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Dietary magnesium deficiency alters gut microbiota and leads to depressive-like behaviour

Published online by Cambridge University Press:  18 February 2015

Gudrun Winther ,
Betina M Pyndt Jørgensen ,
Betina Elfving ,
Denis Sandris Nielsen ,
Pernille Kihl ,
Sten Lund ,
Dorte Bratbo Sørensen  and
Gregers Wegener
Gudrun Winther*
Affiliation:
Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Skovagervej 2, DK-8240 Risskov, Denmark
Betina M Pyndt Jørgensen
Affiliation:
Section of Experimental Animal Models, Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Thorvaldsensvej 57, DK-1871 Frederiksberg C, Denmark
Betina Elfving
Affiliation:
Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Skovagervej 2, DK-8240 Risskov, Denmark
Denis Sandris Nielsen
Affiliation:
Department of Food Science, Faculty of Science, University of Copenhagen, Denmark
Pernille Kihl
Affiliation:
Section of Experimental Animal Models, Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Thorvaldsensvej 57, DK-1871 Frederiksberg C, Denmark
Sten Lund
Affiliation:
Medical Department MEA (Endocrinology and Diabetes), Aarhus University Hospital, 8000 Aarhus C, Denmark
Dorte Bratbo Sørensen
Affiliation:
Section of Experimental Animal Models, Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Thorvaldsensvej 57, DK-1871 Frederiksberg C, Denmark
Gregers Wegener
Affiliation:
Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Skovagervej 2, DK-8240 Risskov, Denmark Pharmaceutical Centre of Excellence, School of Pharmacy, North West University, Potchefstroom, South Africa
*
Gudrun Winther, Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Skovagervej 2, DK-8240 Risskov, Denmark. Tel: +457 847 1141; E-mail: [email protected]
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Abstract

Objective

Gut microbiota (GM) has previously been associated with alterations in rodent behaviour, and since the GM is affected by the diet, the composition of the diet may be an important factor contributing to behavioural changes. Interestingly, a magnesium restricted diet has been shown to induce anxiety and depressive-like behaviour in humans and rodents, and it could be suggested that magnesium deficiency may mediate the effects through an altered GM.

Methods

The present study therefore fed C57BL/6 mice with a standard diet or a magnesium deficient diet (MgD) for 6 weeks, followed by behavioural testing in the forced swim test (FST) to evaluate depressive-like behaviour. An intraperitoneal glucose tolerance test (GTT) was performed 2 day after the FST to assess metabolic alterations. Neuroinflammatory markers were analysed from hippocampus. GM composition was analysed and correlated to the behaviour and hippocampal markers.

Results

It was found that mice exposed to MgD for 6 weeks were more immobile than control mice in the FST, suggesting an increased depressive-like behaviour. No significant difference was detected in the GTT. GM composition correlated positively with the behaviour of undisturbed C57BL/6 mice, feeding MgD diet altered the microbial composition. The altered GM correlated positively to the hippocampal interleukin-6.

Conclusion

In conclusion, we hypothesise that imbalances of the microbiota–gut–brain axis induced by consuming a MgD diet, contributes to the development of depressive-like behaviour.

Keywords

animal modelsbehaviourdepressiongut microbiotamagnesium deficiency
Type
Original Articles
Information
Acta Neuropsychiatrica , Volume 27 , Issue 3 , June 2015 , pp. 168 - 176
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Copyright
© Scandinavian College of Neuropsychopharmacology 2015 

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References

1.Grubbs, RD, Maguire, ME. Magnesium as a regulatory cation: criteria and evaluation. Magnesium 1987;6:113–127.Google ScholarPubMed
2.Saris, NE, Mervaala, E, Karppanen, H, Khawaja, JA, Lewenstam, A. Magnesium. An update on physiological, clinical and analytical aspects. Clin Chim Acta 2000;294:1–26.CrossRefGoogle ScholarPubMed
3.Wolf, FI, Trapani, V, Cittadini, A. Magnesium and the control of cell proliferation: looking for a needle in a haystack. Magnes Res 2008;21:83–91.Google ScholarPubMed
4.Barbagallo, M, Dominguez, LJ. Magnesium and aging. Curr Pharm Des 2010;16:832–839.CrossRefGoogle ScholarPubMed
5.Ryan, MF. The role of magnesium in clinical biochemistry: an overview. Ann Clin Biochem 1991;28(Pt 1):19–26.CrossRefGoogle ScholarPubMed
6.Koenig, JH, Ikeda, K. Synaptic vesicles have two distinct recycling pathways. J Cell Biol 1996;135:797–808.CrossRefGoogle ScholarPubMed
7.Zarate, CA Jr., Du, J, Quiroz, Jet al. Regulation of cellular plasticity cascades in the pathophysiology and treatment of mood disorders: role of the glutamatergic system. Ann N Y Acad Sci 2003;1003:273–291.CrossRefGoogle ScholarPubMed
8.Murck, H. Magnesium and affective disorders. Nutr Neurosci 2002;5:375–389.CrossRefGoogle ScholarPubMed
9.Rasmussen, HH, Mortensen, PB, Jensen, IW. Depression and magnesium deficiency. Int J Psychiatry Med 1989;19:57–63.CrossRefGoogle ScholarPubMed
10.Levine, J, Stein, D, Rapoport, A, Kurtzman, L. High serum and cerebrospinal fluid Ca/Mg ratio in recently hospitalized acutely depressed patients. Neuropsychobiology 1999;39:63–70.CrossRefGoogle ScholarPubMed
11.Cox, IM, Campbell, MJ, Dowson, D. Red blood cell magnesium and chronic fatigue syndrome. Lancet 1991;337:757–760.CrossRefGoogle ScholarPubMed
12.Barragan-Rodriguez, L, Rodriguez-Moran, M, Guerrero-Romero, F. Efficacy and safety of oral magnesium supplementation in the treatment of depression in the elderly with type 2 diabetes: a randomized, equivalent trial. Magnes Res 2008;21:218–223.Google ScholarPubMed
13.Chaudhary, DP, Sharma, R, Bansal, DD. Implications of magnesium deficiency in type 2 diabetes: a review. Biol Trace Elem Res 2010;134:119–129.CrossRefGoogle ScholarPubMed
14.Celik, N, Andiran., N, Yilmaz, AE. The relationship between serum magnesium levels with childhood obesity and insulin resistance: a review of the literature. J Pediatr Endocrinol Metab 2011;24:675–678.Google ScholarPubMed
15.Garfinkel, D, Garfinkel, L. Magnesium and regulation of carbohydrate metabolism at the molecular level. Magnesium 1988;7:249–261.Google ScholarPubMed
16.Suarez, A, Pulido, N, Casla, A, Casanova, B, Arrieta, FJ, Rovira, A. Impaired tyrosine-kinase activity of muscle insulin receptors from hypomagnesaemic rats. Diabetologia 1995;38:1262–1270.CrossRefGoogle ScholarPubMed
17.Nadler, JL, Buchanan, T, Natarajan, R, Antonipillai, I, Bergman, R, Rude, R. Magnesium deficiency produces insulin resistance and increased thromboxane synthesis. Hypertension 1993;21:1024–1029.CrossRefGoogle ScholarPubMed
18.Paolisso, G, Sgambato, S, Giugliano, Det al. Impaired insulin-induced erythrocyte magnesium accumulation is correlated to impaired insulin-mediated glucose disposal in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1988;31:910–915.CrossRefGoogle ScholarPubMed
19.Weglicki, WB, Phillips, TM, Freedman, AM, Cassidy, MM, Dickens, BF. Magnesium-deficiency elevates circulating levels of inflammatory cytokines and endothelin. Mol Cell Biochem 1992;110:169–173.CrossRefGoogle ScholarPubMed
20.Pachikian, BD, Neyrinck, AM, Deldicque, Let al. Changes in intestinal bifidobacteria levels are associated with the inflammatory response in magnesium-deficient mice. J Nutr 2010;140:509–514.CrossRefGoogle ScholarPubMed
21.Collins, SM, Kassam, Z, Bercik, P. The adoptive transfer of behavioral phenotype via the intestinal microbiota: experimental evidence and clinical implications. Curr Opin Microbiol 2013;16:240–245.CrossRefGoogle ScholarPubMed
22.Bangsgaard Bendtsen, KM, Krych, L, Sorensen, DBet al. Gut microbiota composition is correlated to grid floor induced stress and behavior in the BALB/c mouse. PloS One 2012;7:e46231.CrossRefGoogle ScholarPubMed
23.Cryan, JF, Dinan, TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci 2012;13:701–712.CrossRefGoogle ScholarPubMed
24.Cryan, JF, O’Mahony, SM. The microbiome-gut-brain axis: from bowel to behavior. Neurogastroenterol Motil 2011;23:187–192.CrossRefGoogle ScholarPubMed
25.Johnson, S. The multifaceted and widespread pathology of magnesium deficiency. Med Hypotheses 2001;56:163–170.CrossRefGoogle ScholarPubMed
26.Kantak, KM. Magnesium deficiency alters aggressive behavior and catecholamine function. Behav Neurosci 1988;102:304–311.CrossRefGoogle ScholarPubMed
27.Singewald, N, Sinner, C, Hetzenauer, A, Sartori, SB, Murck, H. Magnesium-deficient diet alters depression- and anxiety-related behavior in mice–influence of desipramine and Hypericum perforatum extract. Neuropharmacology 2004;47:1189–1197.CrossRefGoogle ScholarPubMed
28.Porsolt, RD, Le Pichon, M, Jalfre, M. Depression: a new animal model sensitive to antidepressant treatments. Nature 1977;266:730–732.CrossRefGoogle ScholarPubMed
29.Pyndt, JBHJ, Krych, L, Larsen, Cet al. A possible link between food and mood: dietary impact on gut microbiota and behavior in balb/c mice. PloS One 2014;9:1–15.Google Scholar
30.Elfving, B, Bonefeld, BE, Rosenberg, R, Wegener, G. Differential expression of synaptic vesicle proteins after repeated electroconvulsive seizures in rat frontal cortex and hippocampus. Synapse 2008;62:662–670.CrossRefGoogle ScholarPubMed
31.Andersen, CL, Jensen, JL, Orntoft, TF. Normalization of real-time quantitative reverse transcription-PCR data: a model-based variance estimation approach to identify genes suited for normalization, applied to bladder and colon cancer data sets. Cancer Res 2004;64:5245–5250.CrossRefGoogle Scholar
32.Lundberg, R, Clausen, SK, Pang, Wet al. Gastrointestinal microbiota and local inflammation during oxazolone-induced dermatitis in BALB/cA mice. Comp Med 2012;62:371–380.Google ScholarPubMed
33.Muyzer, G, Smalla, K. Application of denaturing gradient gel electrophoresis (DGGE) and temperature gradient gel electrophoresis (TGGE) in microbial ecology. Antonie Van Leeuwenhoek 1998;73:127–141.CrossRefGoogle Scholar
34.Decollogne, S, Tomas, A, Lecerf, C, Adamowicz, E, Seman, M. NMDA receptor complex blockade by oral administration of magnesium: comparison with MK-801. Pharmacol, Biochem Behav 1997;58:261–268.CrossRefGoogle ScholarPubMed
35.Poleszak, E, Szewczyk, B, K’dzierska, E, Wlaź, P, Pilc, A, Nowak, G. Antidepressant- and anxiolytic-like activity of magnesium in mice. Pharmacol Biochem Behav 2004;78:7–12.CrossRefGoogle ScholarPubMed
36.Eby, GA, Eby, KL. Rapid recovery from major depression using magnesium treatment. Med Hypotheses 2006;67:362–370.CrossRefGoogle ScholarPubMed
37.Crunelli, V, Mayer, ML. Mg2+ dependence of membrane resistance increases evoked by NMDA in hippocampal neurones. Brain Res 1984;311:392–396.CrossRefGoogle ScholarPubMed
38.Ennis, M, Aston-Jones, G, Shiekhattar, R. Activation of locus coeruleus neurons by nucleus paragigantocellularis or noxious sensory stimulation is mediated by intracoerulear excitatory amino acid neurotransmission. Brain Res 1992;598:185–195.CrossRefGoogle ScholarPubMed
39.Shiekhattar, R, Aston-Jones, G. NMDA-receptor-mediated sensory responses of brain noradrenergic neurons are suppressed by in vivo concentrations of extracellular magnesium. Synapse 1992;10:103–109.CrossRefGoogle ScholarPubMed
40.Whittle, N, Li, L, Chen, WQet al. Changes in brain protein expression are linked to magnesium restriction-induced depression-like behavior. Amino Acids 2011;40:1231–1248.CrossRefGoogle ScholarPubMed
41.Tizabi, Y, Bhatti, BH, Manaye, KF, Das, JR, Akinfiresoye, L. Antidepressant-like effects of low ketamine dose is associated with increased hippocampal AMPA/NMDA receptor density ratio in female wistar-kyoto rats. Neuroscience 2012;72–80.CrossRefGoogle ScholarPubMed
42.Sartori, SB, Whittle, N, Hetzenauer, A, Singewald, N. Magnesium deficiency induces anxiety and HPA axis dysregulation: modulation by therapeutic drug treatment. Neuropharmacology 2012;62:304–312.CrossRefGoogle ScholarPubMed
43.Poleszak, E, Szewczyk, B, Kedzierska, E, Wlaz, P, Pilc, A, Nowak, G. Antidepressant- and anxiolytic-like activity of magnesium in mice. Pharmacol, Biochem Behav 2004;78:7–12.CrossRefGoogle ScholarPubMed
44.Boadle-Biber, MC. Activation of tryptophan hydroxylase from central serotonergic neurons by calcium and depolarization. Biochem Pharmacol 1978;27:1069–1079.CrossRefGoogle ScholarPubMed
45.Cao, BJ, Peng, NA. Magnesium valproate attenuates hyperactivity induced by dexamphetamine-chlordiazepoxide mixture in rodents. Eur J Pharmacol 1993;237:177–181.CrossRefGoogle ScholarPubMed
46.Djurhuus, MS, Klitgaard, NA, Beck-Nielsen, H. Magnesium deficiency and development of late diabetic complications. Ugeskr Laeger 1991;153:2108–2110.Google ScholarPubMed
47.Turnbaugh, PJ, Ley, RE, Mahowald, MA, Magrini, V, Mardis, ER, Gordon, JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006;444:1027–1031.CrossRefGoogle ScholarPubMed
48.O’Mahony, SM, Marchesi, JR, Scully, Pet al. Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol Psychiatry 2009;65:263–267.CrossRefGoogle ScholarPubMed
49.Collins, S, Verdu, E, Denou, E, Bercik, P. The role of pathogenic microbes and commensal bacteria in irritable bowel syndrome. Dig Dis 2009;27(Suppl. 1):85–89.CrossRefGoogle ScholarPubMed
50.Desbonnet, L, Garrett, L, Clarke, G, Kiely, B, Cryan, JF, Dinan, TG. Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience 2010;170:1179–1188.CrossRefGoogle ScholarPubMed
51.Cryan, JF, Markou, A, Lucki, I. Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol Sci 2002;23:238–245.CrossRefGoogle ScholarPubMed
52.Petit-Demouliere, B, Chenu, F, Bourin, M. Forced swimming test in mice: a review of antidepressant activity. Psychopharmacol (Berl) 2005;177:245–255.CrossRefGoogle ScholarPubMed
53.Wu, TH, Lin, CH. IL-6 mediated alterations on immobile behavior of rats in the forced swim test via ERK1/2 activation in specific brain regions. Behav Brain Res 2008;193:183–191.CrossRefGoogle ScholarPubMed
54.Baticic, L, Detel, D, Kucic, N, Buljevic, S, Pugel, EP, Varljen, J. Neuroimmunomodulative properties of dipeptidyl peptidase IV/CD26 in a TNBS-induced model of colitis in mice. J Cell Biochem 2011;112:3322–3333.CrossRefGoogle Scholar
55.Kanarik, M, Alttoa, A, Matrov, Det al. Brain responses to chronic social defeat stress: effects on regional oxidative metabolism as a function of a hedonic trait, and gene expression in susceptible and resilient rats. Eur Neuropsychopharmacol 2011;21:92–107.CrossRefGoogle ScholarPubMed
56.Iosifescu, DV, Bolo, NR, Nierenberg, AA, Jensen, JE, Fava, M, Renshaw, PF. Brain bioenergetics and response to triiodothyronine augmentation in major depressive disorder. Biol Psychiatry 2008;63:1127–1134.CrossRefGoogle ScholarPubMed
57.Moles, KW, McMullen, JK. Insulin resistance and hypomagnesaemia: case report. Br Med J (Clin Res Ed) 1982;285(6337):262.CrossRefGoogle ScholarPubMed
58.Kandeel, FR, Balon, E, Scott, S, Nadler, JL. Magnesium deficiency and glucose metabolism in rat adipocytes. Metabolism 1996;45:838–843.CrossRefGoogle ScholarPubMed