References

perinatology

Российский вестник перинатологии и педиатрии

Rossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics)

1027-40652500-2228

Ltd. “The National Academy of Pediatric Science and Innovation”

10.21508/1027-4065-2022-67-5-18-26

perinatology-1696

Research Article

ОБЗОР ЛИТЕРАТУРЫ

REVIEWS

Гастроинтестинальные нежелательные эффекты препаратов железа: возможное влияние на микробиоту кишечника

Gastrointestinal side effects of iron supplements: potential effects on gut microbiota

https://orcid.org/0000-0001-5766-6741

Балашова

Е. А.

Balashova

E. A.

д.м.н., доц. кафедры госпитальной педиатрии,

443099 Самара, ул. Чапаевская, д. 89

Samara

e.a.balashova@samsmu.ru

https://orcid.org/0000-0002-6000-1959

Шадрина

И. Л.

Shadrina

I. L.

зам. глав. врача по детству и родовспоможению;

асс. кафедры госпитальной педиатрии,

443112 Самара, п. Управленческий, ул. Крайняя, д. 17

Samara

https://orcid.org/0000-0001-9954-5729

Погодина

А. А.

Pogodina

A. A.

врач-педиатр,

443124 Самара, ул. Ново-Садовая, д. 200 А

Samara

ФГБОУ ВО «Самарский государственный медицинский университет» Минздрава РоссииРоссияSamara State Medical UniversityRussian Federation

ФГБОУ ВО «Самарский государственный медицинский университет» Минздрава России; ГБУЗ Самарской области «Самарская городская больница №7»РоссияSamara State Medical University; Samara City Hospital No. 7Russian Federation

ГБУЗ Самарской области «Самарская городская клинико-диагностическая поликлиника №14»РоссияSamara City Clinical and Diagnostic Policlinic No. 14Russian Federation

2022

16112022

6751826

2022

Ltd. “The National Academy of Pediatric Science and Innovation”

https://www.ped-perinatology.ru/jour/about/submissions#copyrightNotice

https://www.ped-perinatology.ru/jour/article/view/1696

Железодефицитная анемия остается актуальной проблемой в педиатрической практике; распространенность патологии в РФ составляет 6–40%. В качестве первой линии терапии железодефицитной анемии большинство отечественных и зарубежных педиатров, особенно в амбулаторных условиях, отдают предпочтение пероральным препаратам железа. Несмотря на их высокую эффективность, сохраняется проблема побочных эффектов, в первую очередь гастроинтестинальной токсичности. В данном обзоре рассматривается вопрос потенциального влияния саплементации железа на состав микробиоты кишечника, представлены результаты изучения вопроса на животных моделях и в клинических исследованиях.

Iron deficiency anemia remains a significant problem in pediatric practice with its prevalence of 6–40% in the Russian Federation. Oral iron supplementation is the most common first-line treatment especially in outpatient setting. Despite adequate efficacy of oral supplementation, the problem of its side effects and, primarily, gastrointestinal toxicity remains. This review examines the issue of the potential effect of iron supplementation on gut microbiota composition, presents data from studies in animal models and in clinical studies.

детидефицит железасаплементация железамикробиота

childreniron deficiencyiron supplementationmicrobiota

Исследование выполнено при финансовой Правительства Самарской области в рамках губернского гранта в области науки и техники.

References1

WHO. SDG Target 2.2 | Malnutrition: End all forms of malnutrition, including achieving targets on stunting and wasting in children under 5 years of age, and address the nutritional needs of adolescent girls, pregnant and lactating women and older persons. https://www.who.int/data/gho/data/themes/topics/indicator-groups/indicator-group-details/GHO/sdg-target-2.2-child-malnutrition/Ссылка активна на 17.08.2022.

Kassebaum N.J.; GBD 2013 Anemia Collaborators. The Global Burden of Anemia. Hematol Oncol Clin North Am 2016; 30(2): 247-308. DOI: 10.1016/j.hoc.2015.11.002

Федеральные клинические рекомендации по диагностике и лечению железодефицитной анемии. Приказ Минздрава РФ от 3 августа 1999 г (nodgo.org)/ Ссылка активна на 17.08.2022.

Federal clinical guidelines on diagnostics and therapy of iron deficiency anemia. (in Russ.).

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(2): e0117383. DOI: 10.1371/journal.pone.0117383

Cancelo-Hidalgo M.J., Castelo-Branco C., Palacios S., Haya-Palazuelos J., Ciria-Recasens M., Manasanch J., PérezEdo L. Tolerability of different oral iron supplements: a systematic review. Curr Med Res Opin 2013; 29(4): 291-303. DOI: 10.1185/03007995.2012.761599

Лебедев В.В., Демихов В.Г., Фомина М.А., Демихова Е.В., Кравцова Н.Б., Дмитриев А.В. Метод комплексной оценки продуктов окислительной модификации белков для определения безопасности двух и трехвалентных пероральных препаратов железа и их эффективности в лечении железодефицитной анемии у детей. Педиатрия им. Г.Н. Сперанского 2018; 97(5): 47-53. DOI: 10.24110/0031-403X-2018-97-5-47-53

Lebedev V.V., Demikhov V.G., Fomina M.A., Demikhova E.V., Kravtsova N.B., Dmitriev A.V. A method for the complex evaluation of proteins oxidative modification products for determination of bivalent and trivalent oral iron preparations and their efficacy in treatment of iron deficiency anemia in children. Pediatria imeni G.N. Speransky 2018; 97(5): 47-53. (in Russ.). DOI: 10.24110/0031-403X-2018-97-5-47-53

Yasa B., Agaoglu L., Unuvar E. Efficacy, Tolerability, and Acceptability of Iron Hydroxide Polymaltose Complex versus Ferrous Sulfate: A Randomized Trial in Pediatric Patients with Iron Deficiency Anemia. Int J Pediatr 2011; 2011: 524520. DOI: 10.1155/2011/524520

MeliĠ L.E., Mărginean C.O., Mocanu S., Mărginean M.O. A rare case of iron-pill induced gastritis in a female teenager: A case report and a review of the literature. Medicine (Baltimore) 2017; 96(30): e7550. DOI: 10.1097/MD.0000000000007550

Ching D., Mews C., Crompton C., Ravikumar M., Abeysuriya D. Iron Pill-Induced Gastritis in the Paediatric Population. Case Rep Pediatr 2019; 2019: 7527608. DOI: 10.1155/2019/7527608

Abraham S.C., Yardley J.H., Wu T.T. Erosive injury to the upper gastrointestinal tract in patients receiving iron medication: an underrecognized entity. Am J Surg Pathol 1999; 23(10): 1241-1247. DOI: 10.1097/00000478-199910000-00009

Eckstein R.P., Symons P. Iron tablets cause histopathologically distinctive lesions in mucosal biopsies of the stomach and esophagus. Pathology 1996; 28(2): 142-145. DOI: 10.1080/00313029600169763

Russo G., Guardabasso V., Romano F., Corti P., Samperi P., Condorelli A. et al. Monitoring oral iron therapy in children with iron deficiency anemia: an observational, prospective, multicenter study of AIEOP patients (Associazione Italiana Emato-Oncologia Pediatrica). Ann Hematol 2020; 99(3): 413-420. DOI: 10.1007/s00277-020-03906-w

Мачнева Е.Б., Захарова И.Н., Тарасова И.С., Чернов В.М. Результаты рандомизированного исследования лечения железодефицитной анемии у детей и подростков с помощью железа (III) гидроксид полимальтозного комплекса и сульфата железа: критерии эффективности и переносимость. Вопросы гематологии/онкологии и иммунопатологии в педиатрии 2016; 15(2): 47-52. DOI: 10.24287/1726-1708-2016-15-2-47-52

Machneva E.B., Zakharova I.N., Tarasova I.S., Chernov V.M. Results of a randomized study of management of iron deficiency anaemia in children and adolescents using an iron (III) hydroxide polymaltose complex and iron sulfate: criteria of efficacy and tolerance. Voprosy gematologii/onkologii i immunopatologii v pediatrii 2016; 15(2): 47-52. (in Russ.) DOI: 10.24287/1726-1708-2016-15-2-47-52

Торшин И.Ю., Громова О.А., Лиманова О.А., Гришина Т.Р., Башмакова Н.В., Керимкулова Н.В. и др. Метаанализ клинических исследований по применению фумарата железа с целью профилактики и терапии железодефицитной анемии у беременных. Гинекология 2015; 17(5): 24-31.

Torshin I.Y., Gromova O.A., Limanova O.A., Grishina T.R., Bashmakova N.V., Kerimkulova N.V. et al. A meta-analysis of clinical studies on the use of iron fumarate for the prevention and treatment of iron deficiency anemia in pregnant women. Ginekologiya 2015; 17(5): 24-31. (in Russ.)

Melamed N., Ben-Haroush A., Kaplan B., Yogev Y. Iron supplementation in pregnancy: does the preparation matter? Arch Gynecol Obstet 2007; 276(6): 601-604. DOI: 10.1007/s00404-007-0388-3

Gera T., Sachdev H.P. Effect of iron supplementation on incidence of infectious illness in children: systematic review. BMJ 2002; 325(7373): 1142. DOI: 10.1136/bmj.325.7373.1142

Soofi S., Cousens S., Iqbal S.P., Akhund T., Khan J., Ahmed I. et al. Effect of provision of daily zinc and iron with several micronutrients on growth and morbidity among young children in Pakistan: a cluster-randomised trial. Lancet 2013; 382(9886): 29-40. DOI: 10.1016/S0140-6736(13)60437-7

Richard S.A., Zavaleta N., Caulfield L.E., Black R.E., Witzig R.S., Shankar A.H. Zinc and iron supplementation and malaria, diarrhea, and respiratory infections in children in the Peruvian Amazon. Am J Trop Med Hyg 2006; 75(1): 126-132. DOI: 10.4269/ajtmh.2006.75.1.0750126

Chang S., El Arifeen S., Bari S., Wahed M.A., Rahman K.M., Rahman M.T. et al. Supplementing iron and zinc: double blind, randomized evaluation of separate or combined delivery. Eur J Clin Nutr 2010; 64(2): 153-160. DOI: 10.1038/ejcn.2009.127

Halliwell B., Gutteridge J.M. Biologically relevant metal ion-dependent hydroxyl radical generation. An update. FEBS Lett 1992; 307(1): 108-112. DOI: 10.1016/0014- 5793(92)80911-y

Cadenas E. Biochemistry of oxygen toxicity. Annu Rev Biochem 1989; 58: 79-110. DOI: 10.1146/annurev.bi.58.070189.000455

Carrier J., Aghdassi E., Platt I., Cullen J., Allard J.P. Effect of oral iron supplementation on oxidative stress and colonic inflammation in rats with induced colitis. Aliment Pharmacol Ther 2001; 15(12): 1989-1999. DOI: 10.1046/j.1365-2036.2001.01113.x

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(9): 1356-1369. DOI: 10.1039/d0mt00096e

Dainty J.R., Berry R., Lynch S.R., Harvey L.J., Fairweather-Tait S.J. Estimation of dietary iron bioavailability from food iron intake and iron status. PLoS One 2014; 9(10): e111824. DOI: 10.1371/journal.pone.0111824

Roughead Z.K., Zito C.A., Hunt J.R. Initial uptake and absorption of non-heme iron and absorption of heme iron in humans are unaffected by the addition of calcium as cheese to a meal with high iron bioavailability. Am J Clin Nutr 2002; 76(2): 419-425. DOI: 10.1093/ajcn/76.2.419

Naikare H., Palyada K., Panciera R., Marlow D., Stintzi A. Major role for FeoB in Campylobacter jejuni ferrous iron acquisition, gut colonization, and intracellular survival. Infect Immun 2006; 74(10): 5433-5444. DOI: 10.1128/IAI.00052-06

Vasileva D., Janssen H., Hönicke D., Ehrenreich A., Bahl H. Effect of iron limitation and fur gene inactivation on the transcriptional profile of the strict anaerobe Clostridium acetobutylicum. Microbiology (Reading) 2012; 158(Pt 7): 1918- 1929. DOI: 10.1099/mic.0.056978-0

Boyer E., Bergevin I., Malo D., Gros P., Cellier M.F. Acquisition of Mn(II) in addition to Fe(II) is required for full virulence of Salmonella enterica serovar Typhimurium. Infect Immun 2002; 70(11): 6032-6042. DOI: 10.1128/IAI.70.11.6032-6042.2002

Andrews S.C., Robinson A.K., Rodríguez-Quiñones F. Bacterial iron homeostasis. FEMS Microbiol Rev 2003; 27(2-3): 215- 237. DOI: 10.1016/S0168-6445(03)00055-X

Archibald F. Lactobacillus plantarum, an organism not requiring iron. FEMS Microbiology Letters 1983; 19(1): 29- 32. DOI: 10.1111/j.1574-6968.1983.tb00504.x

Pandey A., Bringel F., Meyer J.M. Iron requirement and search for siderophores in lactic acid bacteria. Appl Microbiol Biotechnol 1994; 40: 735-739. DOI: 10.1007/BF00173337

Hütt P., Shchepetova J., Lõivukene K., Kullisaar T., Mikelsaar M. Antagonistic activity of probiotic lactobacilli and bifidobacteria against entero- and uropathogens. J Appl Microbiol 2006; 100(6): 1324-1332. DOI: 10.1111/j.1365-2672.2006.02857.x

Banerjee P., Merkel G.J., Bhunia A.K. Lactobacillus delbrueckii ssp. bulgaricus B-30892 can inhibit cytotoxic effects and adhesion of pathogenic Clostridium difficile to Caco-2 cells. Gut Pathog 2009; 1(1): 8. DOI: 10.1186/1757-4749-1-8

Pereira D.I., Aslam M.F., Frazer D.M., Schmidt A., Walton G.E., McCartney A.L. et al. Dietary iron depletion at weaning imprints low microbiome diversity and this is not recovered with oral Nano Fe(III). Microbiologyopen 2015; 4(1): 12-27. DOI: 10.1002/mbo3.213

Cuisiniere T., Calvé A., Fragoso G., Oliero M., Hajjar R., Gonzalez E. et al. Oral iron supplementation after antibiotic exposure induces a deleterious recovery of the gut microbiota. BMC Microbiol 2021; 21(1): 259. DOI: 10.1186/s12866-021-02320-0

Dostal A., Lacroix C., Bircher L., Pham V.T., Follador R., Zimmermann M.B. et al. Iron Modulates Butyrate Production by a Child Gut Microbiota In Vitro. mBio 2015; 6(6): e01453-15. DOI: 10.1128/mBio.01453-15

Mahalhal A., Frau A., Burkitt M.D., Ijaz U.Z., Lamb C.A., Mansfield J.C. et al. Oral Ferric Maltol Does Not Adversely Affect the Intestinal Microbiome of Patients or Mice, But Ferrous Sulphate Does. Nutrients 2021; 13(7): 2269. DOI: 10.3390/nu13072269

Constante M., Fragoso G., Lupien-Meilleur J., Calvé A., Santos M.M. Iron Supplements Modulate Colon Microbiota Composition and Potentiate the Protective Effects of Probiotics in Dextran Sodium Sulfate-induced Colitis. Inflamm Bowel Dis 2017; 23(5): 753-766. DOI: 10.1097/MIB.0000000000001089

McMillen S., Thomas S., Liang E., Nonnecke E.B., Slupsky C., Lönnerdal B. Gut Microbiome Alterations following Postnatal Iron Supplementation Depend on Iron Form and Persist into Adulthood. Nutrients 2022; 14(3): 412. DOI: 10.3390/nu14030412

Alexeev E.E., He X., Slupsky C.M., Lönnerdal B. Effects of iron supplementation on growth, gut microbiota, metabolomics and cognitive development of rat pups. PLoS One 2017; 12(6): e0179713. DOI: 10.1371/journal.pone.0179713

Zimmermann M.B., Chassard C., Rohner F., N’goran E.K., Nindjin C., Dostal A. et al. 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(6): 1406-1415. DOI: 10.3945/ajcn.110.004564

Jaeggi T., Kortman G.A., Moretti D., Chassard C., Holding P., Dostal A. et al. Iron fortification adversely affects the gut microbiome, increases pathogen abundance and induces intestinal inflammation in Kenyan infants. Gut 2015; 64(5): 731- 742. DOI: 10.1136/gutjnl-2014-307720

Tang M., Frank D.N., Hendricks A.E., Ir D., Esamai F., Liechty E. et al. Iron in Micronutrient Powder Promotes an Unfavorable Gut Microbiota in Kenyan Infants. Nutrients 2017; 9(7): 776. DOI: 10.3390/nu9070776

Dostal A., Baumgartner J., Riesen N., Chassard C., Smuts C.M., Zimmermann M.B. et al. Effects of iron supplementation on dominant bacterial groups in the gut, faecal SCFA and gut inflammation: a randomised, placebo-controlled intervention trial in South African children. Br J Nutr 2014; 112(4): 547- 556. DOI: 10.1017/S0007114514001160

Owolabi A.J., Senbanjo I.O., Oshikoya K.A., Boekhorst J., Eijlander R.T., Kortman G. et al. Multi-Nutrient Fortified Dairy-Based Drink Reduces Anaemia without Observed Adverse Effects on Gut Microbiota in Anaemic Malnourished Nigerian Toddlers: A Randomised Dose-Response Study. Nutrients 2021; 13(5): 1566. DOI: 10.3390/nu13051566

Krebs N.F., Sherlock L.G., Westcott J., Culbertson D., Hambidge K.M., Feazel L.M. et al. Effects of different complemen tary feeding regimens on iron status and enteric microbiota in breastfed infants. J Pediatr 2013; 163(2): 416-423. DOI: 10.1016/j.jpeds.2013.01.024

Rahman S., Kortman G.A.M., Boekhorst J., Lee P., Khan M.R., Ahmed F. Effect of low-iron micronutrient powder (MNP) on the composition of gut microbiota of Bangladeshi children in a high-iron groundwater setting: a randomized controlled trial. Eur J Nutr 2021; 60(6): 3423-3436. DOI: 10.1007/s00394-021-02523-1

Rahman S., Lee P., Raqib R., Roy A.K., Khan M.R., Ahmed F. Effect of Micronutrient Powder (MNP) with a Low-Dose of Iron on Hemoglobin and Iron Biomarkers, and Its Effect on Morbidities in Rural Bangladeshi Children Drinking Groundwater with a High-Level of Iron: A Randomized Controlled Trial. Nutrients 2019; 11(11): 2756. DOI: 10.3390/nu11112756

Tang M., Frank D.N., Sherlock L., Ir D., Robertson C.E., Krebs N.F. Effect of Vitamin E With Therapeutic Iron Supplementation on Iron Repletion and Gut Microbiome in US Iron Deficient Infants and Toddlers. J Pediatr Gastroenterol Nutr 2016; 63(3): 379-385. DOI: 10.1097/MPG.0000000000001154

Paganini D., Uyoga M.A., Kortman G.A.M., Cercamondi C.I., Moretti D., Barth-Jaeggi T. 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(11): 1956-1967. DOI: 10.1136/gutjnl-2017-314418

Popovic A., Bourdon C., Wang P.W., Guttman D.S., Soofi S., Bhutta Z.A. et al. Micronutrient supplements can promote disruptive protozoan and fungal communities in the developing infant gut. Nat Commun 2021; 12(1): 6729. DOI: 10.1038/s41467-021-27010-3

Qasem W., Azad M.B., Hossain Z., Azad E., Jorgensen S., Castillo San Juan S. et al. Assessment of complementary feeding of Canadian infants: effects on microbiome & oxidative stress, a randomized controlled trial. BMC Pediatr 2017; 17(1): 54. DOI: 10.1186/s12887-017-0805-0

The authors declare that there are no conflicts of interest present.