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

Jun 13, 2012Molecular psychiatry

Early life gut microbes influence the brain’s serotonin system in the memory area differently in males and females

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Abstract

Male germ-free animals exhibit a significant elevation in hippocampal serotonin levels compared to conventionally colonized controls.

The absence of a gut microbiota is linked to increased levels of serotonin and its metabolite in the brain.
This elevation in serotonin is specific to males, while other immune and neuroendocrine effects are seen in both sexes.
Increased plasma levels of tryptophan in male germ-free animals suggest a potential pathway for microbiota's influence on brain serotonin activity.
Restoring gut microbiota after weaning does not reverse the neurochemical changes observed in adulthood due to early-life microbiota absence.
While anxiety levels in germ-free animals normalize with gut microbiota restoration, the neurochemical alterations remain unchanged.

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

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