Reduced anxiety-like behavior and central neurochemical change in germ-free mice: Behavior in germ-free mice
Abstract
BACKGROUND: There is increasing interest in the gut-brain axis and the role intestinal microbiota may play in communication between these two systems. Acquisition of intestinal microbiota in the immediate postnatal period has a defining impact on the development and function of the gastrointestinal, immune, neuroendocrine and metabolic systems. For example, the presence of gut microbiota regulates the set point for hypothalamic-pituitary-adrenal (HPA) axis activity. METHODS: We investigated basal behavior of adult germ-free (GF), Swiss Webster female mice in the elevated plus maze (EPM) and compared this to conventionally reared specific pathogen free (SPF) mice. Additionally, we measured brain mRNA expression of genes implicated in anxiety and stress-reactivity. KEY RESULTS: Germ-free mice, compared to SPF mice, exhibited basal behavior in the EPM that can be interpreted as anxiolytic. Altered GF behavior was accompanied by a decrease in the N-methyl-D-aspartate receptor subunit NR2B mRNA expression in the central amygdala, increased brain-derived neurotrophic factor expression and decreased serotonin receptor 1A (5HT1A) expression in the dentate granule layer of the hippocampus. CONCLUSIONS & INFERENCES: We conclude that the presence or absence of conventional intestinal microbiota influences the development of behavior, and is accompanied by neurochemical changes in the brain.
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Some studies involving GF Swiss Webster mice show decreased anxiety-like behavior whereas the opposite has been found in male GF BALB/c mice.
“For example, some studies involving GF Swiss Webster mice show a decreased anxiety-like behavior (Arentsen et al., 2018;Clarke et al., 2013;Neufeld et al., 2011) whereas the opposite has been found in male GF BALB/c mice (Chen et al., 2017b;Nishino et al., 2013).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Neufeld et al., 2011
Due to the lack of commensal microbes, GF animals have impaired immune systems, dysregulated hormone signaling, altered metabolism, and differences in neurotransmission from conventional counterparts.
“Due to the lack of commensal microbes, GF animals have impaired immune systems, dysregulated hormone signaling, altered metabolism, and differences in neurotransmission from conventional counterparts (Kawase et al., 2017;Neufeld et al., 2011;Pan et al., 2018;Sudo et al., 2004;Weger et al., 2019).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Neufeld et al., 2011
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 [581]
Alterations in the GI microbiota can lead to long-term increased anxiety in mice.
“Preliminary studies have demonstrated that alterations in the GI microbiota can lead to long-term increased anxiety (69, 115, 116) and altered exploratory behavior in mice (18, 19).”
From Intestinal microbiota and immune function in the pathogenesis of irritable bowel syndrome (2013) · cites this paper as [116]
Microbial abundance alters expression of neurotransmitter receptors in the brain.
“microbial abundance has been shown to alter the expression of neurotransmitter receptors in the brain (51, 189, 191).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [189]
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 [189]
Germ-free animals show widespread neurodevelopmental changes associated with alterations in monoaminergic neurotransmission in the central nervous system.
“Indeed, germ-free animals show widespread neurodevelopmental changes, associated with alterations in monoaminergic neurotransmission in the CNS (189).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [189]
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 [189]
Behavioral differences in germ-free mice include an anxiolytic-like manner when compared to SPF controls, although some studies report increased anxiety-like behavior in different species.
“Behavioral differences in germ-free mice include their anxiolytic-like manner when compared to SPF controls, although some studies report increased anxiety-like behavior in different species (124, 189, 351, 376).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [189]
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 [189]
These cognitive deficits in rodents can be corrected through colonization of the intestine via a fecal transplant from the control group, but only if it occurs early in life.
“Interestingly, these cognitive deficits in rodents can be corrected through the colonization of the intestine via a fecal transplant from the control group, but only if it occurs early in life.”
From The relation between cesarean birth and child cognitive development (2017) · cites this paper as [30]
Rodents lacking all gut bacteria from birth have memory deficits and behavioral abnormalities compared to animals with normal gut microbiota.
“These studies show that rodents lacking all gut bacteria from birth (germ-free animals) have memory deficits28 and behavioral abnormalities29, 30 when compared to animals with normal gut microbiota.”
From The relation between cesarean birth and child cognitive development (2017) · cites this paper as [30]
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 [81]
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 [81]
Developmental abnormalities found in germ-free mice are totally reversible by colonization with intestinal bacteria early in life but not in adulthood, suggesting that the microbiome influences brain development.
“The developmental abnormalities found in GF mice are totally reversible by colonization with intestinal bacteria early in life but not in adulthood, suggesting that the microbiome influences brain development.9,10”
From The Gut Microbiome and the Brain (2014) · cites this paper as [9]
Some investigations have shown neurochemical changes as a result of gut microbiome dysfunction, such as altered BDNF levels, reduced serotonin receptor expression, reduced synaptic plasticity gene expression, and increased striatal monoamine turnover.
“Some investigations have shown neurochemical changes as a result of gut microbiome dysfunction, such as altered levels of brain-derived neurotropic factor (BDNF), reduced serotonin receptor expression, reduced synaptic plasticity gene expression, and increased striatal monoamine turnover [10–12].”
From Effect of fecal microbiota transplant on symptoms of psychiatric disorders: a systematic review (2020) · cites this paper as [12]
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 [24]
Gut microbes not only regulate gene expression in the mouse brain, but also affect alternative splicing, and can regulate the production of specific isoforms of genes that have been implicated in ASD.
“These findings suggest that gut microbes not only regulate gene expression in the mouse brain (Hoban et al., 2016; Neufeld et al., 2011; Stilling et al., 2015), but also affect alternative splicing (Stilling et al., 2018), and can regulate the production of specific isoforms of genes that have been implicated in ASD.”
From Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice (2019) · cites this paper as Neufeld et al., 2011
Studies using germ-free animals that demonstrated aberrant behavior and neurochemical profile were critical in establishing the link between the gut microbiota and brain development and processes.
“In particular, studies using GF animals that demonstrated aberrant behavior and neurochemical profile were critical in establishing the link between the gut microbiota and brain development and processes (211-217).”
From Diet and the Microbiota–Gut–Brain Axis: Sowing the Seeds of Good Mental Health (2021) · cites this paper as [213]
The gut microbiota plays a crucial role in anxiety, cognitive performance, repetitive behaviors and social communications.
“Animal studies have demonstrated that the gut microbiota plays a crucial role in anxiety (Neufeld et al., 2011), cognitive performance (Desbonnet et al., 2015), repetitive behaviors (Desbonnet et al., 2014) and social communications (Buffington et al., 2016; Sherwin et al., 2017).”
From Microbiota-related Changes in Bile Acid & Tryptophan Metabolism are Associated with Gastrointestinal Dysfunction in a Mouse Model of Autism (2017) · cites this paper as Neufeld et al., 2011
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“microbiome with the host neurophysiological systems is a study showing that the excitability of gut sensory neurons located within the myenteric plexus of the ENS relies on the presence of the normal commensal microbiota for proper functioning (Neufeld et al., 2011).”
BackgroundInfluential
- Authors
- Neufeld, K. M., Kang, N., Bienenstock, J., & Foster, J. A.
- Affiliations
- St. Joseph’s Healthcare Hamilton (CA)
- Corresponding author
- Foster, J. A.
- Venue
- Neurogastroenterology & Motility
- Publisher
- Wiley
- Published
- 2010-11-05
- Volume
- 23
- Issue
- 3
- Pages
- 255-e119
- ISSN
- 1350-1925 (ISSN-L)
- OpenAlex
- W1920510593
- Cited by
- 1,392
- References
- 89
- Citations by year
- 2026: 49 · 2025: 72 · 2024: 90 · 2023: 86 · 2022: 131 · 2021: 173 · 2020: 134 · 2019: 118 · 2018: 108 · 2017: 106 · 2016: 111 · 2015: 71 · 2014: 53 · 2013: 48 · 2012: 29
- FWCI
- 11.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurogastroenterology & Motility (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of California, Irvine
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- germ-free mice, gut microbiota, gut-brain axis, anxiety-like behavior, elevated plus maze, central amygdala, NR2B, brain-derived neurotrophic factor, serotonin receptor 1A, hippocampus, hypothalamic-pituitary-adrenal axis, stress reactivity, neurochemical changes
- MeSH terms
- Animals, Anxiety, Behavior, Animal, Brain, Brain Chemistry, Corticosterone, Female, Germ-Free Life, Humans, Hypothalamo-Hypophyseal System, Motor Activity, Pituitary-Adrenal System, Stress, Psychological, Gene Expression, Receptors, Neurotransmitter, Neurotransmitter Agents, Gastrointestinal Tract, Mice, Metagenome
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