Gamma Aminobutyric Acid Increases Absorption of Glycine-Bound Iron in Mice with Iron Deficiency Anemia


Iron deficiency is a leading cause of anemia. Amino acids are known to promote the absorption of both soluble and insoluble iron. The bioavailability of organic iron is higher than that of inorganic iron. Therefore, the aim of this study was to evaluate the iron absorption of glycine-bound iron (an organic iron) and a combination of glycine-bound iron and gamma aminobutyric acid (GABA) in mice with iron deficiency anemia (IDA). Mice were fed an iron-deficient diet for 3 weeks, followed by oral administration of GABA, inorganic iron, glycine-bound iron, or GABA plus glycine-bound iron for 5 weeks. Ferritin storage in the spleen was measure by immunohistochemistry (IHC). Iron deposition in the liver and spleen tissues was analyzed using atomic absorption spectrometry. Expression levels of iron absorption-related genes were measured by quantitative real-time polymerase chain reaction (qPCR). Iron absorption was enhanced in the glycine-bound iron-treated group compared with the inorganic iron-treated group. Hemoglobin, serum Fe, ferritin, and liver iron levels did not increase in mice treated with GABA alone. However, mice administered GABA in combination with glycine-bound iron showed higher iron absorption than those administered organic iron alone. Our results indicate that glycine-bound iron in combination with GABA might exert a synergistic effect on iron absorption and bioavailability, suggesting that the addition of GABA to existing iron supplements might increase their effectiveness for treating IDA.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4


  1. 1.

    Andrews NC (2000) Iron metabolism: iron deficiency and iron overload. Annu Rev Genomics Hum Genet 1:75–98

    CAS  PubMed  Google Scholar 

  2. 2.

    Kassebaum NJ (2016) The global burden of anemia. Hematol Oncol Clin North Am 30:247–308

    PubMed  Google Scholar 

  3. 3.

    Kassebaum NJ, Jasrasaria R, Naghavi M, Wulf SK, Johns N, Lozano R, Regan M, Weatherall D, Chou DP, Eisele TP et al (2014) A systematic analysis of global anemia burden from 1990 to 2010. Blood 123:615–624

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    WHO (2015) The global prevalence of anaemia in 2011. World Health Organization, Geneva

    Google Scholar 

  5. 5.

    Papanikolaou G, Pantopoulos K (2005) Iron metabolism and toxicity. Toxicol Appl Pharmacol 202:199–211

    CAS  PubMed  Google Scholar 

  6. 6.

    Ugwuja E, Akubugwo E, Ibiam U, Onyechi O (2010) Impact of maternal iron deficiency and anaemia on pregnancy and its outcomes in a Nigerian population. Internet J Nutr Wellness 10:1–11

    Google Scholar 

  7. 7.

    Morgan EH, Oates PS (2002) Mechanisms and regulation of intestinal iron absorption. Blood Cells Mol Dis 29:384–399

    CAS  PubMed  Google Scholar 

  8. 8.

    Conrad ME, Umbreit JN (2000) Iron absorption and transport—an update. Am J Hematol 64:287–298

    CAS  PubMed  Google Scholar 

  9. 9.

    Miret S, Simpson RJ, McKie AT (2003) Physiology and molecular biology of dietary iron absorption. Annu Rev Nutr 23:283–301

    CAS  PubMed  Google Scholar 

  10. 10.

    Glahn RP, Van Campen DR (1997) Iron uptake is enhanced in Caco-2 cell monolayers by cysteine and reduced cysteinyl glycine. J Nutr 127:642–647

    CAS  PubMed  Google Scholar 

  11. 11.

    Li Y, Jiang H, Huang G (2017) Protein hydrolysates as promoters of non-Haem Iron absorption. Nutrients 9:609

    CAS  PubMed Central  Google Scholar 

  12. 12.

    Kegley E, Spears J, Flowers W, Schoenherr W (2002) Iron methionine as a source of iron for the neonatal pig1. Nutr Res 22:1209–1217

    CAS  Google Scholar 

  13. 13.

    Roussel G, Stevens V, Cottin S, McArdle HJ (2017) The effect of amino acid deprivation on the transfer of iron through Caco-2 cell monolayers. J Trace Elem Med Biol 40:82–90

    CAS  PubMed  Google Scholar 

  14. 14.

    Ettle T, Schlegel P, Roth F (2008) Investigations on iron bioavailability of different sources and supply levels in piglets. J Anim Physiol Anim Nutr 92:35–43

    CAS  Google Scholar 

  15. 15.

    Jakobs C, Jaeken J, Gibson K (1993) Inherited disorders of GABA metabolism. J Inherit Metab Dis 16:704–715

    CAS  PubMed  Google Scholar 

  16. 16.

    Park KB, Oh SH (2007) Cloning, sequencing and expression of a novel glutamate decarboxylase gene from a newly isolated lactic acid bacterium, Lactobacillus brevis OPK-3. Bioresour Technol 98:312–319

    CAS  PubMed  Google Scholar 

  17. 17.

    Komatsuzaki N, Shima J, Kawamoto S, Momose H, Kimura T (2005) Production of γ-aminobutyric acid (GABA) by Lactobacillus paracasei isolated from traditional fermented foods. Food Microbiol 22:497–504

    CAS  Google Scholar 

  18. 18.

    Wong T, Guin C, Bottiglieri T, Snead OC (2003) Gaba, γ-hydroxybutyric acid, and neurological disease. Ann Neurol 54:3–12

    Google Scholar 

  19. 19.

    Trenkwalder C, Winkelmann J, Inoue Y, Paulus W (2015) Restless legs syndrome-current therapies and management of augmentation. Nat Rev Neurol 11:434–445

    PubMed  Google Scholar 

  20. 20.

    Lyu S, DeAndrade MP, Mueller S, Oksche A, Walters AS, Li Y (2019) Hyperactivity, dopaminergic abnormalities, iron deficiency and anemia in an in vivo opioid receptors knockout mouse: implications for the restless legs syndrome. Behav Brain Res 374:112123

    CAS  PubMed  Google Scholar 

  21. 21.

    Moreno-Fernandez J, Lopez-Aliaga I, Garcia-Burgos M, Alferez MJM, Diaz-Castro J (2019) Fermented goat milk consumption enhances brain molecular functions during Iron deficiency anemia recovery. Nutrients 11:E2394

    PubMed  Google Scholar 

  22. 22.

    Beard J (2003) Iron deficiency alters brain development and functioning. J Nutr 133:1468S–1472S

    CAS  PubMed  Google Scholar 

  23. 23.

    Barrett E, Ross R, O'toole P, Fitzgerald G, Stanton C (2012) γ-Aminobutyric acid production by culturable bacteria from the human intestine. J Appl Microbiol 113:411–417

    CAS  PubMed  Google Scholar 

  24. 24.

    Kinnersley AM, Turano FJ (2000) Gamma aminobutyric acid (GABA) and plant responses to stress. Crit Rev Plant Sci 19:479–509

    CAS  Google Scholar 

  25. 25.

    Janik R, Thomason LAM, Stanisz AM, Forsythe P, Bienenstock J, Stanisz GJ (2016) Magnetic resonance spectroscopy reveals oral Lactobacillus promotion of increases in brain GABA, N-acetyl aspartate and glutamate. Neuroimage 125:988–995

    CAS  PubMed  Google Scholar 

  26. 26.

    Wu Q, Shah NP (2017) High γ-aminobutyric acid production from lactic acid bacteria: emphasis on Lactobacillus brevis as a functional dairy starter. Crit Rev Food Sci Nutr 57:3661–3672

    CAS  PubMed  Google Scholar 

  27. 27.

    Kim YM, Lee KH, Kim DY, Kang BS, Yoon JS, Lee YB, Jeong JH, Nam SY, Yun YW, Kim JS (2012) Effect of iron-nanoparticles and ironmicroparticles on erythropoiesis and iron-storage in iron-deficiency anemic mice. J Biomed Res 13:119–132

    CAS  Google Scholar 

  28. 28.

    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 25:402–408

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Shi Z, Hu X, Yuan B, Pan X, Meyer HE, Holmboe-Ottesen G (2006) Association between serum ferritin, hemoglobin, iron intake, and diabetes in adults in Jiangsu, China. Diabetes Care 29:1878–1883

    CAS  PubMed  Google Scholar 

  30. 30.

    Chen MH, Su TP, Chen YS, Hsu JW, Huang KL, Chang WH, Chen TJ, Bai YM (2013) Association between psychiatric disorders and iron deficiency anemia among children and adolescents: a nationwide population-based study. BMC Psychiatry 13:161

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Thirupathi A, Chang YZ (2019) Brain iron metabolism and CNS diseases. Adv Exp Med Biol 1173:1–19

    CAS  PubMed  Google Scholar 

  32. 32.

    Sipe JC, Lee P, Beutler E (2002) Brain iron metabolism and neurodegenerative disorders. Dev Neurosci 24:188–196

    CAS  PubMed  Google Scholar 

  33. 33.

    Shukla A, Agarwal KN, Shukla GS (1989) Latent iron deficiency alters gamma-aminobutyric acid and glutamate metabolism in rat brain. Experientia 45:343–345

    CAS  PubMed  Google Scholar 

  34. 34.

    Hill JM (1985) Iron concentration reduced in ventral pallidum, globus pallidus, and substantia nigra by GABA-transaminase inhibitor, gamma-vinyl GABA. Brain Res 342:18–25

    CAS  PubMed  Google Scholar 

  35. 35.

    Finch CA, Hegsted M, Kinney TD, Thomas E, Rath CE, Haskins D, Finch S, Fluharty RG (1950) Iron metabolism: the pathophysiology of iron storage. Blood 5:983–1008

    CAS  PubMed  Google Scholar 

  36. 36.

    Cook JD (2005) Diagnosis and management of iron-deficiency anaemia. Best Pract Res Clin Haematol 18:319–332

    CAS  PubMed  Google Scholar 

  37. 37.

    Conrad ME, Crosby WH, Merrill B (1963) Intestinal mucosal mechanisms controlling iron absorption. Blood 22:406–415

    CAS  PubMed  Google Scholar 

  38. 38.

    Haq SM (2009) Anemia analyzer: algorithm and reflex testing in clinical practice leading to efficiency and cost savings. Stud Health Technol Inform 143:14–16

    PubMed  Google Scholar 

  39. 39.

    Sinha N, Mishra T, Singh T, Gupta N (2012) Effect of iron deficiency anemia on hemoglobin A1c levels. Ann Lab Med 32:17–22

    CAS  PubMed  Google Scholar 

  40. 40.

    Evans TC, Jehle D (1991) The red blood cell distribution width. J Emerg Med 9:71–74

    PubMed  Google Scholar 

  41. 41.

    Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gollan JL, Hediger MA (1997) Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388:482–488

    CAS  PubMed  Google Scholar 

  42. 42.

    Lane DJ, Merlot AM, Huang ML, Bae DH, Jansson PJ, Sahni S, Kalinowski DS, Richardson DR (2015) Cellular iron uptake, trafficking and metabolism: key molecules and mechanisms and their roles in disease. Biochim Biophys Acta 1853:1130–1144

    CAS  PubMed  Google Scholar 

Download references


This work was fully financially supported by the Ministry of Agriculture, Food, and Rural Affairs (MAFRA) through the Agri-Bio Industry Technology Development Project, funded by the Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, and Forestry (IPET) (116084).

Author information



Corresponding author

Correspondence to Young-Hee Lim.

Ethics declarations

Conflict of Interests

The authors declare that they have no conflict of interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Park, KT., Sim, I., Ko, HS. et al. Gamma Aminobutyric Acid Increases Absorption of Glycine-Bound Iron in Mice with Iron Deficiency Anemia. Biol Trace Elem Res 197, 628–638 (2020).

Download citation


  • GABA
  • Organic iron
  • Inorganic iron
  • Iron deficiency anemia
  • Iron absorption