption. Therefore, modified-release tablets have been contraindicated due to the low absorption as a result of the slower iron release rate [26]. Liquid formulations of iron are commonly mixed with fruit juices with a high polyphenol concentration, known to prevent absorption of iron (Table 2), so also not advised [26].
Spatone® iron-Plus water has been found to be a highly bio-available source of iron. However, one sachet of Spatone Iron-Plus water contains just 5 mg of iron to ensure that no gastrointestinal side effects occur. Whilst 28–34% of this is absorbed, this form of iron has only been recommended in a healthy pregnancy to maintain iron levels as lower amounts of supplemental iron are required in comparison with those suffering from iron deficiency anaemia [29,30,31]. Therefore, Spatone® should not be used to treat ID or IDA.
Another oral iron supplement aimed at reducing gastrointestinal side effects is sucrosomial iron. In sucrosomial iron, a phospholipid bilayer and sucrosome protect ferric pyrophosphate until it reaches the intestines. Pre-clinical data indicate that it may be more tolerable than other oral iron formulations whilst having similar effectiveness at restoring iron levels [32].
Experimental evidence suggests that taking iron two to three times a day may not be the best way to take iron supplements despite it being the current guidelines. Moretti et al. 2015 [33] found that high doses of oral iron supplements cause an increase in hepcidin, which inhibits iron absorption for up to 24 h. They found that dosing 48 h apart enhanced iron absorption compared to three daily doses as it allows sufficient time for hepcidin levels to decrease and remove the mucosal block on absorption [34,35]. Other groups have also confirmed enhanced iron absorption with single dosing once daily or alternate day dosing [33,34,36].
Overall, changing the formulation of iron supplementation reduces side effects by lowering the dosage and, in turn, reduces the amount of unabsorbed iron in the GI tract. It appears the best way to restore iron levels with the least number of side effects is with fewer doses of iron (even just two doses per week), which would also be more cost effective [35].

3. Iron and Inflammation

Both iron deficiency and iron overload can cause oxidative stress. Due to its ability to accept or donate electrons, iron can be harmful to the human body. Iron contains unsaturated electrons [37] and is a pro-oxidant [38], favouring the Fenton reaction (Equation (1)) and Haber–Weiss reaction (Equation (2)).
Fe3+ + O2−Ÿ → Fe2+ + O2
Fe2+ + H2O2 → Fe3+ + OH− + OHŸ
In the Fenton reaction, reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) are reduced by electrons to produce free radical species such as hydroxyl ions (OH−) [37,39]. In the GI tract, this can cause oxidative stress to the intestinal cells causing damage to membrane proteins and lipid peroxidation [39]. Therefore, when there is excess iron in the gastrointestinal tract, it can cause damage to intestinal villi resulting in a decrease in height, shape, and stability, along with damage to tight junction proteins between the mucosal enterocytes [39]. This causes inflammation of intestinal mucosa [37]. Inflammation in turn decreases iron absorption by stimulating hepcidin production and secretion and decreasing DMT-1 protein levels [39].

4. Iron and the Gut Microbiota

The gut microbiota are the microorganisms present in the GI tract. To survive, these microorganisms use nutrients from the human diet, and thus dietary changes, nutrient deficiencies, and oral medications can have profound effects on the microbiota. One nutrient the gut microbiota heavily relies on is iron, and its deficiency is often growth and virulence limiting for many bacteria.
As earlier discussed, iron supplements contain significantly more iron than can be absorbed by the body. This means that large amounts of unabsorbed iron are left in the lumen of the GI tract. Increased levels of luminal iron in the GI tract affects the composition of the gut microbiota, with an elevated level of enteropathogens and a decrease in the protective species Lactobacilli [40]. This can be caused by oral iron supplementation and the consumption of fortified food. Iron fortification (~8 mg/day) of African children’s diet resulted in increased growth of pathogenic bacteria such as Salmonella, Shigella and Escherichia coli, and a decrease in Lactobacillus, which is responsible for inhibiting pathogen colonisation [41]. Studies investigating the effect of iron supplementation in Kenyan infants also found increased levels of Enterobacteriaceae and decreased levels of Lactobacillus and Bifidobacterium [42]. However, the effects of iron supplementation and fortification on the gut microbiota in the long term are unknown [43].
Overall, iron has many impacts on the microbiota (Figure 2), but most commonly, it results in enhanced growth of pathogenic species and a decrease in beneficial bacterial species. Iron availability for pathogenic bacteria is so essential that the mammalian immune system has developed pathways known as nutritional immunity—the host’s ability to manipulate metals availability mediated by the expression of metal-binding proteins (lipocalin-2, lactoferrin, transferrin and intracellular ferritin) that can withhold iron [44,45]. This precise mechanism, however, has little chance to mediate balance in ID combined with iron overload. Transferrin and lactoferrin have been implicated in nutritional immunity by iron sequestration from invading pathogens, with evidence that lactoferrin can increase iron absorption by 56% [46,47,48]. Data to determine if lactoferrin can reduce iron-induced GI side effects is ambiguous, but lactoferrin can modulate GI inflammation by helping resolve the infection and prevent tissue damage along with reducing the growth of pathogens [49].
Coupling iron supplementation with prebiotics and probiotics could allow for mitigations against iron-induced microbiota changes. Lactobacillus fermentum increases iron absorption at DMT-1 by converting Fe3+ to Fe2+ via its ferric reducing activity; therefore, it could help reduce the GI side effects of iron [50]. In addition, studies investigating supplementing Kenyan infants with an iron-containing micronutrient powder with and without the prebiotic galacto-oligosaccharides (GOS) found GOS mitigated adverse effects of iron on the gut microbiota [51]. This is because GOS and probiotics decrease the pH of the intestines, which aids iron absorption [52] in addition to enhancing the commensal bacteria to protect against enteropathogens, which prevents colonisation and overgrowth [51]. Therefore, iron supplementation with GOS and lactoferrin may help reduce the impact on the gut microbiota by increasing the absorption of iron [53].
Archaeal species could also be impacted by iron, and it has been hypothesised that ferrous sulphate, a more soluble form of iron, could augment methanogenic species growth [41]. Numerous experiments have found that constipated individuals have a higher abundance of methanogenic species in their intestinal microbiota, along with slower intestinal transit times and higher faecal pH [54,55,56,57,58]. In addition, it is well known that taking oral iron supplements associates with constipation [9]. However, the mechanistic explanation of this relationship is unknown.

5. Methanogens, Methanogenesis, and GI Symptoms

Methanogens are ancient single-celled microorganisms that are part of the kingdom Archaea. They are believed to be present in small numbers in at least 30–50% of the population [57]. Numerous species are known to be able to colonise the human body, the most common being Methanobrevibacter smithii and Methanosphaera stadtmanae in the GI tract and Methanobrevibacter oralis in the oral cavity [57]. There are seven orders of methanogens belonging to the phylum Euryarchaeota, with the seventh order, Methanomassiliicoccales, only recently discovered [59].
Methanogens can produce methane (CH4) via a range of methanogenesis reactions (Table 3) [59]. Methanogenic species within the gastrointestinal tract predominantly use a hydrogenotrophic methanogenesis reaction to produce methane as they use hydrogen produced by the bacterial fermentation of carbohydrates [60]. Very few other species in the microbiota are capable of producing methane, with the exception of Clostridium and Bacteroides species [60,61,62].
The Christensenellaceae family coexist with the Methanobacteriaceae family, and in particular, the Christensenellaceae support M. smithii metabolism via hydrogen production that is then consumed by M. smithii for methane production. In addition, the presence of M. smithii causes an alteration in the short-chain fatty acid production of Christensella minuta towards acetate over butyrate [63], which can then be used for acetotrophic methanogenesis.
Methane has been linked with the slowing of intestinal transit [56]. Oro-caecal and whole gut transit time significantly decrease in methane producers compared to non-methane producers [56] and methane attenuates peristaltic movement in the intestines by promoting the contraction of non-propagating circular muscles [57,64]. Whilst there is an association between methane and constipation, it is uncertain whether methane is a cause or consequence of constipation [58].
Theories as to how methane impacts gut transit have been proposed. Methane has been suggested to be a gaseous transmitter, such as nitric oxide, with the ability to permeate through the intestinal wall to mediate neuronal and smooth muscle activities [56]. How methane slows intestinal transit may be mechanistically similar to the jejunal and ileal brake following the ingestion of fat [56]. Serotonin may also have a role in transit time control, with 95% of the serotonin in the body found in the GI tract [65]. Methane producers have a decreased serotonin level after meals, and methane gas was found to inhibit serotonin uptake in circulation [57,65].

6. Methanogenesis and Iron

In the Earth’s history, the main source of methane was via hydrogenotrophic methanogenesis in anaerobic ferruginous oceans. A modern-day example of this is Lake Matano in Indonesia, where iron oxides and methane are heavily abundant, and there is supportive evidence for methanogenesis in the presence of low reactive Fe3+ [61]. Biogas production experiments are also in favour of iron supported methanogenesis. The addition of zero-valent iron to algal sludge or wastewater fermenters has been found to enhance methane production by up to 17% [62,66].
Iron, along with other metals, is essential trace elements for methanogen growth, metabolism and enzymatic activity [67]. This is due to the large number of key proteins in methanogens using the iron-sulfur (Fe-S) clusters [68], on which methanogenesis is dependent [69]. However, iron may be important for methanogenesis in other ways, including as a source of electrons in the reduction in carbon dioxide to methane (Equation (3)). Metal corrosion experiments found that iron can be oxidised via the methanogenesis reaction, producing methane gas and creating energy to assist methanogenic species growth [70]. The methanogenesis reaction is the only way methanogens gain energy for growth [71]. However, some evidence suggests that pure cultures of hydrogenotrophic methanogens can have a decrease in methane production when iron is present [72].
8H+ + 4Fe0 + CO2 → CH4 + 4Fe2+ + 2H2O  ΔGO’ = −136 kJ
Sulphate-reducing bacteria (SRB) and methanogens live in similar environments and, as a result, commonly compete for the same substrates [73], which in turn can limit methanogenesis. Iron can help methanogens outcompete SRB as iron can precipitate sulphides to ferrous sulphide (FeS) [74]. This assists with methanogenesis by preventing the formation of hydrogen sulphide (H2S), which is toxic to methanogens and SRB [75].

7. Modulating Methane and Methanogens

Whilst few drugs and supplements have been found to have an impact on methane production, little is known on how to effectively reduce methane production or eradicate methanogens completely.
An increase in methane is a direct biomarker that correlates with slow transit, and a decrease in methane has a clinical benefit; therefore, it is important to understand ways to reduce methane. Whilst most antibiotics are not suitable for treating excessive methane production, a combination of rifaximin and neomycin have been effective in reducing methanogens with concurrent improvement in constipation symptoms [76,77,78]. Taking these antibiotics in combination with a pro-motility agent can help prevent the reestablishment of methanogens [79].
The mevalonate pathway targeted by cholesterol-lowering drugs (statins) is involved in the formation of cholesterol for archaeal cell walls. Therefore, the archaeal mevalonate pathway could act as a suitable target for the reduction in methane. There is evidence that lovastatin can inhibit archaeal cell wall biosynthesis when converted to its hydroxyacid form without impacting other bacteria, therefore, selectively targeting methanogens [80,81]. Inhibition occurs at the first step in cholesterol biosynthesis to 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG CoA reductase). Red yeast rice extract contains a chemically identical compound to lovastatin, monacolin K, and oyster mushroom extract naturally contains lovastatin, so these are also a potential candidate for a reduction in methane gas within the GI tract [82,83].
The supplement Atrantil could also be explored for use in methane eradication. Evidence suggests a benefit of methane-positive patients with a response rate of 88% of constipation-predominant IBS patients and marked improvements in both constipation and abdominal pain [84]. However, this has not been tested alongside breath testing to investigate whether the decrease in symptoms is accompanied by a decrease in methane levels.
Seaweed could be a natural anti-methanogenic compound [85]. Sheep that have been confined to a Scottish Orkney island beach shore surviving on a diet of seaweed do not produce any methane [86] in comparison to the 70–120 kg a year of methane produced by cattle [87]. Seaweed species such as Asparagopsis taxiformis and Asparagopsis armata contain bromoforms and dibromochloromethane, which can prevent methane production during digestion [85,88]. Just 1–2% of Asparagoposis per day of a cattle feed may reduce methane production by up to 70% [89], and 5% of A. taxiformis can reduce methane by 95% [90]. There is currently no evidence for seaweed reducing methane in humans and could be explored further.
Other methane treatment options could be with faecal microbiota transplantation (FMT). Previously this has worked in the eradication of Clostridium difficile infection; however, it has only been recently postulated as a treatment for methanogen overgrowth [91]. Probiotics containing Lactobacillus reuteri (DSM 17938) could also be beneficial as studies in infants with chronic constipation indicate L. reuteri could increase the frequency of bowel movements [92]. In addition, L. reuteri taken over a 4-week period is known to reduce methane production [58]. Multistrain probiotics used in adults with functional constipation reduced whole gut transit time by 13.75 h and increased the number of weekly bowel movements [93]. In the same meta-analysis, the use of multistrain formulations also significantly reduced bloating; however, methane production was not assessed.
Increasing iron absorption would reduce the availability of methanogens. The probiotic strain Lactiplantibacillus plantarum 299v has been shown to increased iron absorption. A study with pregnant women taking a capsule containing L. plantarum 299v along with 4.2 mg iron and low dose folic acid and ascorbic acid from the first trimester found improved iron status in comparison to the placebo [94]. Therefore, investigating probiotics that could enhance iron absorption could be a way of modulating methane production.

8. Conclusions and Future Directions

Oral iron supplementation is known to cause microbiota changes that could potentially include the increase in methanogenic species. Future experiments are needed to further understand the mechanism(s) at work to develop effective treatments resulting in better adherence to iron and an increased cost benefit for healthcare services. This will require assessment of biomarkers of bacterial fermentation and microbiota composition before and after administration of oral iron supplementation and capturing information on provoked symptoms.
There are several potential treatments that could target methanogens; however, besides antibiotics, there remains little evidence of their ability to reduce methane production and limit methanogen growth. Important future directions for this field need to evaluate the effectiveness of the variety of treatments explored in this review.
We have highlighted the current clinical issues with oral iron supplements. Whilst they are effective at restoring iron levels in ID and IDA patients, they are poorly tolerated by a large proportion of patients, including the IBD patient community. Their frequent GI side effects can lead to treatment non-adherence and therefore delays in restoration of iron levels resulting in GI inflammation. However, the mechanism by which oral iron supplements cause these adverse GI effects is unknown.
We hypothesize that potential causes of GI side effects provoked by oral iron supplementation include changes to the gut microbiota. Methanogenic archaea, methanogenesis, and methane gas up-regulation, could be a likely mechanism. The evidence suggests that iron is essential to support methanogenic species growth and methane production. This, taken together with the growing clinical evidence of the effect of methanogens on a range of GI symptoms and conditions, make it an attractive target. Future steps to investigate the mechanism of oral iron-induced GI side effects have been laid out.

Author Contributions

S.R.B. and A.R.H. developed the concept for the article. S.R.B. prepared the manuscript; R.S. and A.R.H. provided critical feedback to the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Acknowledgments

We thank Selim Cellek, and Malwina Naghibi for their comments on the manuscript.

Conflicts of Interest

Anthony Hobson is the cofounder of Functional Gut Diagnostics and has an equity interest in the company.

References

  1. Bethell, D.R.; Huang, J. Recombinant Human Lactoferrin Treatment for Global Health Issues: Iron Deficiency and Acute Diarrhea. J. Biometals 2004, 17, 337–342. [Google Scholar] [CrossRef]
  2. Zimmermann, M.B.; Hurrell, R.F. Nutritional Iron Deficiency. Lancet 2007, 370, 511–520. [Google Scholar] [CrossRef]
  3. Barton, C.; Cowan, K.; Faulds, J.; Holloway, D.; Johnston, S.; Mason, I.; McMahon, A. Iron Deficiency and Anaemia in Adults: RCN Guidance for Nursing Practice. Available online: https://www.rcn.org.uk/professional-development/publications/pub-007460 (accessed on 4 January 2021).
  4. Bonovas, S.; Fiorino, G.; Allocca, M.; Lytras, T.; Tsantes, A.; Peyrin-Biroulet, L.; Danese, S. Intravenous Versus Oral Iron for the Treatment of Anemia in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Medicine 2016, 95, e2308. [Google Scholar] [CrossRef] [PubMed]
  5. Santiago, P. Ferrous versus Ferric Oral Iron Formulations for the Treatment of Iron Deficiency: A Clinical Overview. Sci. World J. 2012, 2012, 846824. [Google Scholar] [CrossRef]
  6. Grzywacz, A.; Lubas, A.; Fiedor, P.; Fiedor, M.; Niemczyk, S. Safety and Efficacy of Intravenous Administration of Iron Preparations. Acta Pol. Pharm 2017, 74, 13–24. [Google Scholar] [PubMed]
  7. Low, M.S.Y.; Speedy, J.; Styles, C.E.; De-Regil, L.M.; Pasricha, S.-R. Daily Iron Supplementation for Improving Anaemia, Iron Status and Health in Menstruating Women. Cochrane Database Syst. Rev. 2016. [Google Scholar] [CrossRef]
  8. Wu, T.-W.; Tsai, F.-P. Comparison of the Therapeutic Effects and Side Effects of Oral Iron Supplements in Iron Deficiency Anemia. Drug Res. 2016, 66, 257–261. [Google Scholar] [CrossRef]
  9. Tolkien, Z.; Stecher, L.; Mander, A.P.; Pereira, D.I.; Powell, J.J. Ferrous Sulfate Supplementation Causes Significant Gastrointestinal Side-Effects in Adults: A Systematic Review and Meta-Analysis. PLoS ONE 2015, 10, e0117383. [Google Scholar] [CrossRef] [Green Version]
  10. Cançado, R.D.; Muñoz, M. Intravenous Iron Therapy: How Far Have We Come? Rev. Bras. Hematol. Hemoter. 2011, 33, 461–469. [Google Scholar] [CrossRef]
  11. Macdougall, I.C.; Vernon, K. Complement Activation-Related Pseudo-Allergy: A Fresh Look at Hypersensitivity Reactions to Intravenous Iron. Am. J. Nephrol. 2017, 45, 60–62. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Onken, J.E.; Bregman, D.B.; Harrington, R.A.; Morris, D.; Acs, P.; Akright, B.; Barish, C.; Bhaskar, B.S.; Smith-Nguyen, G.N.; Butcher, A.; et al. A Multicenter, Randomized, Active-Controlled Study to Investigate the Efficacy and Safety of Intravenous Ferric Carboxymaltose in Patients with Iron Deficiency Anemia. Transfusion 2014, 54, 306–315. [Google Scholar] [CrossRef]
  13. Bhandal, N.; Russell, R. Intravenous versus Oral Iron Therapy for Postpartum Anaemia. BJOG 2006, 113, 1248–1252. [Google Scholar] [CrossRef]
  14. Stein, J.; Dignass, A.U. Management of Iron Deficiency Anemia in Inflammatory Bowel Disease—A Practical Approach. Ann. Gastroenterol. 2013, 26, 104–113. [Google Scholar] [PubMed]
  15. Kortman, G.A.; Boleij, A.; Swinkels, D.W.; Tjalsma, H. Iron Availability Increases the Pathogenic Potential of Salmonella Typhimurium and Other Enteric Pathogens at the Intestinal Epithelial Interface. PLoS ONE 2012, 7, e29968. [Google Scholar] [CrossRef] [PubMed]
  16. Lee, T.W.; Kolber, M.R.; Fedorak, R.N.; van Zanten, S.V. Iron Replacement Therapy in Inflammatory Bowel Disease Patients with Iron Deficiency Anemia: A Systematic Review and Meta-Analysis. J. Crohn’s Colitis 2012, 6, 267–275. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Aksan, A.; Schoepfer, A.; Juillerat, P.; Vavricka, S.; Bettencourt, M.; Ramirez de Arellano, A.; Gavata, S.; Morin, N.; Valentine, W.; Hunt, B. Iron Formulations for the Treatment of Iron Deficiency Anemia in Patients with Inflammatory Bowel Disease: A Cost-Effectiveness Analysis in Switzerland. Adv. Ther. 2021, 38, 660–677. [Google Scholar] [CrossRef]
  18. Qi, X.; Zhang, Y.; Guo, H.; Hai, Y.; Luo, Y.; Yue, T. Mechanism and Intervention Measures of Iron Side Effects on the Intestine. Crit. Rev. Food Sci. Nutr. 2019, 60, 2113–2125. [Google Scholar] [CrossRef]
  19. Przybyszewska, J.; Żekanowska, E. The Role of Hepcidin, Ferroportin, HCP1, and DMT1 Protein in Iron Absorption in the Human Digestive Tract. Prz. Gastroenterol. 2014, 9, 208–213. [Google Scholar] [CrossRef]
  20. Rishi, G.; Subramaniam, V.N. The Liver in Regulation of Iron Homeostasis. Am. J. Physiol. Gastrointest. Liver Physiol. 2017, 313, G157–G165. [Google Scholar] [CrossRef] [Green Version]
  21. Fuqua, B.K.; Vulpe, C.D.; Anderson, G.J. Intestinal Iron Absorption. J. Trace Elem. Med. Biol. Organ Soc. Miner. Trace Elem. 2012, 26, 115–119. [Google Scholar] [CrossRef]
  22. Deschemin, J.-C.; Noordine, M.-L.; Remot, A.; Willemetz, A.; Afif, C.; Canonne-Hergaux, F.; Langella, P.; Karim, Z.; Vaulont, S.; Thomas, M.; et al. The Microbiota Shifts the Iron Sensing of Intestinal Cells. FASEB J. 2016, 30, 252–261. [Google Scholar] [CrossRef]
  23. Schrier, S.L. So You Know How to Treat Iron Deficiency Anemia. Blood 2015, 126, 1971. [Google Scholar] [CrossRef] [PubMed]
  24. NICE Scenario: Management|Management|Anaemia—Iron Deficienc|CKS|NICE. Available online: https://cks.nice.org.uk/topics/anaemia-iron-deficiency/management/management/ (accessed on 11 January 2021).
  25. Cook, J.D. Diagnosis and Management of Iron-Deficiency Anaemia. Best Pract. Res. Clin. Haematol. 2005, 18, 319–332. [Google Scholar] [CrossRef] [PubMed]
  26. Zariwala, M.G.; Somavarapu, S.; Farnaud, S.; Renshaw, D. Comparison Study of Oral Iron Preparations Using a Human Intestinal Model. Sci. Pharm. 2013, 81, 1123–1139. [Google Scholar] [CrossRef] [Green Version]
  27. Zijp, I.M.; Korver, O.; Tijburg, L.B.M. Effect of Tea and Other Dietary Factors on Iron Absorption. Crit. Rev. Food Sci. Nutr. 2000, 40, 371–398. [Google Scholar] [CrossRef] [PubMed]
  28. Tempel, M.; Chawla, A.; Messina, C.; Çeliker, M.Y. Effects of Omeprazole on Iron Absorption: Preliminary Study. Turk. J. Hematol. 2013, 30, 307. [Google Scholar] [CrossRef]
  29. Halksworth, G.; Moseley, L.; Carter, K.; Worwood, M. Iron Absorption from Spatone (a Natural Mineral Water) for Prevention of Iron Deficiency in Pregnancy. Clin. Lab. Haematol. 2003, 25, 227–231. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  30. McKenna, D.; Spence, D.; Haggan, S.E.; McCrum, E.; Dornan, J.C.; Lappin, T.R. A Randomized Trial Investigating an Iron-Rich Natural Mineral Water as a Prophylaxis against Iron Deficiency in Pregnancy. Clin. Lab. Haematol. 2003, 25, 99–103. [Google Scholar] [CrossRef] [Green Version]
  31. Worwood, M.; Evans, W.D.; Villis, R.J.; Burnett, A.K. Iron Absorption from a Natural Mineral Water (Spatone Iron-Plus). Available online: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2257.1996.tb00732.x (accessed on 10 July 2019).
  32. Gómez-Ramírez, S.; Brilli, E.; Tarantino, G.; Muñoz, M. Sucrosomial® Iron: A New Generation Iron for Improving Oral Supplementation. Pharmaceuticals 2018, 11, 97. [Google Scholar] [CrossRef] [Green Version]
  33. Moretti, D.; Goede, J.S.; Zeder, C.; Jiskra, M.; Chatzinakou, V.; Tjalsma, H.; Melse-Boonstra, A.; Brittenham, G.; Swinkels, D.W.; Zimmermann, M.B. Oral Iron Supplements Increase Hepcidin and Decrease Iron Absorption from Daily or Twice-Daily Doses in Iron-Depleted Young Women. Blood 2015, 126, 1981–1989. [Google Scholar] [CrossRef]
  34. Stoffel, N.U.; Zeder, C.; Brittenham, G.M.; Moretti, D.; Zimmermann, M.B. Iron Absorption from Supplements Is Greater with Alternate Day than with Consecutive Day Dosing in Iron-Deficient Anemic Women. Haematologica 2019, 105, 1232. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Hawamdeh, H.M.; Rawashdeh, M.; Aughsteen, A.A. Comparison between Once Weekly, Twice Weekly, and Daily Oral Iron Therapy in Jordanian Children Suffering from Iron Deficiency Anemia. Matern. Child Health J. 2013, 17, 368–373. [Google Scholar] [CrossRef]
  36. Stoffel, N.U.; Cercamondi, C.I.; Brittenham, G.; Zeder, C.; Geurts-Moespot, A.J.; Swinkels, D.W.; Moretti, D.; Zimmermann, M.B. Iron Absorption from Oral Iron Supplements given on Consecutive versus Alternate Days and as Single Morning Doses versus Twice-Daily Split Dosing in Iron-Depleted Women: Two Open-Label, Randomised Controlled Trials. Lancet Haematol. 2017, 4, e524–e533. [Google Scholar] [CrossRef]
  37. Junqueira Franco, M.M.V.; Nicoletti, C.F.; Nonino, C.B.; Vannucchi, H.; Marchini, J.S. Oxidative Stress after Iron Supplementation in Crohn’s Disease. J. Clin. Case Rep. 2016, 6, 2. [Google Scholar] [CrossRef]
  38. Rajendran, S.; Bobby, Z.; Habeebullah, S.; Jacob, S.E. Differences in the Response to Iron Supplementation on Oxidative Stress, Inflammation, and Hematological Parameters in Nonanemic and Anemic Pregnant Women. J. Matern. Fetal Neonatal Med. 2020, 1–7. [Google Scholar] [CrossRef]
  39. Ding, H.; Yu, X.; Chen, L.; Han, J.; Zhao, Y.; Feng, J. Tolerable Upper Intake Level of Iron Damages the Intestine and Alters the Intestinal Flora in Weaned Piglets. Metallomics 2020, 12, 1356–1369. [Google Scholar] [CrossRef]
  40. Oh, C.-K.; Moon, Y. Dietary and Sentinel Factors Leading to Hemochromatosis. Nutrients 2019, 11, 1047. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  41. Zimmermann, M.B.; Chassard, C.; Rohner, F.; N’goran, E.K.; Nindjin, C.; Dostal, A.; Utzinger, J.; Ghattas, H.; Lacroix, C.; Hurrell, R.F. The Effects of Iron Fortification on the Gut Microbiota in African Children: A Randomized Controlled Trial in Cote d’Ivoire. Am. J. Clin. Nutr. 2010, 92, 1406–1415. [Google Scholar] [CrossRef] [PubMed]
  42. Jaeggi, T.; Kortman, G.A.M.; Moretti, D.; Chassard, C.; Holding, P.; Dostal, A.; Boekhorst, J.; Timmerman, H.M.; Swinkels, D.W.; Tjalsma, H.; et al. Iron Fortification Adversely Affects the Gut Microbiome, Increases Pathogen Abundance and Induces Intestinal Inflammation in Kenyan Infants. Gut 2015, 64, 731–742. [Google Scholar] [CrossRef] [PubMed]
  43. Yilmaz, B.; Li, H. Gut Microbiota and Iron: The Crucial Actors in Health and Disease. Pharmaceuticals 2018, 11, 98. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Poole, R.K. Advances in Bacterial Pathogen Biology; Elsevier Science & Technology: Kent, UK, 2014; ISBN 978-0-12-800305-3. [Google Scholar]
  45. Cherayil, B.J. The Role of Iron in the Immune Response to Bacterial Infection. Immunol. Res. 2011, 50, 1–9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Iatsenko, I.; Marra, A.; Boquete, J.-P.; Peña, J.; Lemaitre, B. Iron Sequestration by Transferrin 1 Mediates Nutritional Immunity in Drosophila Melanogaster. Proc. Natl. Acad. Sci. USA 2020, 117, 7317–7325. [Google Scholar] [CrossRef] [PubMed]
  47. Mikulic, N.; Uyoga, M.A.; Mwasi, E.; Stoffel, N.U.; Zeder, C.; Karanja, S.; Zimmermann, M.B. Iron Absorption Is Greater from Apo-Lactoferrin and Is Similar Between Holo-Lactoferrin and Ferrous Sulfate: Stable Iron Isotope Studies in Kenyan Infants. J. Nutr. 2020, 150, 3200–3207. [Google Scholar] [CrossRef]
  48. Kell, D.B.; Heyden, E.L.; Pretorius, E. The Biology of Lactoferrin, an Iron-Binding Protein That Can Help Defend Against Viruses and Bacteria. Front. Immunol. 2020, 11, 1221. [Google Scholar] [CrossRef]
  49. Drago-Serrano, M.E.; Campos-Rodríguez, R.; Carrero, J.C.; de la Garza, M. Lactoferrin: Balancing Ups and Downs of Inflammation Due to Microbial Infections. Int. J. Mol. Sci. 2017, 18, 501. [Google Scholar] [CrossRef] [Green Version]
  50. González, A.; Gálvez, N.; Martín, J.; Reyes, F.; Pérez-Victoria, I.; Dominguez-Vera, J.M. Identification of the Key Excreted Molecule by Lactobacillus Fermentum Related to Host Iron Absorption. Food Chem. 2017, 228, 374–380. [Google Scholar] [CrossRef] [Green Version]
  51. Paganini, D.; Uyoga, M.A.; Kortman, G.A.M.; Cercamondi, C.I.; Moretti, D.; Barth-Jaeggi, T.; Schwab, C.; Boekhorst, J.; Timmerman, H.M.; Lacroix, C.; et al. Prebiotic Galacto-Oligosaccharides Mitigate the Adverse Effects of Iron Fortification on the Gut Microbiome: A Randomised Controlled Study in Kenyan Infants. Gut 2017, 66, 1956–1967. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Rusu, I.G.; Suharoschi, R.; Vodnar, D.C.; Pop, C.R.; Socaci, S.A.; Vulturar, R.; Istrati, M.; Moroșan, I.; Fărcaș, A.C.; Kerezsi, A.D.; et al. Iron Supplementation Influence on the Gut Microbiota and Probiotic Intake Effect in Iron Deficiency—A Literature-Based Review. Nutrients 2020, 12, 1993. [Google Scholar] [CrossRef]
  53. Zimmermann, M.B. Global Look at Nutritional and Functional Iron Deficiency in Infancy. Hematol. Am. Soc. Hematol. Educ. Program 2020, 2020, 471–477. [Google Scholar] [CrossRef]
  54. Attaluri, A.; Jackson, M.; Valestin, J.; Rao, S.S.C. Methanogenic Flora Is Associated with Altered Colonic Transit but Not Stool Characteristics in Constipation without IBS. Am. J. Gastroenterol. 2010, 105, 1407–1411. [Google Scholar] [CrossRef] [Green Version]
  55. Stephen, A.M.; Wiggins, H.S.; Englyst, H.N.; Cole, T.J.; Wayman, B.J.; Cummings, J.H. The Effect of Age, Sex and Level of Intake of Dietary Fibre from Wheat on Large-Bowel Function in Thirty Healthy Subjects. Br. J. Nutr. 1986, 56, 349–361. [Google Scholar] [CrossRef] [Green Version]
  56. Pimentel, M.; Lin, H.C.; Enayati, P.; van den Burg, B.; Lee, H.R.; Chen, J.H.; Park, S.; Kong, Y.; Conklin, J. Methane, a Gas Produced by Enteric Bacteria, Slows Intestinal Transit and Augments Small Intestinal Contractile Activity. Am. J. Physiol. Gastrointest. Liver Physiol. 2006, 290, G1089–G1095. [Google Scholar] [CrossRef] [Green Version]
  57. Triantafyllou, K.; Chang, C.; Pimentel, M. Methanogens, Methane and Gastrointestinal Motility. J. Neurogastroenterol. Motil. 2014, 20, 31–40. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Ojetti, V.; Petruzziello, C.; Migneco, A.; Gnarra, M.; Gasbarrini, A.; Franceschi, F.L. Reuteri in Methane Producer Constipated Patients. Eur. Rev. Med. Pharmacol. Sci. 2017, 21, 1702–1708. [Google Scholar]
  59. Gaci, N.; Borrel, G.; Tottey, W.; O’Toole, P.W.; Brugère, J.F. Archaea and the Human Gut: New Beginning of an Old Story. World J. Gastroenterol. 2014, 20, 16062–16078. [Google Scholar] [CrossRef] [PubMed]
  60. Nkamga, V.D.; Henrissat, B.; Drancourt, M. Archaea: Essential Inhabitants of the Human Digestive Microbiota. Hum. Microbiome J. 2017, 3, 1–8. [Google Scholar] [CrossRef]
  61. Bray, M.S.; Wu, J.; Reed, B.C.; Kretz, C.B.; Belli, K.M.; Simister, R.L.; Henny, C.; Stewart, F.J.; DiChristina, T.J.; Brandes, J.A.; et al. Shifting Microbial Communities Sustain Multiyear Iron Reduction and Methanogenesis in Ferruginous Sediment Incubations. Geobiology 2017, 15, 678–689. [Google Scholar] [CrossRef]
  62. Geng, S.; Song, K.; Li, L.; Xie, F. Improved Algal Sludge Methane Production and Dewaterability by Zerovalent Iron-Assisted Fermentation. Acs Omega 2020, 5, 6146–6152. [Google Scholar] [CrossRef]
  63. Ruaud, A.; Esquivel-Elizondo, S.; de la Cuesta-Zuluaga, J.; Waters, J.L.; Angenent, L.T.; Youngblut, N.D.; Ley, R.E. Syntrophy via Interspecies H2 Transfer between Christensenella and Methanobrevibacter Underlies Their Global Cooccurrence in the Human Gut. mBio 2020, 11, e03235-19. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Suri, J.; Kataria, R.; Malik, Z.A.; Parkman, H.P.; Schey, R. Elevated Methane Levels in Small Intestinal Bacterial Overgrowth Suggests Delayed Small Bowel and Colonic Transit. Gastroenterology 2017, 152, S525. [Google Scholar] [CrossRef]
  65. Pimentel, M.; Kong, Y.; Park, S. IBS Subjects with Methane on Lactulose Breath Test Have Lower Postprandial Serotonin Levels than Subjects with Hydrogen. Dig. Dis. Sci. 2004, 49, 84–87. [Google Scholar] [CrossRef] [PubMed]
  66. Carpenter, A.W.; Laughton, S.N.; Wiesner, M.R. Enhanced Biogas Production from Nanoscale Zero Valent Iron-Amended Anaerobic Bioreactors. Environ. Eng. Sci. 2015, 32, 647–655. [Google Scholar] [CrossRef] [PubMed]
  67. Ünal, B.; Perry, V.R.; Sheth, M.; Gomez-Alvarez, V.; Chin, K.-J.; Nüsslein, K. Trace Elements Affect Methanogenic Activity and Diversity in Enrichments from Subsurface Coal Bed Produced Water. Front. Microbiol. 2012, 3, 175. [Google Scholar] [CrossRef] [Green Version]
  68. Deere, T.M.; Lessner, F.H.; Duin, E.C.; Lessner, D.J. Building an ancient cofactor: Iron-sulfur cluster biogenesis in methanogenic archaea. 1. In Proceedings of the Diverse Life and its Detection on Different Worlds, Mesa, AZ, USA, 24–28 April 2017; p. 3507. [Google Scholar]
  69. Deere, T.M.; Prakash, D.; Lessner, F.H.; Duin, E.C.; Lessner, D.J. Methanosarcina Acetivorans Contains a Functional ISC System for Iron-Sulfur Cluster Biogenesis. BMC Microbiol. 2020, 20, 323. [Google Scholar] [CrossRef]
  70. Daniels, L.; Belay, N.; Rajagopal, B.S.; Weimer, P.J. Bacterial Methanogenesis and Growth from CO2 with Elemental Iron as the Sole Source of Electrons. Science 1987, 237, 509–511. [Google Scholar] [CrossRef] [PubMed]
  71. Weiss, D.S.; Thauer, R.K. Methanogenesis and the Unity of Biochemistry. Cell 1993, 72, 819–822. [Google Scholar] [CrossRef]
  72. Sivan, O.; Shusta, S.S.; Valentine, D.L. Methanogens Rapidly Transition from Methane Production to Iron Reduction. Geobiology 2016, 14, 190–203. [Google Scholar] [CrossRef]
  73. Chou, H.-H.; Huang, J.-S.; Chen, W.-G.; Ohara, R. Competitive Reaction Kinetics of Sulfate-Reducing Bacteria and Methanogenic Bacteria in Anaerobic Filters. Bioresour. Technol. 2008, 99, 8061–8067. [Google Scholar] [CrossRef] [PubMed]
  74. Ge, H.; Zhang, L.; Batstone, D.J.; Keller, J.; Yuan, Z. Impact of Iron Salt Dosage to Sewers on Downstream Anaerobic Sludge Digesters: Sulfide Control and Methane Production. J. Environ. Eng. 2013, 139, 594–601. [Google Scholar] [CrossRef]
  75. Liu, Y.; Zhang, Y.; Ni, B.-J. Zero Valent Iron Simultaneously Enhances Methane Production and Sulfate Reduction in Anaerobic Granular Sludge Reactors. Water Res. 2015, 75, 292–300. [Google Scholar] [CrossRef]
  76. Pimentel, M.; Chang, C.; Chua, K.S.; Mirocha, J.; DiBaise, J.; Rao, S.; Amichai, M. Antibiotic Treatment of Constipation-Predominant Irritable Bowel Syndrome. Dig. Dis. Sci. 2014, 59, 1278–1285. [Google Scholar] [CrossRef]
  77. Pimentel, M.; Lembo, A.; Chey, W.D.; Zakko, S.; Ringel, Y.; Yu, J.; Mareya, S.M.; Shaw, A.L.; Bortey, E.; Forbes, W.P.; et al. Rifaximin Therapy for Patients with Irritable Bowel Syndrome without Constipation. N. Engl. J. Med. 2011, 364, 22–32. [Google Scholar] [CrossRef] [Green Version]
  78. Pimentel, M.; Chatterjee, S.; Chow, E.J.; Park, S.; Kong, Y. Neomycin Improves Constipation-Predominant Irritable Bowel Syndrome in a Fashion That Is Dependent on the Presence of Methane Gas: Subanalysis of a Double-Blind Randomized Controlled Study. Dig. Dis. Sci. 2006, 51, 1297–1301. [Google Scholar] [CrossRef]
  79. Kresser, C.; Pimentel, M. A New Understanding of SIBO and IBS, with Mark Pimentel. Available online: https://chriskresser.com/a-new-understanding-of-sibo-and-ibs-with-mark-pimentel/ (accessed on 20 October 2020).
  80. Gottlieb, K.; Le, C.; Wacher, V.; Sliman, J.; Cruz, C.; Porter, T.; Carter, S. Selection of a Cut-off for High- and Low-Methane Producers Using a Spot-Methane Breath Test: Results from a Large North American Dataset of Hydrogen, Methane and Carbon Dioxide Measurements in Breath. Gastroenterol. Rep. 2017, 5, 193–199. [Google Scholar] [CrossRef] [Green Version]
  81. Hubert, S.; Chadwick, A.; Wacher, V.; Coughlin, O.; Kokai-Kun, J.; Bristol, A. Development of a Modified-Release Formulation of Lovastatin Targeted to Intestinal Methanogens Implicated in Irritable Bowel Syndrome With Constipation. J. Pharm. Sci. 2018, 107, 662–671. [Google Scholar] [CrossRef] [Green Version]
  82. Candyrine, S.C.L.; Mahadzir, M.F.; Garba, S.; Jahromi, M.F.; Ebrahimi, M.; Goh, Y.M.; Samsudin, A.A.; Sazili, A.Q.; Chen, W.L.; Ganesh, S.; et al. Effects of Naturally-Produced Lovastatin on Feed Digestibility, Rumen Fermentation, Microbiota and Methane Emissions in Goats over a 12-Week Treatment Period. PLoS ONE 2018, 13, e0199840. [Google Scholar] [CrossRef] [PubMed]
  83. Ramakrishnan, M.; Dubey, C.; Tulasi, V.; Kislai, P.; Manohar, N. Investigation of Lovastatin, the Anti-Hypercholesterolemia Drug Molecule from Three Oyster Mushroom Species. Int. J. Biomed. Clin. Sci. 2017, 2, 26–31. [Google Scholar]
  84. Brown, K.; Scott-Hoy, B.; Jennings, L.W. Response of Irritable Bowel Syndrome with Constipation Patients Administered a Combined Quebracho/Conker Tree/M. Balsamea Willd Extract. World J Gastrointest Pharm. 2016, 7, 463–468. [Google Scholar] [CrossRef] [Green Version]
  85. Thompson, L.R.; Rowntree, J.E. Invited Review: Methane Sources, Quantification, and Mitigation in Grazing Beef Systems. Appl. Anim. Sci. 2020, 36, 556–573. [Google Scholar] [CrossRef]
  86. Kirby, E.J. The Seaweed-Eating Sheep that Belch in a Good Way. Available online: https://www.bbc.com/news/stories-50856275 (accessed on 30 March 2020).
  87. University of Adelaide Study Shows Potential for Reduced Methane from Cows. Available online: https://phys.org/news/2019-07-potential-methane-cows.html (accessed on 30 March 2020).
  88. Roque, B.M.; Venegas, M.; Kinley, R.D.; de Nys, R.; Duarte, T.L.; Yang, X.; Kebreab, E. Red Seaweed (Asparagopsis Taxiformis) Supplementation Reduces Enteric Methane by over 80 Percent in Beef Steers. PLoS ONE 2021, 16, e0247820. [Google Scholar] [CrossRef] [PubMed]
  89. Smith, J. Seaweed as a Tool for Methane Reduction in Livestock|Coral Reef Ecology. Available online: https://scripps.ucsd.edu/labs/coralreefecology/research/seaweed-as-a-tool-for-methane-reduction-in-livestock/ (accessed on 30 March 2020).
  90. Roque, B.M.; Brooke, C.G.; Ladau, J.; Polley, T.; Marsh, L.J.; Najafi, N.; Pandey, P.; Singh, L.; Kinley, R.; Salwen, J.K.; et al. Effect of the Macroalgae Asparagopsis Taxiformis on Methane Production and Rumen Microbiome Assemblage. Anim. Microbiome 2019, 1, 3. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  91. Aroniadis, O.C.; Brandt, L.J. Intestinal Microbiota and the Efficacy of Fecal Microbiota Transplantation in Gastrointestinal Disease. Gastroenterol. Hepatol. 2014, 10, 230–237. [Google Scholar]
  92. Coccorullo, P.; Strisciuglio, C.; Martinelli, M.; Miele, E.; Greco, L.; Staiano, A. Lactobacillus Reuteri (DSM 17938) in Infants with Functional Chronic Constipation: A Double-Blind, Randomized, Placebo-Controlled Study. J. Pediatrics 2010, 157, 598–602. [Google Scholar] [CrossRef] [PubMed]
  93. Zhang, C.; Jiang, J.; Tian, F.; Zhao, J.; Zhang, H.; Zhai, Q.; Chen, W. Meta-Analysis of Randomized Controlled Trials of the Effects of Probiotics on Functional Constipation in Adults. Clin. Nutr. 2020, 39, 2960–2969. [Google Scholar] [CrossRef]
  94. Axling, U.; Önning, G.; Martinsson Niskanen, T.; Larsson, N.; Hansson, S.R.; Hulthén, L. The Effect of Lactiplantibacillus Plantarum 299v Together with a Low Dose of Iron on Iron Status in Healthy Pregnant Women: A Randomized Clinical Trial. Acta Obstet. Gynecol. Scand. 2021. [Google Scholar] [CrossRef] [PubMed]
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Figure 1. Iron absorption in the body. This can be in the form of heme or non-heme iron. Heme iron is transported into the duodenal enterocyte cytoplasm via HCP-1 (heme carrier protein 1), where the heme iron is then removed from the protoporphyrin X1 ring by heme oxygenase. The Fe2+ iron then forms part of the cLIP (cytosolic labile iron pool). Non-heme iron must be in the ferrous state before entering the enterocyte lumen. DCYTB (duodenal cytochrome B) reduces Fe3+ iron to Fe2+ iron, and then DMT-1 (divalent metal transporter 1) transports Fe2+ into the enterocyte, where it forms part of the cLIP. Iron in the cLIP can either bind to ferritin for storage or be transported out of the enterocyte via ferroportin and hephaestin, which oxidises the iron to its ferric state and can bind to transferrin in the blood for transport around the body.
Figure 1. Iron absorption in the body. This can be in the form of heme or non-heme iron. Heme iron is transported into the duodenal enterocyte cytoplasm via HCP-1 (heme carrier protein 1), where the heme iron is then removed from the protoporphyrin X1 ring by heme oxygenase. The Fe2+ iron then forms part of the cLIP (cytosolic labile iron pool). Non-heme iron must be in the ferrous state before entering the enterocyte lumen. DCYTB (duodenal cytochrome B) reduces Fe3+ iron to Fe2+ iron, and then DMT-1 (divalent metal transporter 1) transports Fe2+ into the enterocyte, where it forms part of the cLIP. Iron in the cLIP can either bind to ferritin for storage or be transported out of the enterocyte via ferroportin and hephaestin, which oxidises the iron to its ferric state and can bind to transferrin in the blood for transport around the body.
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Figure 2. Summary of the impact of iron on the GI tract. Oral iron supplementation causes up to 60% of patients to report gastrointestinal side effects such as constipation, nausea, and bloating. Iron is known to cause intestinal inflammation via the production of ROS. Iron also causes changes to the gut microbiota by increasing the level of enteropathogens and decreasing protective species and may cause changes to archaeal species.
Figure 2. Summary of the impact of iron on the GI tract. Oral iron supplementation causes up to 60% of patients to report gastrointestinal side effects such as constipation, nausea, and bloating. Iron is known to cause intestinal inflammation via the production of ROS. Iron also causes changes to the gut microbiota by increasing the level of enteropathogens and decreasing protective species and may cause changes to archaeal species.
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Table
Table 1. The three most common oral iron supplements used for the treatment of iron deficiency anaemia.
Table 1. The three most common oral iron supplements used for the treatment of iron deficiency anaemia.
Oral Iron SupplementDose (mg)Elemental Iron Dose (mg)
Ferrous sulphate20065
Ferrous fumarate20065
Ferrous gluconate30035
Table
Table 2. Foods and medications that either enhance or inhibit the absorption of iron heme and non-heme iron [27,28].
Table 2. Foods and medications that either enhance or inhibit the absorption of iron heme and non-heme iron [27,28].
Increase AbsorptionDecrease Absorption
Ascorbic acid (Vitamin C)Antacid medications (e.g., proton pump inhibitors)
MeatPhytates and polyphenols
FishCalcium
Table
Table 3. Methods of methanogenesis by different methanogens.
Table 3. Methods of methanogenesis by different methanogens.
Type of MethanogenesisSubstratesMechanism
HydrogenotrophicHydrogen or formateThe substrates can reduce carbon dioxide to produce methane
MethylotrophicMethanol, methyl-sulphides, methylaminesMethyl group of the substrate is converted to methane using specific methyltransferases
AcetotrophicAcetateFermentation of acetate or decarboxylation to carbon dioxide followed by reduction
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Bloor, S.R.; Schutte, R.; Hobson, A.R. Oral Iron Supplementation—Gastrointestinal Side Effects and the Impact on the Gut Microbiota. Microbiol. Res. 2021, 12, 491-502. https://doi.org/10.3390/microbiolres12020033

AMA Style

Bloor SR, Schutte R, Hobson AR. Oral Iron Supplementation—Gastrointestinal Side Effects and the Impact on the Gut Microbiota. Microbiology Research. 2021; 12(2):491-502. https://doi.org/10.3390/microbiolres12020033

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Bloor, Sarah R., Rudolph Schutte, and Anthony R. Hobson. 2021. "Oral Iron Supplementation—Gastrointestinal Side Effects and the Impact on the Gut Microbiota" Microbiology Research 12, no. 2: 491-502. https://doi.org/10.3390/microbiolres12020033

APA Style

Bloor, S. R., Schutte, R., & Hobson, A. R. (2021). Oral Iron Supplementation—Gastrointestinal Side Effects and the Impact on the Gut Microbiota. Microbiology Research, 12(2), 491-502. https://doi.org/10.3390/microbiolres12020033

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