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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Disruption in neuronal and microbial organization in prenatal and postnatal periods of mammalian development may lead to the onset of neurodevelopmental and other brain disorders later in life.
“disruption in the neuronal and microbial organization in prenatal and postnatal periods of mammalian development may lead to the onset of neurodevelopmental and other brain disorders later in life (9, 38–40).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [40]
Studies in germ-free animals showed that the brain is affected in the absence of microbiota.
“Firstly, studies in germ-free (GF) animals showed that the brain is affected in the absence of microbiota (see Table 2) (Clarke et al., 2013;Diaz Heijtz et al., 2011;Gareau et al., 2011;Hegstrand and Hine, 1986;Neufeld et al., 2011;Sudo et al., 2004).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Clarke et al., 2013
The increased circulating tryptophan in GF animals was associated with elevated hippocampal 5-HT, which was not corrected by colonization.
“This was associated with elevated hippocampal 5-HT, which was not corrected by colonization.”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Clarke et al., 2013
GF animals exhibit increased circulating tryptophan levels, which are corrected following colonization with a microbiota.
“GF animals exhibit increased circulating tryptophan levels, which are corrected following colonization with a microbiota (Clarke et al., 2013).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Clarke et al., 2013
Strong preclinical evidence indicates that early-life disruption of the microbiota alters a wide range of behavioral and neural outcomes both during development and later in life.
“Such investigations are becoming more widespread based on strong preclinical evidence that early-life disruption of the microbiota alters a wide range of behavioral and neural outcomes both during development and later in life (Clarke et al., 2013;Diaz Heijtz et al., 2011;Leclercq et al., 2017;Minter et al., 2017;O'Mahony et al., 2014;Olszak et al., 2012;Stilling et al., 2015).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Clarke et al., 2013
The amygdala, hippocampus, and PFC are all modulated by changes in the microbiota.
“and these brain regions are all modulated by changes in the microbiota (Bercik et al., 2011a;Clarke et al., 2013;Cowan et al., 2018;Gacias et al., 2016;Hoban et al., 2017;Hoban et al., 2016b;Luczynski et al., 2016b;Neufeld et al., 2011;Ogbonnaya et al., 2015;Stilling et al., 2015).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Clarke et al., 2013
BDNF is expressed at lower than normal levels in the germ-free mouse cortex and hippocampus.
“has been reported to be expressed in lower than normal levels in the GF mouse cortex and hippocampus (Clarke et al., 2013;Diaz Heijtz et al., 2011).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Clarke et al., 2013
Aβ clearance is thought to be enhanced during sleep.
“Aβ clearance is thought to be enhanced during sleep [572], although how SD regulates Aβ and tau metabolism remains unclear [419].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [572]
Expression of NMDAR and BDNF is significantly reduced in GF mice.
“In addition, expression of NMDAR and BDNF is significantly reduced in GF mice [572, 581, 582]”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [572]
Tryptophan and serotonin metabolism is regulated by gut microbes.
“Animal studies have confirmed that tryptophan and serotonin metabolism is regulated by gut microbes”
Germ-free mice displayed reduced anxiety-like behavior in the elevated plus maze and the light-dark test.
“GF mice displayed reduced anxiety-like behavior in the elevated plus maze and the light-dark test [62][63][64][65].”
From The Role of Microbiota-Gut-Brain Axis in Neuropsychiatric and Neurological Disorders (2021) · cites this paper as [63]
The central nervous system neurotransduction can be profoundly disturbed by the absence of a normal gut microbiota and this aberrant neurochemical, but not behavioral, profile is resistant to restoration of a normal gut flora in later life.
“It was concluded that the CNS neurotransduction can be profoundly disturbed by the absence of a normal gut microbiota and that this aberrant neurochemical, but not behavioral, profile is resistant to restoration of a normal gut flora in later life [63].”
From The Role of Microbiota-Gut-Brain Axis in Neuropsychiatric and Neurological Disorders (2021) · cites this paper as [63]
In germ-free mice, hippocampal serotonin concentration was markedly higher than in controls.
“The first of the above-mentioned research teams indicated that in GF mice the hippocampal serotonin concentration was markedly higher than in controls [63]”
From The Role of Microbiota-Gut-Brain Axis in Neuropsychiatric and Neurological Disorders (2021) · cites this paper as [63]
Abnormalities in social behavior in germ-free animals improved after re-colonization with standard gut microbiota.
“Abnormalities in social behavior [222] in GF animals were improved after re-colonization with the standard gut microbiota.”
From The Role of Microbiota-Gut-Brain Axis in Neuropsychiatric and Neurological Disorders (2021) · cites this paper as [222]
Postnatal colonization of germ-free mice with wildtype mouse gut microbiota at weaning corrects some social impairments.
“Moreover, some of the social impairments are corrected by postnatal colonization of germ-free mice with a wildtype mouse gut microbiota at weaning, pointing to the ability to reverse abnormalities in social interactions (26).”
From Emerging Roles for the Gut Microbiome in Autism Spectrum Disorder (2017) · cites this paper as [26]
Low levels or absence of gut microbiota (germ-free animals) increase tryptophan and serotonin levels and modify central higher order behavior.
“There is strong evidence that low levels or an absence of gut microbiota (i.e. GF animals) increase tryptophan and serotonin levels and modify central higher order behavior [106].”
From Exercise-induced stress behavior, gut-microbiota-brain axis and diet: a systematic review for athletes (2016) · cites this paper as [106]
Findings of enhanced stress reactivity in germ-free mice have been reproduced in both male and female mice to novel environmental stressors.
“These findings have subsequently been reproduced, with both male and female mice demonstrating enhanced stress reactivity to a novel environmental stressors (189, 350, 351).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [350]
Several metabolomic studies show alterations in the dopamine and serotonin systems in germ-free animals.
“Several metabolomic studies show alterations in the dopamine and serotonin systems (124, 189, 350, 378–380).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [350]
Several studies have documented sex-specific differences in the serotonergic system of germ-free animals.
“The role of sexual dimorphism must be noted, as several studies have documented sex-specific differences in the serotonergic system of germ-free animals (350).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [350]
These changes include increased hippocampal dopamine D1 receptor mRNA levels, decreased dopamine D1 receptor in the striatum and nucleus accumbens, increased serotonin in the blood and hippocampus, and decreased serotonin receptor expression.
“These changes include increased hippocampal dopamine D1 receptor mRNA levels and decreased dopamine D1 receptor in the striatum and nucleus accumbens, as well as increased serotonin in the blood and hippocampus, with decreased serotonin receptor expression, respectively.”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [350]
Microbial colonization has been shown to rescue elements of cognition in germ-free mice, but only if administered during early stages of life.
“Microbial colonization has been shown to rescue these elements of cognition, but only if administered during early stages of life (124, 350).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [350]
Reduced cognitive function is inversely associated with BDNF mRNA levels.
“Further studies have demonstrated that reduced cognitive function is inversely associated with BDNF mRNA levels (124, 350).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [350]
HPA axis and serotonergic system were altered in mice lacking microbiota.
“Previous studies had demonstrated that the HPA axis and serotonergic system were altered in mice lacking microbiota (Sudo et al., 2004; Clarke et al., 2013; Zheng et al., 2016).”
From Intestinal microbiota modulates adrenomedullary response through Nod1 sensing in chromaffin cells (2021) · cites this paper as Clarke et al., 2013
Early experiments using germ-free or specific pathogen-free mice treated with antibiotics to reduce microbial diversity showed that several neurological problems occur in mice with reduced or lack of proper mature gut microbiota.
“Early experiments using germ-free (GF) or specific pathogen-free (SPF) mice treated with antibiotics, to reduce the microbial diversity within the intestine, showed that several neurological problems occur in mice with reduced or lack of proper mature gut microbiota (7, 10, 14, 15, 34, 80, 81).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [7]
Compared to colonized mice, germ-free mice show exaggerated hypothalamic-pituitary-adrenal stress reaction, impaired social behaviors, reduced anxiety-like behavior, and increased motor and rearing activity.
“In details, compared to colonized mice, GF mice showed exaggerated hypothalamic–pituitary–adrenal (HPA) restrain stress reaction (10), impared social behaviors (12, 15, 82), reduced anxiety-like behavior (7, 81–83) and increased motor and rearing activity (80, 84).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [7]
Male germ-free animals have significantly higher levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the hippocampus and serum compared with conventionally colonized control animals.
“The importance of tryptophan metabolism in maintaining CNS homeostasis was already known a few years earlier, since male GF animals have significantly higher levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the hippocampus and the serum, compared with conventionally colonized control animals (7).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [7]
Colonizing germ-free animals post-weaning was sufficient to restore tryptophan levels in the periphery and reduce anxiety in germ-free animals, but insufficient to reverse CNS neurochemical consequences present in adult germ-free animals.
“Interestingly, colonizing GF animals post-weaning was sufficient to restore the levels of tryptophan in the periphery and to reduce anxiety in GF animals, but was insufficient to reverse the CNS neurochemical consequences present in adult GF animals (7).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [7]
Germ-free mouse models have shown that the serotonergic system in the brain is influenced by the microbiota, whereby excess peripheral tryptophan may cross the blood-brain barrier to influence the rate of serotonin synthesis in the brain.
“GF mouse models have shown that the serotonergic system in the brain is also influenced by the microbiota [24, 26], whereby excess peripheral Trp may cross the BBB to influence the rate serotonin synthesis in the brain [108].”
From The Gut Microbiota and Dysbiosis in Autism Spectrum Disorders (2018) · cites this paper as [26]
Animal studies have shown that early exposure to microbes is essential for neurodevelopment and that some behavioral effects related to a missing or altered microbiota cannot be reversed later in life or can only be reversed during a specific period of time.
“Animal studies have shown that this early exposure to microbes is essential for neurodevelopment and that some behavioral effects related to a missing or altered microbiota cannot be reversed later in life or can only be reversed during a specific period of time (218, 245, 252).”
From Diet and the Microbiota–Gut–Brain Axis: Sowing the Seeds of Good Mental Health (2021) · cites this paper as [252]
Germ-free mice have reduced kynurenine pathway activity that is normalized by colonization with a conventional gut microbiota.
“Germ-free mice had reduced kynurenine pathway activity that was normalized by colonization of a conventional gut microbiota184.”
From The gut microbiota and the brain–gut–kidney axis in hypertension and chronic kidney disease (2018) · cites this paper as [184]
The finding that microbiota colonization normalizes kynurenine pathway activity in germ-free mice indirectly suggests a role of immune activation in regulation of the kynurenine pathway.
“This finding indirectly suggests a role of immune activation in the regulation of the kynure-nine pathway.”
From The gut microbiota and the brain–gut–kidney axis in hypertension and chronic kidney disease (2018) · cites this paper as [184]
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Self-citationThe progress of gut microbiome research related to brain disorders
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Microbiota-Gut-Brain Axis: New Therapeutic Opportunities
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- Authors
- Clarke, G., Grenham, S., Scully, P., Fitzgerald, P., Moloney, R. D., Shanahan, F., Dinan, T. G., & Cryan, J. F.
- Affiliations
- University College Cork (IE)
- Corresponding author
- Clarke, G
- Cryan, J F
- Venue
- Molecular Psychiatry
- Published
- 2012-06-12
- Volume
- 18
- Issue
- 6
- Pages
- 666-673
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- OpenAlex
- W2047798386
- Cited by
- 1,893
- References
- 66
- Citations by year
- 2026: 118 · 2025: 146 · 2024: 187 · 2023: 182 · 2022: 190 · 2021: 218 · 2020: 193 · 2019: 168 · 2018: 127 · 2017: 117 · 2016: 109 · 2015: 71 · 2014: 40 · 2013: 24 · 2012: 2
- FWCI
- 17.60
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- microbiome-gut-brain axis, gut microbiota, germ-free animals, hippocampus, serotonergic system, serotonin, 5-hydroxyindoleacetic acid, tryptophan, sex differences, anxiety, neuroendocrine regulation, postnatal development
- MeSH terms
- Analysis of Variance, Animals, Body Weight, Disease Models, Animal, Female, Gene Expression Regulation, Hippocampus, Hydroxyindoleacetic Acid, Lipopolysaccharides, Male, Receptors, Serotonin, Serotonin, Sex Characteristics, Stress, Psychological, Tryptophan, Tryptophan Hydroxylase, Tumor Necrosis Factor-alpha, Brain-Derived Neurotrophic Factor, Gastrointestinal Tract, Serotonin Plasma Membrane Transport Proteins, Mice, Microbiota
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