{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T04:00:46Z","timestamp":1792036846358,"version":"4.4.0"},"reference-count":49,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T00:00:00Z","timestamp":1643241600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31970717"],"award-info":[{"award-number":["31970717"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82170429"],"award-info":[{"award-number":["82170429"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005236","name":"Chinese Universities Scientific Fund","doi-asserted-by":"publisher","award":["2020TC015"],"award-info":[{"award-number":["2020TC015"]}],"id":[{"id":"10.13039\/501100005236","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2021M703520"],"award-info":[{"award-number":["2021M703520"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004826","name":"Beijing Municipal Natural Science Foundation","doi-asserted-by":"publisher","award":["7222111"],"award-info":[{"award-number":["7222111"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Ferrous sulfate is a commonly used iron supplement for the correction of iron-deficiency anemia but with frequent gastrointestinal side effects. Milk-derived iron-binding glycoprotein lactoferrin possesses well gastrointestinal tolerance and fewer side effects caused by the intake of high-dose iron. However, the underlying mechanism of the iron-enhancing effect of lactoferrin remains unclear. In addition, the comparative efficacies between lactoferrin and ferrous sulfate are also remained to be determined. We conducted a systematic review and meta-analysis on published intervention studies to investigate how lactoferrin modulate iron metabolism and evaluate the comparative effects between lactoferrin and ferrous sulfate supplementation on iron absorption, iron storage, erythropoiesis and inflammation. Lactoferrin supplementation had better effects on serum iron (WMD: 41.44 ug\/dL; p &lt; 0.00001), ferritin (WMD: 13.60 ng\/mL; p = 0.003) and hemoglobin concentration (11.80 g\/dL; p &lt; 0.00001), but a reducing effect on fractional iron absorption (WMD: \u22122.08%; p = 0.02) and IL-6 levels (WMD: \u221245.59 pg\/mL; p &lt; 0.00001) compared with ferrous sulfate. In conclusion, this study supports lactoferrin as a superior supplement to ferrous sulfate regarding the improvement in serum iron parameters and hemoglobin levels. Considering the weak influence of lactoferrin on iron absorption, the anti-inflammation effect of lactoferrin may be the potential mechanism to explain its efficacy on iron status and erythropoiesis.<\/jats:p>","DOI":"10.3390\/nu14030543","type":"journal-article","created":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T22:00:56Z","timestamp":1643320856000},"page":"543","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["Comparative Effects between Oral Lactoferrin and Ferrous Sulfate Supplementation on Iron-Deficiency Anemia: A Comprehensive Review and Meta-Analysis of Clinical Trials"],"prefix":"10.3390","volume":"14","author":[{"given":"Xiya","family":"Zhao","sequence":"first","affiliation":[{"name":"Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teng","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8987-0533","authenticated-orcid":false,"given":"Junjie","family":"Luo","sequence":"additional","affiliation":[{"name":"Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7834-8742","authenticated-orcid":false,"given":"Yongting","family":"Luo","sequence":"additional","affiliation":[{"name":"Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0421-0035","authenticated-orcid":false,"given":"Peng","family":"An","sequence":"additional","affiliation":[{"name":"Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"100866","DOI":"10.1016\/j.blre.2021.100866","article-title":"The critical roles of iron during the journey from fetus to adolescent: Developmental aspects of iron homeostasis","volume":"50","author":"Donker","year":"2021","journal-title":"Blood Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1016\/S0140-6736(15)60865-0","article-title":"Iron deficiency anaemia","volume":"387","author":"Lopez","year":"2016","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S6","DOI":"10.1111\/hdi.12542","article-title":"Overview of iron metabolism in health and disease","volume":"21","author":"Dev","year":"2017","journal-title":"Hemodial. Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1038\/s41390-020-0907-5","article-title":"Prevention of iron deficiency anemia in infants and toddlers","volume":"89","author":"Sundararajan","year":"2021","journal-title":"Pediatr. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1182\/blood-2018-05-815944","article-title":"Iron deficiency","volume":"133","author":"Camaschella","year":"2019","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/S0140-6736(20)32594-0","article-title":"Iron deficiency","volume":"397","author":"Pasricha","year":"2021","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1016\/S0140-6736(17)32154-2","article-title":"Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990\u20132016: A systematic analysis for the Global Burden of Disease Study 2016","volume":"390","author":"Vos","year":"2017","journal-title":"Lancet"},{"key":"ref_8","unstructured":"World Health Organization (2020). Global Anaemia Reduction Efforts among Women of Reproductive Age: Impact, Achievement of Targets and the Way forward for Optimizing Efforts."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1182\/blood-2013-06-508325","article-title":"A systematic analysis of global anemia burden from 1990 to 2010","volume":"123","author":"Kassebaum","year":"2014","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e16","DOI":"10.1016\/S2214-109X(13)70001-9","article-title":"Global, regional, and national trends in haemoglobin concentration and prevalence of total and severe anaemia in children and pregnant and non-pregnant women for 1995\u20132011: A systematic analysis of population-representative data","volume":"1","author":"Stevens","year":"2013","journal-title":"Lancet Glob. Health"},{"key":"ref_11","unstructured":"World Health Organization (2015). The Global Prevalence of Anaemia in 2011."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e548","DOI":"10.1016\/S2214-109X(18)30078-0","article-title":"Risk of maternal mortality in women with severe anaemia during pregnancy and post partum: A multilevel analysis","volume":"6","author":"Daru","year":"2018","journal-title":"Lancet Glob. Health"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1053\/j.seminhematol.2015.07.003","article-title":"Iron Deficiency Anemia in Pregnancy","volume":"52","author":"Breymann","year":"2015","journal-title":"Semin Hematol."},{"key":"ref_14","unstructured":"(2019). Global Nutrition Targets 2025: Anaemia Policy Brief."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1016\/S0140-6736(18)32427-9","article-title":"Progress in adolescent health and wellbeing: Tracking 12 headline indicators for 195 countries and territories, 1990\u20132016","volume":"393","author":"Azzopardi","year":"2019","journal-title":"Lancet"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1038\/35001596","article-title":"Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter","volume":"403","author":"Donovan","year":"2000","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"7811","DOI":"10.1074\/jbc.M008923200","article-title":"A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload","volume":"276","author":"Pigeon","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2090","DOI":"10.1126\/science.1104742","article-title":"Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization","volume":"306","author":"Nemeth","year":"2004","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1136\/jcp.2010.079046","article-title":"Disorders of iron metabolism. Part 1: Molecular basis of iron homoeostasis","volume":"64","author":"Remacha","year":"2011","journal-title":"J. Clin. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1073\/pnas.0409808102","article-title":"Regulation of hepcidin transcription by interleukin-1 and interleukin-6","volume":"102","author":"Lee","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3204","DOI":"10.1182\/blood-2006-06-027631","article-title":"Interleukin-6 induces hepcidin expression through STAT3","volume":"108","author":"Wrighting","year":"2006","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.cmet.2019.10.005","article-title":"Microbial Metabolite Signaling Is Required for Systemic Iron Homeostasis","volume":"31","author":"Das","year":"2020","journal-title":"Cell Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3053","DOI":"10.1093\/jn\/nxaa314","article-title":"The Effects of Different Forms of Lactoferrin on Iron Absorption","volume":"150","author":"Griffin","year":"2020","journal-title":"J. Nutr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.nut.2014.07.006","article-title":"Iron metabolism in infants: Influence of bovine lactoferrin from iron-fortified formula","volume":"31","author":"Ke","year":"2015","journal-title":"Nutrition"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1634\/theoncologist.2010-0020","article-title":"Efficacy and Safety of Oral Lactoferrin Supplementation in Combination with rHuEPO-\u03b2 for the Treatment of Anemia in Advanced Cancer Patients Undergoing Chemotherapy: Open-Label, Randomized Controlled Study","volume":"15","author":"Madeddu","year":"2010","journal-title":"Oncologist"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s10534-020-00236-2","article-title":"Influence of oral administration mode on the efficacy of commercial bovine Lactoferrin against iron and inflammatory homeostasis disorders","volume":"33","author":"Rosa","year":"2020","journal-title":"Biometals"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.cbpc.2004.09.012","article-title":"Evolution of duplications in the transferrin family of proteins","volume":"140","author":"Lambert","year":"2005","journal-title":"Comp. Biochem. Physiol. Part B Biochem. Mol. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1139\/bcb-2020-0069","article-title":"New insights into the systemic effects of oral lactoferrin: Transcriptome profiling","volume":"99","author":"Kruzel","year":"2021","journal-title":"Biochem. Cell Biol."},{"key":"ref_29","unstructured":"(2021, September 30). Available online: http:\/\/vassarstats.net\/."},{"key":"ref_30","unstructured":"(2021, October 10). Available online: https:\/\/methods.cochrane.org\/bias\/news\/rob-2-tool\/."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.3109\/14767058.2015.1049149","article-title":"Lactoferrin versus ferrous sulphate for the treatment of iron deficiency anemia during pregnancy: A randomized clinical trial","volume":"29","author":"Rezk","year":"2016","journal-title":"J. Matern.-Fetal Neonatal Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1139\/o06-040","article-title":"Oral administration of lactoferrin increases hemoglobin and total serum iron in pregnant women","volume":"84","author":"Paesano","year":"2006","journal-title":"Biochem. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1007\/s10534-014-9723-x","article-title":"Safety and efficacy of lactoferrin versus ferrous sulphate in curing iron deficiency and iron deficiency anaemia in hereditary thrombophilia pregnant women: An interventional study","volume":"27","author":"Paesano","year":"2014","journal-title":"Biometals"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1177\/039463201002300220","article-title":"Lactoferrin efficacy versus ferrous sulfate in curing iron disorders in pregnant and non-pregnant women","volume":"23","author":"Paesano","year":"2010","journal-title":"Int. J. Immunopathol. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1080\/00016340903117994","article-title":"Efficacy and tolerability of oral bovine lactoferrin compared to ferrous sulfate in pregnant women with iron deficiency anemia: A prospective controlled randomized study","volume":"88","author":"Nappi","year":"2009","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.3389\/fimmu.2018.02123","article-title":"Efficacy of Lactoferrin Oral Administration in the Treatment of Anemia and Anemia of Inflammation in Pregnant and Non-pregnant Women: An Interventional Study","volume":"9","author":"Lepanto","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1093\/ajcn\/83.2.305","article-title":"Absorption of iron from recombinant human lactoferrin in young US women","volume":"83","author":"Bryant","year":"2006","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3200","DOI":"10.1093\/jn\/nxaa226","article-title":"Iron Absorption is Greater from Apo-Lactoferrin and is Similar Between Holo-Lactoferrin and Ferrous Sulfate: Stable Iron Isotope Studies in Kenyan Infants","volume":"150","author":"Mikulic","year":"2020","journal-title":"J. Nutr."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Sienkiewicz, M., Ja\u015bkiewicz, A., Tarasiuk, A., and Fichna, J. (2021). Lactoferrin: An overview of its main functions, immunomodulatory and antimicrobial role, and clinical significance. Crit. Rev. Food Sci. Nutr., 1\u201318.","DOI":"10.1080\/10408398.2021.1895063"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1128\/MCB.23.1.178-185.2003","article-title":"Iron status in mice carrying a targeted disruption of lactoferrin","volume":"23","author":"Ward","year":"2003","journal-title":"Mol. Cell Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4038","DOI":"10.1182\/blood-2006-10-051755","article-title":"Hepcidin antimicrobial peptide transgenic mice exhibit features of the anemia of inflammation","volume":"109","author":"Roy","year":"2007","journal-title":"Blood"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4596","DOI":"10.1073\/pnas.072632499","article-title":"Severe iron deficiency anemia in transgenic mice expressing liver hepcidin","volume":"99","author":"Nicolas","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1111\/j.1365-2141.2011.08800.x","article-title":"Resveratrol ameliorates TNF\u03b1-mediated suppression of erythropoiesis in human CD34+ cells via modulation of NF-\u03baB signalling","volume":"155","author":"Jeong","year":"2011","journal-title":"Br. J. Haematol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Vega-Bautista, A., de la Garza, M., Carrero, J.C., Campos-Rodr\u00edguez, R., God\u00ednez-Victoria, M., and Drago-Serrano, M.E. (2019). The Impact of Lactoferrin on the Growth of Intestinal Inhabitant Bacteria. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20194707"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1136\/gutjnl-2017-314418","article-title":"Prebiotic galacto-oligosaccharides mitigate the adverse effects of iron fortification on the gut microbiome: A randomised controlled study in Kenyan infants","volume":"66","author":"Paganini","year":"2017","journal-title":"Gut"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.3945\/ajcn.116.145060","article-title":"Consumption of galacto-oligosaccharides increases iron absorption from a micronutrient powder containing ferrous fumarate and sodium iron EDTA: A stable-isotope study in Kenyan infants","volume":"106","author":"Paganini","year":"2017","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_47","unstructured":"(2022, January 20). Main Elements of Proposed Model. Available online: https:\/\/www.freepik.com\/."},{"key":"ref_48","unstructured":"(2022, January 20). Main Elements of Proposed Model. Available online: http:\/\/smart.servier.com\/."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1136\/jcp.2010.086991","article-title":"Disorders of iron metabolism. Part II: Iron deficiency and iron overload","volume":"64","author":"Remacha","year":"2011","journal-title":"J. Clin. Pathol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/3\/543\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:08:38Z","timestamp":1760134118000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/3\/543"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,27]]},"references-count":49,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["nu14030543"],"URL":"https:\/\/doi.org\/10.3390\/nu14030543","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,27]]}}}