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The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner

Abstract

Bacterial colonisation of the intestine has a major role in the post-natal development and maturation of the immune and endocrine systems. These processes are key factors underpinning central nervous system (CNS) signalling. Regulation of the microbiome–gut–brain axis is essential for maintaining homeostasis, including that of the CNS. However, there is a paucity of data pertaining to the influence of microbiome on the serotonergic system. Germ-free (GF) animals represent an effective preclinical tool to investigate such phenomena. Here we show that male GF animals have a significant elevation in the hippocampal concentration of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid, its main metabolite, compared with conventionally colonised control animals. Moreover, this alteration is sex specific in contrast with the immunological and neuroendocrine effects which are evident in both sexes. Concentrations of tryptophan, the precursor of serotonin, are increased in the plasma of male GF animals, suggesting a humoral route through which the microbiota can influence CNS serotonergic neurotransmission. Interestingly, colonisation of the GF animals post weaning is insufficient to reverse the CNS neurochemical consequences in adulthood of an absent microbiota in early life despite the peripheral availability of tryptophan being restored to baseline values. In addition, reduced anxiety in GF animals is also normalised following restoration of the intestinal microbiota. These results demonstrate that CNS neurotransmission can be profoundly disturbed by the absence of a normal gut microbiota and that this aberrant neurochemical, but not behavioural, profile is resistant to restoration of a normal gut flora in later life.

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Acknowledgements

The Alimentary Pharmabiotic Centre is a research centre funded by Science Foundation Ireland (SFI), through the Irish Government's National Development Plan. The authors and their work were supported by SFI (grant nos. 02/CE/B124 and 07/CE/B1368) and by GlaxoSmithKline. GC is in receipt of a research grant from the American Neurogastroenterology and Motility Society (ANMS). GC, JFC and TD are also funded by the Irish Health Research Board (HRB) Health Research Awards (grant no HRA_POR/2011/23). We acknowledge the contribution of Ms Frances O’Brien, Dr Monica Tramullas and Mr Kieran Davey to the study.

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Correspondence to G Clarke or J F Cryan.

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Clarke, G., Grenham, S., Scully, P. et al. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry 18, 666–673 (2013). https://doi.org/10.1038/mp.2012.77

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  • DOI: https://doi.org/10.1038/mp.2012.77

Keywords

  • anxiety
  • central nervous system
  • germ-free
  • microbiota
  • recolonisation
  • serotonin

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