The microbiota regulate neuronal function and fear extinction learning

Chu, Coco; Murdock, Mitchell H.; Jing, Deqiang; Won, Tae Hyung; Chung, Hattie; Kressel, Adam M.; Tsaava, Tea; Addorisio, Meghan E.; Putzel, Gregory G.; Zhou, Lei; Bessman, Nicholas J.; Yang, Ruirong; Moriyama, Saya; Parkhurst, Christopher N.; Li, Anfei; Meyer, Heidi C.; Teng, Fei; Chavan, Sangeeta S.; Tracey, Kevin J.; Regev, Aviv; Schroeder, Frank C.; Lee, Francis S.; Liston, Conor; Artis, David

doi:10.1038/s41586-019-1644-y

Cited by 421Memory and Neural MechanismsGut microbiota and healthNeuroscience and Neuropharmacology Research

The microbiota regulate neuronal function and fear extinction learning

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Chu, Coco, Murdock, Mitchell H., Jing, Deqiang, Won, Tae Hyung, Chung, Hattie, Kressel, Adam M., Tsaava, Tea, Addorisio, Meghan E. +16 more·2019·Nature

DOI 10.1038/s41586-019-1644-yPMC PMC6818753

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Abstract

Multicellular organisms have co-evolved with complex consortia of viruses, bacteria, fungi and parasites, collectively referred to as the microbiota 1. In mammals, changes in the composition of the microbiota can influence many physiologic processes (including development, metabolism and immune cell function) and are associated with susceptibility to multiple diseases 2. Alterations in the microbiota can also modulate host behaviours-such as social activity, stress, and anxiety-related responses-that are linked to diverse neuropsychiatric disorders 3. However, the mechanisms by which the microbiota influence neuronal activity and host behaviour remain poorly defined. Here we show that manipulation of the microbiota in antibiotic-treated or germ-free adult mice results in significant deficits in fear extinction learning. Single-nucleus RNA sequencing of the medial prefrontal cortex of the brain revealed significant alterations in gene expression in excitatory neurons, glia and other cell types. Transcranial two-photon imaging showed that deficits in extinction learning after manipulation of the microbiota in adult mice were associated with defective learning-related remodelling of postsynaptic dendritic spines and reduced activity in cue-encoding neurons in the medial prefrontal cortex. In addition, selective re-establishment of the microbiota revealed a limited neonatal developmental window in which microbiota-derived signals can restore normal extinction learning in adulthood. Finally, unbiased metabolomic analysis identified four metabolites that were significantly downregulated in germ-free mice and have been reported to be related to neuropsychiatric disorders in humans and mouse models, suggesting that microbiota-derived compounds may directly affect brain function and behaviour. Together, these data indicate that fear extinction learning requires microbiota-derived signals both during early postnatal neurodevelopment and in adult mice, with implications for our understanding of how diet, infection, and lifestyle influence brain health and subsequent susceptibility to neuropsychiatric disorders.

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Selective colonization revealed a critical developmental period, indicating that microbiota-derived signals were required during early post-natal and adult life for normal learning.
“Selective colonization revealed a critical developmental period, indicating that microbiota-derived signals were required during early post-natal and adult life for normal learning.”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [385]
Without a complex microbiota, both antibiotic-treated and germ-free mice exhibited altered fear-associated behavior, changes in gene expression in brain cells, and alterations in the firing patterns and rewiring ability of neurons.
“Without a complex microbiota, both types of mice exhibited altered fear-associated behavior, changes in gene expression in brain cells, and alterations in the firing patterns and rewiring ability of neurons.”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [385]
A relevant contribution of gut microbiota is not restricted to neuroinflammatory and psychiatric disorders but also extends to brain development.
“Moreover, a relevant contribution of gut microbiota is not only restricted to neuroinflammatory and psychiatric disorders (23–32) but also to brain development (13).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [29]
SPF mice treated with broad-spectrum antibiotics, germ-free mice, and germ-free mice recolonized after weaning with a simple or complex microbiota have defects in fear extinction learning compared to SPF mice or germ-free mice colonized with SPF flora at birth.
“In 2019, Artis D.’s group showed that SPF mice treated with a cocktail of broad-spectrum antibiotics, GF mice, GF mice recolonized after weaning age with a simple microbiota or a complex microbiota, have defects in fear extinction learning, compared to SPF mice or GF mice colonized with SPF flora at the time of birth (29).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [29]
The microbiota-mediated changes in synapse formation and fear extinction behavior were not results of the hypothalamic-pituitary-adrenal axis but of reduced levels of potential neuroactive metabolites (phenyl sulfate, pyrocatechol sulfate, 3-(3-sulfooxyphenyl)propanoic acid, and indoxyl sulfate) in cerebrospinal fluid, serum, and fecal samples of germ-free mice compared to SPF mice.
“The researchers showed that the microbiota-mediated changes in synapse formation and fear extinction behavior were not the results of the hypothalamic-pituitary-adrenal axis but of the reduced level of potential neuroactive metabolites (phenyl sulfate, pyrocatechol sulfate, 3-(3-sulfooxyphenyl)propanoic acid, and indoxyl sulfate) in the cerebrospinal fluid, serum and in fecal samples of GF mice”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [29]

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Indoxyl sulfate, not p-cresyl sulfate, is associated with cognitive impairment in early-stage chronic kidney disease
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INVESTIGATION OF THE RELATION BETWEEN ANAEROBIC BACTERIA GENUSCLOSTRIDIUMAND LATE-ONSET AUTISM ETIOLOGY IN CHILDREN
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The Effects of Antipsoriatic Treatment on Cutaneous Blood Flow in Psoriasis Measured by 133Xe Washout Method and Laser Doppler Velocimetry
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Subdiaphragmatic Vagotomy With Pyloroplasty Ameliorates the Obesity Caused by Genetic Deletion of the Melanocortin 4 Receptor in the Mouse
Dezfuli, G., Gillis, R. A., Tatge, J. E., Duncan, K. R., Dretchen, K. L., Jackson, P. G., Verbalis, J. G., & Sahibzada, N. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00104 · Cited by 29 · see citing works
THIAZIDES AND CEREBRAL ISCHÆMIA
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[66]Ntranos V, Yi L, Melsted P & Pachter L Identification of transcriptional signatures for cell types from single-cell RNA-Seq. bioRxiv, 258566 (2018).

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The gut microbiota–brain axis in behaviour and brain disorders
Morais, L. H., Schreiber, H. L., & Mazmanian, S. K. (2021) · Nature Reviews Microbiology · doi:10.1038/s41579-020-00460-0 · Cited by 2,149 · see citing works
Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
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Mass spectrometry-based metabolomics: a guide for annotation, quantification and best reporting practices
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The microbiota-gut-brain axis: from motility to mood
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The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology
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The Role of Astrocytes in CNS Inflammation
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Microbiota-derived metabolites as drivers of gut–brain communication
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Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis
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Gut-licensed IFNγ+ NK cells drive LAMP1+TRAIL+ anti-inflammatory astrocytes
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Microbiota in neuroinflammation and synaptic dysfunction: a focus on Alzheimer’s disease
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Mucosal fungi promote gut barrier function and social behavior via Type 17 immunity
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Imprinting of the immune system by the microbiota early in life
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Interplay of gut microbiota and oxidative stress: Perspective on neurodegeneration and neuroprotection
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Childhood Development and the Microbiome—The Intestinal Microbiota in Maintenance of Health and Development of Disease During Childhood Development
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Microbiota-derived metabolite Indoles induced aryl hydrocarbon receptor activation and inhibited neuroinflammation in APP/PS1 mice
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A Review of Gut Microbiota‐Derived Metabolites in Tumor Progression and Cancer Therapy
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Inulin fibre promotes microbiota-derived bile acids and type 2 inflammation
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Dendritic Spine Plasticity: Function and Mechanisms
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Bacteroides species differentially modulate depression-like behavior via gut-brain metabolic signaling
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Tryptophan-metabolizing gut microbes regulate adult neurogenesis via the aryl hydrocarbon receptor
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The Role of Gut Bacterial Metabolites in Brain Development, Aging and Disease
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Colon-delivered short-chain fatty acids attenuate the cortisol response to psychosocial stress in healthy men: a randomized, placebo-controlled trial
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Gut-innervating nociceptors regulate the intestinal microbiota to promote tissue protection
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The microbiome-gut-brain axis in acute and chronic brain diseases
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Annual Research Review: Critical windows – the microbiota-gut-brain axis in neurocognitive development
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Revisiting the seven pillars of RDoC
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The Role of Gut Dysbiosis in the Pathophysiology of Neuropsychiatric Disorders
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Gut microbiome modulates Drosophila aggression through octopamine signaling
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Obesity impairs short-term and working memory through gut microbial metabolism of aromatic amino acids
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Production of Indole and Indole-Related Compounds by the Intestinal Microbiota and Consequences for the Host: The Good, the Bad, and the Ugly
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Identification of environmental factors that promote intestinal inflammation
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Paternal microbiome perturbations impact offspring fitness
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Gut hormones in microbiota-gut-brain cross-talk
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High-coverage metabolomics uncovers microbiota-driven biochemical landscape of interorgan transport and gut-brain communication in mice
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COVID-19 in pregnancy: implications for fetal brain development
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Gut-Brain Connection: Microbiome, Gut Barrier, and Environmental Sensors
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Oral feeding of nanoplastics affects brain function of mice by inducing macrophage IL-1 signal in the intestine
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Gut bacterial isoamylamine promotes age-related cognitive dysfunction by promoting microglial cell death
Teng, Y., Mu, J., Xu, F., Zhang, X., Sriwastva, M. K., Liu, Q. M., Li, X., Lei, C., Sundaram, K., Hu, X., et al. (2022) · Cell Host & Microbe · doi:10.1016/j.chom.2022.05.005 · Cited by 135 · see citing works
Primary Human Colonic Mucosal Barrier Crosstalk with Super Oxygen-Sensitive Faecalibacterium prausnitzii in Continuous Culture
Zhang, J., Huang, Y.-J., Yoon, J. Y., Kemmitt, J., Wright, C. W., Schneider, K., Sphabmixay, P., Hernandez‐Gordillo, V., Holcomb, S. J., Bhushan, B. M., et al. (2020) · Med · doi:10.1016/j.medj.2020.07.001 · Cited by 133 · see citing works
Sensing of ATP via the Purinergic Receptor P2RX7 Promotes CD8+ Trm Cell Generation by Enhancing Their Sensitivity to the Cytokine TGF-β
da Silva, H. B., Peng, C., Wang, H.-G., Wanhainen, K. M., Ma, C.-Y., Lopez, S., Khoruts, A., Zhang, N., & Jameson, S. (2020) · Immunity · doi:10.1016/j.immuni.2020.06.010 · Cited by 115 · see citing works
The neurovascular unit and systemic biology in stroke — implications for translation and treatment
Tiedt, S., Buchan, A. M., Dichgans, M., Lizasoaín, I., Moro, M. Á., & Lo, E. H. (2022) · Nature Reviews Neurology · doi:10.1038/s41582-022-00703-z · Cited by 130 · see citing works
Alterations in the gut microbiota contribute to cognitive impairment induced by the ketogenic diet and hypoxia
Olson, C. A., Iñiguez, A. J., Yang, G. E., Fang, P., Pronovost, G. N., Jameson, K. G., Rendon, T. K., Paramo, J., Barlow, J. T., Ismagilov, R. F., et al. (2021) · Cell Host & Microbe · doi:10.1016/j.chom.2021.07.004 · Cited by 125 · see citing works
Gut microbial dysbiosis after traumatic brain injury modulates the immune response and impairs neurogenesis
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Gut microbiota depletion by chronic antibiotic treatment alters the sleep/wake architecture and sleep EEG power spectra in mice
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Gut microbiota composition is associated with newborn functional brain connectivity and behavioral temperament
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Type 2 Diabetes Mellitus Associated with Obesity (Diabesity). The Central Role of Gut Microbiota and Its Translational Applications
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Psychological stress-induced microbial metabolite indole-3-acetate disrupts intestinal cell lineage commitment
Wei, W., Liu, Y., Hou, Y., Cao, S., Chen, Z., Zhang, Y., Cai, X., Yan, Q., Li, Z., Yuan, Y., et al. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2023.12.026 · Cited by 117 · see citing works
Boundaries and integration between microbiota, the nervous system, and immunity
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The gut microbiome modulates the transformation of microglial subtypes
Huang, Y., Wu, J., Zhang, H., Li, Y., Wen, L., Tan, X., Cheng, K., Liu, Y., Pu, J., Liu, L., et al. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02017-y · Cited by 111 · see citing works
Infusion of donor feces affects the gut–brain axis in humans with metabolic syndrome
Hartstra, A. V., Schüppel, V. L., Imangaliyev, S., Schrantee, A., Prodan, A., Collard, D., Levin, E., Dallinga‐Thie, G. M., Ackermans, M. T., Winkelmeijer, M., et al. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101076 · Cited by 113 · see citing works
The Developing Microbiome From Birth to 3 Years: The Gut-Brain Axis and Neurodevelopmental Outcomes
Laue, H. E., Coker, M. O., & Madan, J. C. (2022) · Frontiers in Pediatrics · doi:10.3389/fped.2022.815885 · Cited by 106 · see citing works
Abnormal synaptic pruning during adolescence underlying the development of psychotic disorders
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The Gut-Brain Axis in Multiple Sclerosis. Is Its Dysfunction a Pathological Trigger or a Consequence of the Disease?
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Emerging targetome and signalome landscape of gut microbial metabolites
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Gut bacteria–derived serotonin promotes immune tolerance in early life
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Gut Microbiota in Acute Ischemic Stroke: From Pathophysiology to Therapeutic Implications
Battaglini, D., Pimentel‐Coelho, P. M., Robba, C., dos Santos, C. C., Cruz, F. F., Pelosi, P. P., & Rocco, P. R. M. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.00598 · Cited by 99 · see citing works
Dysregulation of synaptic pruning as a possible link between intestinal microbiota dysbiosis and neuropsychiatric disorders
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Exposure to greenspaces could reduce the high global burden of pain
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Prebiotic and Probiotic Modulation of the Microbiota–Gut–Brain Axis in Depression
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Autism Spectrum Disorders and the Gastrointestinal Tract: Insights into Mechanisms and Clinical Relevance
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The role of the probiotic Akkermansia muciniphila in brain functions: insights underpinning therapeutic potential
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Functional metabolomics innovates therapeutic discovery of traditional Chinese medicine derived functional compounds
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Loss of vagal integrity disrupts immune components of the microbiota-gut-brain axis and inhibits the effect of Lactobacillus rhamnosus on behavior and the corticosterone stress response
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The gut microbiome and Alzheimer’s disease: Complex and bidirectional interactions
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Recent Advances in Understanding the Structure and Function of the Human Microbiome
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The gut-brain connection: Exploring the influence of the gut microbiota on neuroplasticity and neurodevelopmental disorders
Damiani, F., Cornuti, S., & Tognini, P. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2023.109491 · Cited by 87 · see citing works
Nicheformer: a foundation model for single-cell and spatial omics
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The Gut Microbiome as a Regulator of the Neuroimmune Landscape
Yu, L. W., Agirman, G., & Hsiao, E. Y. (2022) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101320-014237 · Cited by 75 · see citing works
Gut Microbiota: Implications in Alzheimer’s Disease
He, Y., Li, B., Sun, D., & Chen, S. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9072042 · Cited by 81 · see citing works
Chains of evidence from correlations to causal molecules in microbiome-linked diseases
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Hepatic soluble epoxide hydrolase activity regulates cerebral Aβ metabolism and the pathogenesis of Alzheimer’s disease in mice
Wu, Y., Dong, J.-H., Dai, Y.-F., Zhu, M.-Z., Wang, M.-Y., Zhang, Y., Pan, Y.-D., Yuan, X.-R., Guo, Z.-X., Wang, C.-X., et al. (2023) · Neuron · doi:10.1016/j.neuron.2023.06.002 · Cited by 84 · see citing works
Gut-brain axis: A matter of concern in neuropsychiatric disorders…!
Naveed, M., Zhou, Q.-G., Chu, X., Taleb, A., Meng, F. J., Ahmed, B., Zhang, Y., Fukunaga, K., & Han, F. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.110051 · Cited by 81 · see citing works
A biological framework for emotional dysregulation in alcohol misuse: from gut to brain
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Alternative stable states, nonlinear behavior, and predictability of microbiome dynamics
Fujita, H., Ushio, M., Suzuki, K. T., Abe, M., Yamamichi, M., Iwayama, K., Canarini, A., Hayashi, I., Fukushima, K., Fukuda, S., et al. (2023) · Microbiome · doi:10.1186/s40168-023-01474-5 · Cited by 79 · see citing works
Anxiolytic effects of a galacto-oligosaccharides prebiotic in healthy females (18–25 years) with corresponding changes in gut bacterial composition
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The Gut–Immune–Brain Axis: An Important Route for Neuropsychiatric Morbidity in Inflammatory Bowel Disease
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Gut colonization by Proteobacteria alters host metabolism and modulates cocaine neurobehavioral responses
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Authors: Chu, C., Murdock, M. H., Jing, D., Won, T. H., Chung, H., Kressel, A. M., Tsaava, T., Addorisio, M. E., Putzel, G. G., Zhou, L., Bessman, N. J., Yang, R., Moriyama, S., Parkhurst, C. N., Li, A., Meyer, H. C., Teng, F., Chavan, S. S., Tracey, K. J., Regev, A., Schroeder, F. C., Lee, F. S., Liston, C., & Artis, D.
Affiliations: Cornell University (US)
Broad Institute (US)
Northwell Health (US)
Corresponding author: Liston, Conor
Artis, David
ORCID: Chu, Coco
Murdock, Mitchell H.
Won, Tae Hyung
Chung, Hattie
Kressel, Adam M.
Putzel, Gregory G.
Zhou, Lei
Bessman, Nicholas J.
Moriyama, Saya
Parkhurst, Christopher N.
Li, Anfei
Meyer, Heidi C.
Teng, Fei
Chavan, Sangeeta S.
Tracey, Kevin J.
Regev, Aviv
Schroeder, Frank C.
Lee, Francis S.
Liston, Conor
Artis, David
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2019-10-23
Volume: 574
Issue: 7779
Pages: 543-548
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-019-1644-y
PMC: PMC6818753
OpenAlex: W2981552290
Cited by: 421
References: 78
Citations by year: 2026: 27 · 2025: 49 · 2024: 57 · 2023: 72 · 2022: 77 · 2021: 64 · 2020: 69 · 2019: 3 · 2017: 1 · 2014: 1
FWCI: 30.96
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute of Mental Health (R01MH109685, R01MH118451)
National Institute of General Medical Sciences (R35GM118182, R01GM132672)
National Institute of Allergy and Infectious Diseases (R01AI095466, R21AI142213, R01AI102942, R01AI151599, F32AI124517, P01AI102852, R01AI074878, U01AI095608)
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK126871)
National Institute of Neurological Disorders and Stroke (R01NS052819)
Topics: Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: gut microbiota, fear extinction learning, germ-free mice, antibiotic-treated mice, medial prefrontal cortex, neuroplasticity, single-nucleus RNA sequencing, metabolomics, neuropsychiatric disorders, anxiety-like behavior
MeSH terms: Animals, Anti-Bacterial Agents, Autistic Disorder, Blood, Calcium, Cerebrospinal Fluid, Cues, Extinction, Psychological, Fear, Feces, Germ-Free Life, Indican, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Neural Inhibition, Neuroglia, Neurons, Phenylpropionates, Schizophrenia, Vagus Nerve, Prefrontal Cortex, Dendritic Spines, Mice, Metabolomics, Transcriptome, Microbiota

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