Prebiotic feeding elevates central brain derived neurotrophic factor, N-methyl-D-aspartate receptor subunits and D-serine

Helene M Savignac, Giulia Corona, Henrietta Mills, Li Chen, Jeremy P E Spencer, George Tzortzis, Philip W J Burnet, Helene M Savignac, Giulia Corona, Henrietta Mills, Li Chen, Jeremy P E Spencer, George Tzortzis, Philip W J Burnet

Abstract

The influence of the gut microbiota on brain chemistry has been convincingly demonstrated in rodents. In the absence of gut bacteria, the central expression of brain derived neurotropic factor, (BDNF), and N-methyl-d-aspartate receptor (NMDAR) subunits are reduced, whereas, oral probiotics increase brain BDNF, and impart significant anxiolytic effects. We tested whether prebiotic compounds, which increase intrinsic enteric microbiota, also affected brain BDNF and NMDARs. In addition, we examined whether plasma from prebiotic treated rats released BDNF from human SH-SY5Y neuroblastoma cells, to provide an initial indication of mechanism of action. Rats were gavaged with fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS) or water for five weeks, prior to measurements of brain BDNF, NMDAR subunits and amino acids associated with glutamate neurotransmission (glutamate, glutamine, and serine and alanine enantiomers). Prebiotics increased hippocampal BDNF and NR1 subunit expression relative to controls. The intake of GOS also increased hippocampal NR2A subunits, and frontal cortex NR1 and d-serine. Prebiotics did not alter glutamate, glutamine, l-serine, l-alanine or d-alanine concentrations in the brain, though GOSfeeding raised plasma d-alanine. Elevated levels of plasma peptide YY (PYY) after GOS intake was observed. Plasma from GOS rats increased the release of BDNF from SH-SY5Y cells, but not in the presence of PYY antisera. The addition of synthetic PYY to SH-SY5Y cell cultures, also elevated BDNF secretion. We conclude that prebiotic-mediated proliferation of gut microbiota in rats, like probiotics, increases brain BDNF expression, possibly through the involvement of gut hormones. The effect of GOS on components of central NMDAR signalling was greater than FOS, and may reflect the proliferative potency of GOS on microbiota. Our data therefore, provide a sound basis to further investigate the utility of prebiotics in the maintenance of brain health and adjunctive treatment of neuropsychiatric disorders.

Keywords: Amino acids; Bifidobacteria; Dentate gyrus; Glutamate; HPLC; Western blot.

Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Fig. 1
Fig. 1
The effect of an oral administration of water or prebiotic (FOS or GOS) on the levels of (A) BDNF and (B) NR1 subunits in the cortex and hippocampus of the rat. Representative Western blot images of NR1 and β-actin immunoreactivity in protein extracts from water (W), FOS (F) and GOS (G)-fed rats are shown in (B, inset). NR1 levels were expressed as a ratio of β-actin. ∗p < 0.05 (n = 8/group).
Fig. 2
Fig. 2
The effect of an oral administration of water or prebiotic (FOS or GOS) on the levels of (A) NR2A and (B) NR2B subunits in the cortex and hippocampus of the rat. Representative Western blot images of NR subunits and β-actin immunoreactivity in protein extracts from water (W), FOS (F) and GOS (G)-fed rats are shown (inset). NR2 subunit levels were expressed as a ratio of β-actin. ∗p < 0.05 (n = 8/group).
Fig. 3
Fig. 3
Representative autoradiographs of BDNF (A, C and E) and NR1 subunit (B, D and F) mRNA expression in the rat hippocampus following an oral administration of water (A and B), FOS (C and D) or GOS (E and F). Arrows delineate increased expression, and arrow head indicates reduced expression. DG = dentate gyrus, CA1 and CA3 = Cornu Ammons subfields of the hippocampus. Scale bar = 200 μM.
Fig. 4
Fig. 4
Prebiotics (FOS, GOS) differentially alter the abundance of mRNAs encoding BDNF (A), NR1 (B), NR2A (C), but not NR2B (D) subunits. DG = dentate gyrus, CA1 and CA3 = Cornu Ammons subfields of the hippocampus. ∗p < 0.05 (n = 8/group).
Fig. 5
Fig. 5
The effect of prebiotic-fed rat plasmas on BDNF release from SH-SY5Y cells, in the absence or presence of PYY (A) or GLP-1 (B) antisera. ∗p < 0.05, compared to cells exposed to plasma from water-fed rats; #p < 0.001, compared to cells exposed to plasma from water-fed rats containing PYY or GLP-1 antisera; +p < 0.05, compared to cells exposed to plasma from water-fed rats containing PYY or GLP-1 peptide (n = 8 plasmas/group).

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