{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T00:47:52Z","timestamp":1794012472443,"version":"4.8.0"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,10,5]],"date-time":"2024-10-05T00:00:00Z","timestamp":1728086400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,10,5]],"date-time":"2024-10-05T00:00:00Z","timestamp":1728086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000925","name":"Department of Health | National Health and Medical Research Council","doi-asserted-by":"publisher","award":["GNT1158696"],"award-info":[{"award-number":["GNT1158696"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"Department of Health | National Health and Medical Research Council","doi-asserted-by":"publisher","award":["GNT2009047"],"award-info":[{"award-number":["GNT2009047"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Anemia is highly prevalent globally, especially in young children in low-income countries, where it often overlaps with a high burden of diarrheal disease. Distribution of iron interventions (as supplements or iron-containing multiple micronutrient powders, MNPs) is a key anemia reduction strategy. Small studies in Africa indicate iron may reprofile the gut microbiome towards pathogenic species. We seek to evaluate the safety of iron and MNPs based on their effects on diversity, composition, and function of the gut microbiome in children in rural Bangladesh as part of a large placebo-controlled randomized controlled trial of iron or MNPs given for 3 months (ACTRN12617000660381). In 923 infants, we evaluate the microbiome before, immediately following, and nine months after interventions, using 16S rRNA gene sequencing and shotgun metagenomics in a subset. We identify no increase in diarrhea with either treatment. In our primary analysis, neither iron nor MNPs alter gut microbiome diversity or composition. However, when not adjusting for multiple comparisons, compared to placebo, children receiving iron and MNPs exhibit reductions in commensal species (e.g., <jats:italic>Bifidobacterium, Lactobacillus<\/jats:italic>) and increases in potential pathogens, including <jats:italic>Clostridium<\/jats:italic>. These increases are most evident in children with baseline iron repletion and are further supported by trend-based statistical analyses.<\/jats:p>","DOI":"10.1038\/s41467-024-53013-x","type":"journal-article","created":{"date-parts":[[2024,10,5]],"date-time":"2024-10-05T01:01:39Z","timestamp":1728090099000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Effects of iron supplements and iron-containing micronutrient powders on the gut microbiome in Bangladeshi infants: a randomized controlled trial"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2581-1718","authenticated-orcid":false,"given":"Andrew","family":"Baldi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1997-3999","authenticated-orcid":false,"given":"Sabine","family":"Braat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed Imrul","family":"Hasan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9796-9381","authenticated-orcid":false,"given":"Cavan","family":"Bennett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1367-7163","authenticated-orcid":false,"given":"Marilou","family":"Barrios","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1661-1872","authenticated-orcid":false,"given":"Imadh","family":"Abdul Azeez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Wilcox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pradip Kumar","family":"Roy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Saiful Alam","family":"Bhuiyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Ataide","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Clucas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2570-7323","authenticated-orcid":false,"given":"Leila M.","family":"Larson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jena","family":"Hamadani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4029-1645","authenticated-orcid":false,"given":"Michael","family":"Zimmermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8596-0366","authenticated-orcid":false,"given":"Rory","family":"Bowden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Jex","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beverley-Ann","family":"Biggs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5502-0434","authenticated-orcid":false,"given":"Sant-Rayn","family":"Pasricha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,5]]},"reference":[{"key":"53013_CR1","unstructured":"World Health Organization. The global prevalence of anaemia in 2011 (World Health Organization, Geneva, 2015)."},{"key":"53013_CR2","unstructured":"World Health Organization. Global Health Observatory data repository: Anaemia in children estimates by country and WHO region (World Health Organization, Geneva, 2021)."},{"key":"53013_CR3","unstructured":"United Nations Children\u2019s Fund (UNICEF). One is too many: Ending child deaths from pneumonia and diarrhea. (UNICEF, New York, 2016)."},{"key":"53013_CR4","unstructured":"World Health Organization. Daily iron supplementation in children 6\u201323 months of age. e-Library of Evidence for Nutrition Actions (eLENA), Vol. 2016 (World Health Organization, Geneva, 2016)."},{"key":"53013_CR5","unstructured":"WHO Guidelines Approved by the Guidelines Review Committee. Use of multiple micronutrient powders for point-of-use fortification of foods consumed by infants and young children aged 6\u201323 months and children aged 2\u201312 years (World Health Organization, Geneva, 2016)."},{"key":"53013_CR6","first-page":"60437","volume":"6736","author":"S Soofi","year":"2013","unstructured":"Soofi, S. 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 6736, 60437 (2013).","journal-title":"Lancet"},{"key":"53013_CR7","doi-asserted-by":"publisher","first-page":"1202","DOI":"10.1111\/1574-6976.12086","volume":"38","author":"GA Kortman","year":"2014","unstructured":"Kortman, G. A., Raffatellu, M., Swinkels, D. W. & Tjalsma, H. Nutritional iron turned inside out: intestinal stress from a gut microbial perspective. FEMS Microbiol. Rev. 38, 1202\u20131234 (2014).","journal-title":"FEMS Microbiol. Rev."},{"key":"53013_CR8","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1136\/gutjnl-2014-307720","volume":"64","author":"T Jaeggi","year":"2015","unstructured":"Jaeggi, T. et al. Iron fortification adversely affects the gut microbiome, increases pathogen abundance and induces intestinal inflammation in Kenyan infants. Gut 64, 731\u2013742 (2015).","journal-title":"Gut"},{"key":"53013_CR9","doi-asserted-by":"publisher","first-page":"1956","DOI":"10.1136\/gutjnl-2017-314418","volume":"66","author":"D Paganini","year":"2017","unstructured":"Paganini, D. et al. Prebiotic galacto-oligosaccharides mitigate the adverse effects of iron fortification on the gut microbiome: a randomised controlled study in Kenyan infants. Gut 66, 1956\u20131967 (2017).","journal-title":"Gut"},{"key":"53013_CR10","doi-asserted-by":"crossref","unstructured":"Nemeth, E. & Ganz, T. Hepcidin and iron in health and disease. Annu. Rev. Med. 74, 261\u2013277 (2022).","DOI":"10.1146\/annurev-med-043021-032816"},{"key":"53013_CR11","unstructured":"United Nations Children\u2019s Fund (UNICEF). Home Fortification with Multiple Micronutrient Powders for the Prevention of Iron Deficiency Anaemia in Early Childhood. Brief Guidance Note (UNICEF, New York, 2023)."},{"key":"53013_CR12","doi-asserted-by":"publisher","first-page":"982","DOI":"10.1056\/NEJMoa2034187","volume":"385","author":"S-R Pasricha","year":"2021","unstructured":"Pasricha, S.-R. et al. Benefits and risks of iron interventions in infants in rural Bangladesh. N. Engl. J. Med. 385, 982\u2013995 (2021).","journal-title":"N. Engl. J. Med."},{"key":"53013_CR13","doi-asserted-by":"publisher","first-page":"533","DOI":"10.3945\/ajcn.2008.26589","volume":"89","author":"MF Young","year":"2009","unstructured":"Young, M. F. et al. Serum hepcidin is significantly associated with iron absorption from food and supplemental sources in healthy young women. Am. J. Clin. Nutr. 89, 533\u2013538 (2009).","journal-title":"Am. J. Clin. Nutr."},{"key":"53013_CR14","doi-asserted-by":"publisher","first-page":"e1564","DOI":"10.1016\/S2214-109X(19)30393-6","volume":"7","author":"A Bah","year":"2019","unstructured":"Bah, A. et al. Hepcidin-guided screen-and-treat interventions against iron-deficiency anaemia in pregnancy: a randomised controlled trial in The Gambia. Lancet Glob. Health 7, e1564\u2013e1574 (2019).","journal-title":"Lancet Glob. Health"},{"key":"53013_CR15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/19490976.2021.1874855","volume":"13","author":"Y Seyoum","year":"2021","unstructured":"Seyoum, Y., Baye, K. & Humblot, C. Iron homeostasis in host and gut bacteria - a complex interrelationship. Gut Microbes 13, 1\u201319 (2021).","journal-title":"Gut Microbes"},{"key":"53013_CR16","unstructured":"WHO Guidelines Approved by the Guidelines Review Committee. WHO guideline on use of ferritin concentrations to assess iron status in individuals and populations (World Health Organization, Geneva, 2020)."},{"key":"53013_CR17","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1093\/jalm\/jfaa038","volume":"5","author":"P Gutschow","year":"2020","unstructured":"Gutschow, P. et al. Clinical immunoassay for human Hepcidin predicts iron deficiency in first-time blood donors. J. Appl. Lab Med. 5, 943\u2013953 (2020).","journal-title":"J. Appl. Lab Med."},{"key":"53013_CR18","doi-asserted-by":"publisher","first-page":"e1071","DOI":"10.1016\/S2214-109X(20)30240-0","volume":"8","author":"SR Pasricha","year":"2020","unstructured":"Pasricha, S. R. et al. Net benefit and cost-effectiveness of universal iron-containing multiple micronutrient powders for young children in 78 countries: a microsimulation study. Lancet Glob. Health 8, e1071\u2013e1080 (2020).","journal-title":"Lancet Glob. Health"},{"key":"53013_CR19","doi-asserted-by":"publisher","first-page":"1406","DOI":"10.3945\/ajcn.110.004564","volume":"92","author":"MB Zimmermann","year":"2010","unstructured":"Zimmermann, M. B. et al. The effects of iron fortification on the gut microbiota in African children: a randomized controlled trial in Cote d\u2019Ivoire. Am. J. Clin. Nutr. 92, 1406\u20131415 (2010).","journal-title":"Am. J. Clin. Nutr."},{"key":"53013_CR20","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1111\/tmi.12650","volume":"21","author":"YB Cheung","year":"2016","unstructured":"Cheung, Y. B. et al. Gut microbiota in Malawian infants in a nutritional supplementation trial. Trop. Med. Int. Health 21, 283\u2013290 (2016).","journal-title":"Trop. Med. Int. Health"},{"key":"53013_CR21","doi-asserted-by":"publisher","first-page":"776","DOI":"10.3390\/nu9070776","volume":"9","author":"M Tang","year":"2017","unstructured":"Tang, M. et al. Iron in micronutrient powder promotes an unfavorable gut microbiota in Kenyan Infants. Nutrients 9, 776 (2017).","journal-title":"Nutrients"},{"key":"53013_CR22","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1017\/S0007114514001160","volume":"112","author":"A Dostal","year":"2014","unstructured":"Dostal, A. 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. 112, 547\u2013556 (2014).","journal-title":"Br. J. Nutr."},{"key":"53013_CR23","doi-asserted-by":"crossref","unstructured":"Braat, S. et al. The Benefits and Risks of Iron interventions in Children (BRISC) trial: statistical analysis plan. F1000Research 9, 427 (2020).","DOI":"10.12688\/f1000research.23383.1"},{"key":"53013_CR24","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.coi.2014.03.003","volume":"29","author":"MC Abt","year":"2014","unstructured":"Abt, M. C. & Pamer, E. G. Commensal bacteria mediated defenses against pathogens. Curr. Opin. Immunol. 29, 16\u201322 (2014).","journal-title":"Curr. Opin. Immunol."},{"key":"53013_CR25","doi-asserted-by":"publisher","first-page":"e105","DOI":"10.1016\/S2214-109X(22)00449-1","volume":"11","author":"R Wegmuller","year":"2023","unstructured":"Wegmuller, R. et al. Hepcidin-guided screen-and-treat interventions for young children with iron-deficiency anaemia in The Gambia: an individually randomised, three-arm, double-blind, controlled, proof-of-concept, non-inferiority trial. Lancet Glob. Health 11, e105\u2013e116 (2023).","journal-title":"Lancet Glob. Health"},{"key":"53013_CR26","doi-asserted-by":"publisher","first-page":"e2493","DOI":"10.1093\/cid\/ciaa840","volume":"73","author":"M Taniuchi","year":"2020","unstructured":"Taniuchi, M. et al. Etiology of diarrhea requiring hospitalization in Bangladesh by quantitative polymerase chain reaction, 2014\u20132018. Clin. Infect. Dis. 73, e2493\u2013e2499 (2020).","journal-title":"Clin. Infect. Dis."},{"key":"53013_CR27","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-51326-5","volume":"15","author":"A Baldi","year":"2024","unstructured":"Baldi, A. et al. Community use of oral antibiotics transiently reprofiles the intestinal microbiome in young Bangladeshi children. Nat. Commun. 15, 6980 (2024).","journal-title":"Nat. Commun."},{"key":"53013_CR28","unstructured":"World Health Organization. Diarrhoeal disease. (World Health Organization, Geneva, 2010)."},{"key":"53013_CR29","doi-asserted-by":"publisher","first-page":"e018325","DOI":"10.1136\/bmjopen-2017-018325","volume":"7","author":"MI Hasan","year":"2017","unstructured":"Hasan, M. I. et al. Benefits and risks of Iron interventions in children (BRISC): protocol for a three-arm parallel-group randomised controlled field trial in Bangladesh. BMJ Open 7, e018325 (2017).","journal-title":"BMJ Open"},{"key":"53013_CR30","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-22491-7","volume":"8","author":"JS Penington","year":"2018","unstructured":"Penington, J. S. et al. Influence of fecal collection conditions and 16S rRNA gene sequencing at two centers on human gut microbiota analysis. Sci. Rep. 8, 4386 (2018).","journal-title":"Sci. Rep."},{"key":"53013_CR31","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1038\/nmeth.3869","volume":"13","author":"BJ Callahan","year":"2016","unstructured":"Callahan, B. J. et al. DADA2: High-resolution sample inference from Illumina amplicon data. Nat. Methods 13, 581\u2013583 (2016).","journal-title":"Nat. Methods"},{"key":"53013_CR32","doi-asserted-by":"publisher","first-page":"e61217","DOI":"10.1371\/journal.pone.0061217","volume":"8","author":"PJ McMurdie","year":"2013","unstructured":"McMurdie, P. J. & Holmes, S. phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data. PLoS ONE 8, e61217 (2013).","journal-title":"PLoS ONE"},{"key":"53013_CR33","unstructured":"Ssekagiri, A. T., Sloan, W. & Ijaz, U. Z. microbiomeSeq: an R package for analysis of microbial communities in an environmental context. in ISCB Africa ASBCB Conference (Kumasi, Ghana, 2017)."},{"key":"53013_CR34","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","volume":"57","author":"Y Benjamini","year":"1995","unstructured":"Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. Ser. B 57, 289\u2013300 (1995).","journal-title":"J. R. Stat. Soc. Ser. B"},{"key":"53013_CR35","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17041-7","volume":"11","author":"H Lin","year":"2020","unstructured":"Lin, H. & Peddada, S. D. Analysis of compositions of microbiomes with bias correction. Nat. Commun. 11, 3514 (2020).","journal-title":"Nat. Commun."},{"key":"53013_CR36","doi-asserted-by":"publisher","first-page":"e65088","DOI":"10.7554\/eLife.65088","volume":"10","author":"F Beghini","year":"2021","unstructured":"Beghini, F. et al. Integrating taxonomic, functional, and strain-level profiling of diverse microbial communities with bioBakery 3. eLife 10, e65088 (2021).","journal-title":"eLife"},{"key":"53013_CR37","doi-asserted-by":"publisher","first-page":"e1009442","DOI":"10.1371\/journal.pcbi.1009442","volume":"17","author":"H Mallick","year":"2021","unstructured":"Mallick, H. et al. Multivariable association discovery in population-scale meta-omics studies. PLoS Comput. Biol. 17, e1009442 (2021).","journal-title":"PLoS Comput. Biol."},{"key":"53013_CR38","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","volume":"43","author":"ME Ritchie","year":"2015","unstructured":"Ritchie, M. E. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015).","journal-title":"Nucleic Acids Res."},{"key":"53013_CR39","doi-asserted-by":"publisher","first-page":"e133","DOI":"10.1093\/nar\/gks461","volume":"40","author":"D Wu","year":"2012","unstructured":"Wu, D. & Smyth, G. K. Camera: a competitive gene set test accounting for inter-gene correlation. Nucleic Acids Res. 40, e133 (2012).","journal-title":"Nucleic Acids Res."},{"key":"53013_CR40","doi-asserted-by":"publisher","first-page":"D523","DOI":"10.1093\/nar\/gkac1052","volume":"51","author":"UniProt Consortium.","year":"2023","unstructured":"UniProt Consortium. UniProt: the Universal Protein Knowledgebase in 2023. Nucleic Acids Res. 51, D523\u2013d531 (2023).","journal-title":"Nucleic Acids Res."},{"key":"53013_CR41","doi-asserted-by":"publisher","first-page":"D445","DOI":"10.1093\/nar\/gkz862","volume":"48","author":"R Caspi","year":"2020","unstructured":"Caspi, R. et al. The MetaCyc database of metabolic pathways and enzymes - a 2019 update. Nucleic Acids Res. 48, D445\u2013d453 (2020).","journal-title":"Nucleic Acids Res."},{"key":"53013_CR42","doi-asserted-by":"publisher","first-page":"e1000465","DOI":"10.1371\/journal.pcbi.1000465","volume":"5","author":"Y Ye","year":"2009","unstructured":"Ye, Y. & Doak, T. G. A parsimony approach to biological pathway reconstruction\/inference for genomes and metagenomes. PLoS Comput. Biol. 5, e1000465 (2009).","journal-title":"PLoS Comput. Biol."}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-53013-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-53013-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-53013-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,5]],"date-time":"2024-10-05T01:02:28Z","timestamp":1728090148000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-53013-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,5]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["53013"],"URL":"https:\/\/doi.org\/10.1038\/s41467-024-53013-x","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,5]]},"assertion":[{"value":"9 April 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 September 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 October 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"8640"}}