{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T02:54:18Z","timestamp":1781578458196,"version":"3.54.5"},"reference-count":44,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2020,8,20]],"date-time":"2020-08-20T00:00:00Z","timestamp":1597881600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>Iron is an essential micronutrient for the brain development of the fetus. Altered intestinal microbiota might affect behavior and cognition through the so-called microbiota-gut-brain axis. We used a Sprague-Dawley rat model of a maternal low-iron diet to explore the changes in cognition, dorsal hippocampal brain-derived neurotrophic factor (BDNF) and related pathways, gut microbiota, and related metabolites in adult male offspring. We established maternal iron-deficient rats by feeding them a low-iron diet (2.9 mg\/kg), while the control rats were fed a standard diet (52.3 mg\/kg). We used a Morris water maze test to assess spatial learning and long-term memory. Western blot (WB) assays and a quantitative reverse-transcription polymerase chain reaction (qRT-PCR) were used to detect the BDNF concentration and related signaling pathways. We collected fecal samples for microbiota profiling and measured the concentrations of plasma short-chain fatty acids. The adult male offspring of maternal rats fed low-iron diets before pregnancy, during pregnancy and throughout the lactation period had (1) spatial deficits, (2) a decreased BDNF mRNA expression and protein concentrations, accompanied by a decreased TrkB protein abundance, (3) a decreased plasma acetate concentration, and (4) an enrichment of the Bacteroidaceae genus Bacteroides and Lachnospiraceae genus Marvinbryantia. Maternal iron deficiency leads to an offspring spatial deficit and is associated with alternations in gastrointestinal microbiota and metabolites.<\/jats:p>","DOI":"10.3390\/ijerph17176070","type":"journal-article","created":{"date-parts":[[2020,8,20]],"date-time":"2020-08-20T09:35:31Z","timestamp":1597916131000},"page":"6070","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Maternal Iron Deficiency Programs Offspring Cognition and Its Relationship with Gastrointestinal Microbiota and Metabolites"],"prefix":"10.3390","volume":"17","author":[{"given":"Hsin-Yi","family":"Hsieh","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Chieh","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei-Hsin","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Ren","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung-Hao","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Chiayi Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Chiayi 613, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7059-6407","authenticated-orcid":false,"given":"You-Lin","family":"Tain","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7403-288X","authenticated-orcid":false,"given":"Li-Tung","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiunn-Ming","family":"Sheen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan"},{"name":"Department of Pediatrics, Chiayi Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Chiayi 613, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/S0140-6736(07)61235-5","article-title":"Nutritional iron deficiency","volume":"370","author":"Zimmermann","year":"2007","journal-title":"Lancet"},{"key":"ref_2","unstructured":"World Health Organization (2020). WHO Guideline on Use of Ferritin Concentrations to Assess Iron Status in Individuals and Populations, WHO. Licence: CC BY-NC-SA 3."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Arulkumaran, S., Regan, L., Papageorghiou, A., and Monga, A. (2011). Oxford Desk Reference: Obstetrics and Gynaecology, OUP.","DOI":"10.1093\/med\/9780199552214.001.0001"},{"key":"ref_4","unstructured":"(2020, July 01). Recommendations to prevent and control iron deficiency in the United States. Centers for Disease Control and Prevention. MMWR. Recomm. Rep. 1998, 47, Available online: http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/9563847."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1554S","DOI":"10.1093\/jn\/133.5.1554S","article-title":"Iron and copper interactions in development and the effect on pregnancy outcome","volume":"133","author":"Gambling","year":"2003","journal-title":"J. Nutr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1067\/mpd.2002.120688","article-title":"Cord serum ferritin concentrations and mental and psychomotor development of children at five years of age","volume":"140","author":"Tamura","year":"2002","journal-title":"J. Pediatr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1179\/1476830511Y.0000000001","article-title":"Fetal and neonatal iron deficiency causes volume loss and alters the neurochemical profile of the adult rat hippocampus","volume":"14","author":"Rao","year":"2011","journal-title":"Nutr. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2040","DOI":"10.3945\/jn.112.162198","article-title":"Behavior and Monoamine Deficits in Prenatal and Perinatal Iron Deficiency Are Not Corrected by Early Postnatal Moderate-Iron or High-Iron Diets in Rats12","volume":"142","author":"Unger","year":"2012","journal-title":"J. Nutr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/S0006-8993(99)01592-9","article-title":"Deprivation of endogenous brain-derived neurotrophic factor results in impairment of spatial learning and memory in adult rats","volume":"835","author":"Mu","year":"1999","journal-title":"Brain Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2495","DOI":"10.3945\/jn.108.091553","article-title":"Early-Life Iron Deficiency Anemia Alters Neurotrophic Factor Expression and Hippocampal Neuron Differentiation in Male Rats1\u20133","volume":"138","author":"Tran","year":"2008","journal-title":"J. Nutr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/s41372-017-0023-5","article-title":"Effect of maternal iron deficiency anemia on fetal neural development","volume":"38","author":"Basu","year":"2017","journal-title":"J. Perinatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.neuron.2006.11.025","article-title":"Persistence of Long-Term Memory Storage Requires a Late Protein Synthesis- and BDNF- Dependent Phase in the Hippocampus","volume":"53","author":"Bekinschtein","year":"2007","journal-title":"Neuron"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"252","DOI":"10.26502\/jppd.2572-519X0025","article-title":"The role of brain-derived neurotrophic factor in the pathophysiology of psychiatric and neurological disorders","volume":"1","author":"Anneken","year":"2017","journal-title":"J. Psychiatry Psychiatr. Disord."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/nrn3346","article-title":"Mind-altering microorganisms: The impact of the gut microbiota on brain and behaviour","volume":"13","author":"Cryan","year":"2012","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"271","DOI":"10.3945\/jn.111.148643","article-title":"Iron Depletion and Repletion with Ferrous Sulfate or Electrolytic Iron Modifies the Composition and Metabolic Activity of the Gut Microbiota in Rats","volume":"142","author":"Dostal","year":"2011","journal-title":"J. Nutr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"46573","DOI":"10.1038\/srep46573","article-title":"Modest and Severe Maternal Iron Deficiency in Pregnancy are Associated with Fetal Anaemia and Organ-Specific Hypoxia in Rats","volume":"7","author":"Woodman","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.neuint.2011.01.002","article-title":"Prenatal stress in rat causes long-term spatial memory deficit and hippocampus MRI abnormality: Differential effects of postweaning enriched environment","volume":"58","author":"Lui","year":"2011","journal-title":"Neurochem. Int."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Sheen, J.-M., Chen, Y.-C., Hsu, M.-H., Tain, Y.-L., Yu, H.-R., and Huang, L.-T. (2016). Combined Intraperitoneal and Intrathecal Etanercept Reduce Increased Brain Tumor Necrosis Factor-Alpha and Asymmetric Dimethylarginine Levels and Rescues Spatial Deficits in Young Rats after Bile Duct Ligation. Front. Cell. Neurosci., 10.","DOI":"10.3389\/fncel.2016.00167"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.ijdevneu.2019.09.003","article-title":"Young rats with increased circulatory asymmetric dimethylarginine exhibited spatial deficit and alterations in dorsal hippocampus brain-derived neurotrophic factor and asymmetric dimethylarginine: Effects of melatonin","volume":"78","author":"Sheen","year":"2019","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1146\/annurev.nutr.23.020102.075739","article-title":"Iron status and neural functioning","volume":"23","author":"Beard","year":"2003","journal-title":"Annu. Rev. Nutr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.spen.2006.08.004","article-title":"Iron Deficiency and Brain Development","volume":"13","author":"Lozoff","year":"2006","journal-title":"Semin. Pediatr. Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1037\/0735-7044.121.3.475","article-title":"Dissociating the long-term effects of fetal\/neonatal iron deficiency on three types of learning in the rat","volume":"121","author":"Schmidt","year":"2007","journal-title":"Behav. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e755","DOI":"10.1542\/peds.2011-3513","article-title":"Effect of iron deficiency anemia in pregnancy on child mental development in rural China","volume":"131","author":"Chang","year":"2013","journal-title":"Pediatrics"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1093\/jn\/126.3.693","article-title":"Brain iron and behavior of rats are not normalized by treatment of iron deficiency anemia during early development","volume":"126","author":"Felt","year":"1996","journal-title":"J. Nutr."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Mihaila, C., Schramm, J.C., Strathmann, F.G., Lee, D.L., Gelein, R.M., Luebke, A.E., and Mayer-Proschel, M. (2011). Identifying a window of vulnerability during fetal development in a maternal iron restriction model. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0017483"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.yhbeh.2013.04.005","article-title":"Spatial memory deficits in maternal iron deficiency paradigms are associated with altered glucocorticoid levels","volume":"64","author":"Ranade","year":"2013","journal-title":"Horm. Behav."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.1073\/pnas.0711863105","article-title":"BDNF is essential to promote persistence of long-term memory storage","volume":"105","author":"Bekinschtein","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1203\/01.PDR.0000061588.39652.26","article-title":"Changes in neurotrophin levels in umbilical cord blood from infants with different gestational ages and clinical conditions","volume":"53","author":"Chouthai","year":"2003","journal-title":"Pediatr. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/0006-8993(95)01321-0","article-title":"Presence of brain-derived neurotrophic factor in brain and human and rat but not mouse serum detected by a sensitive and specific immunoassay","volume":"709","author":"Radka","year":"1996","journal-title":"Brain Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Cunha, C., Brambilla, R., and Thomas, K.L. (2010). A simple role for BDNF in learning and memory?. Front. Mol. Neurosci., 3.","DOI":"10.3389\/neuro.02.001.2010"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1179\/1476830513Y.0000000084","article-title":"Molecular mechanisms of cognitive impairment in iron deficiency: Alterations in brain-derived neurotrophic factor and Insulin-like growth factor expression and function in the central nervous system","volume":"17","author":"Estrada","year":"2013","journal-title":"Nutr. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Novotn\u00fd, M., Klimova, B., and Valis, M. (2019). Microbiome and cognitive impairment: Can any diets influence learning processes in a positive way?. Front. Aging Neurosci., 11.","DOI":"10.3389\/fnagi.2019.00170"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.bbi.2016.02.020","article-title":"Cognitive impairment by antibiotic-induced gut dysbiosis: Analysis of gut microbiota-brain communication","volume":"56","author":"Farzi","year":"2016","journal-title":"Brain Behav. Immun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"S120","DOI":"10.1097\/MCG.0b013e31822fecfe","article-title":"Fermentation in the human large intestine","volume":"45","author":"Macfarlane","year":"2011","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"124","DOI":"10.4103\/bc.bc_34_19","article-title":"Microbiota and memory: A symbiotic therapy to counter cognitive decline?","volume":"5","author":"Ibarra","year":"2019","journal-title":"Brain Circ."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"13510","DOI":"10.1038\/s41598-017-13368-2","article-title":"Therapeutic potential of Bifidobacterium breve strain A1 for preventing cognitive impairment in Alzheimer\u2019s disease","volume":"7","author":"Kobayashi","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1016\/j.cell.2013.11.024","article-title":"Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders","volume":"155","author":"Hsiao","year":"2013","journal-title":"Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1113\/JP273106","article-title":"Gut instincts: Microbiota as a key regulator of brain development, ageing and neurodegeneration","volume":"595","author":"Dinan","year":"2016","journal-title":"J. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1111\/imr.12563","article-title":"The intestinal microbiota: Antibiotics, colonization resistance, and enteric pathogens","volume":"279","author":"Kim","year":"2017","journal-title":"Immunol. Rev."},{"key":"ref_40","first-page":"2095.1","article-title":"Administration of ferrous sulfate drops has significant effects on the gut microbiota of iron-sufficient infants: A randomised controlled study","volume":"68","author":"Lagerqvist","year":"2018","journal-title":"Gut"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1556\/030.65.2018.045","article-title":"Iron deficiency anemia-related gut microbiota dysbiosis in infants and young children: A pilot study","volume":"65","author":"Muleviciene","year":"2018","journal-title":"Acta Microbiol. Et Immunol. Hung."},{"key":"ref_42","first-page":"1","article-title":"The relationship between the gut microbiome and mild cognitive impairment in patients without dementia: A cross-sectional study conducted in Japan","volume":"9","author":"Saji","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Treangen, T.J., Wagner, J., Burns, M.P., and Villapol, S. (2018). Traumatic brain injury in mice induces acute bacterial dysbiosis within the fecal microbiome. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.02757"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s11940-002-0004-6","article-title":"Cognitive impairment following traumatic brain injury","volume":"4","author":"Arciniegas","year":"2002","journal-title":"Curr. Treat. Options Neurol."}],"container-title":["International Journal of Environmental Research and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-4601\/17\/17\/6070\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:04:09Z","timestamp":1760177049000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-4601\/17\/17\/6070"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,20]]},"references-count":44,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["ijerph17176070"],"URL":"https:\/\/doi.org\/10.3390\/ijerph17176070","relation":{},"ISSN":["1660-4601"],"issn-type":[{"value":"1660-4601","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,20]]}}}