Cited by 498Gut microbiota and healthTryptophan and brain disordersNeurogenesis and neuroplasticity mechanisms

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A gut-derived metabolite alters brain activity and anxiety behaviour in mice

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Needham, Brittany D., Funabashi, Masanori, Adame, Mark D., Wang, Zhuo, Boktor, Joseph C., Haney, Jillian, Wu, Wei-Li, Rabut, Claire, Ladinsky, Mark S., Hwang, Son-Jong, Guo, Yumei, Zhu, Qiyun, Griffiths, Jessica A., Knight, Rob, Bjorkman, Pamela J., Shapiro, Mikhail G., Geschwind, Daniel H., Holschneider, Daniel P., Fischbach, Michael A., Mazmanian, Sarkis K.·2022·Nature

DOI 10.1038/s41586-022-04396-8PMC PMC9170029

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Abstract

Integration of sensory and molecular inputs from the environment shapes animal behaviour. A major site of exposure to environmental molecules is the gastrointestinal tract, in which dietary components are chemically transformed by the microbiota 1 and gut-derived metabolites are disseminated to all organs, including the brain 2. In mice, the gut microbiota impacts behaviour 3, modulates neurotransmitter production in the gut and brain 4,5, and influences brain development and myelination patterns 6,7. The mechanisms that mediate the gut-brain interactions remain poorly defined, although they broadly involve humoral or neuronal connections. We previously reported that the levels of the microbial metabolite 4-ethylphenyl sulfate (4EPS) were increased in a mouse model of atypical neurodevelopment 8. Here we identified biosynthetic genes from the gut microbiome that mediate the conversion of dietary tyrosine to 4-ethylphenol (4EP), and bioengineered gut bacteria to selectively produce 4EPS in mice. 4EPS entered the brain and was associated with changes in region-specific activity and functional connectivity. Gene expression signatures revealed altered oligodendrocyte function in the brain, and 4EPS impaired oligodendrocyte maturation in mice and decreased oligodendrocyte-neuron interactions in ex vivo brain cultures. Mice colonized with 4EP-producing bacteria exhibited reduced myelination of neuronal axons. Altered myelination dynamics in the brain have been associated with behavioural outcomes 7,9-14. Accordingly, we observed that mice exposed to 4EPS displayed anxiety-like behaviours, and pharmacological treatments that promote oligodendrocyte differentiation prevented the behavioural effects of 4EPS. These findings reveal that a gut-derived molecule influences complex behaviours in mice through effects on oligodendrocyte function and myelin patterning in the brain.

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Authors: Needham, B. D., Funabashi, M., Adame, M. D., Wang, Z., Boktor, J. C., Haney, J., Wu, W.-L., Rabut, C., Ladinsky, M. S., Hwang, S.-J., Guo, Y., Zhu, Q., Griffiths, J. A., Knight, R., Bjorkman, P. J., Shapiro, M. G., Geschwind, D. H., Holschneider, D. P., Fischbach, M. A., & Mazmanian, S. K.
Affiliations: California Institute of Technology (US)
Daiichi Sankyo RD Novare (Japan) (JP)
University of Southern California (US)
University of California, Los Angeles (US)
University of California San Diego (US)
Stanford University (US)
Corresponding author: Needham, Brittany D.
ORCID: Needham, Brittany D.
Adame, Mark D.
Wang, Zhuo
Boktor, Joseph C.
Haney, Jillian
Rabut, Claire
Ladinsky, Mark S.
Hwang, Son-Jong
Zhu, Qiyun
Griffiths, Jessica A.
Knight, Rob
Bjorkman, Pamela J.
Shapiro, Mikhail G.
Geschwind, Daniel H.
Holschneider, Daniel P.
Fischbach, Michael A.
Mazmanian, Sarkis K.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2022-02-14
Volume: 602
Issue: 7898
Pages: 647-653
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-022-04396-8
PMC: PMC9170029
OpenAlex: W4213093937
Cited by: 489
References: 73
Citations by year: 2026: 83 · 2025: 123 · 2024: 128 · 2023: 101 · 2022: 53
FWCI: 33.71
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)
CaltechAUTHORS (California Institute of Technology) (submittedVersion)
RePEc: Research Papers in Economics (submittedVersion)
eScholarship (California Digital Library) (submittedVersion)
IUScholarWorks (Indiana University) (submittedVersion)
Funders: National Institute on Aging (U19AG063744)
National Heart, Lung, and Blood Institute (P01HL147823)
National Institute of Mental Health (R01MH100556)
National Institute of General Medical Sciences (P50GM082545)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords: 4-ethylphenol, gut microbiota, gut-brain axis, anxiety-like behavior, oligodendrocyte maturation, myelination, tyrosine metabolism, microbial metabolites, brain functional connectivity, brain development
MeSH terms: Gastrointestinal Microbiome, Animals, Anxiety, Bacteria, Brain, Mice, Inbred C57BL, Myelin Sheath, Phenols, Mice, Microbiota

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A gut-derived metabolite alters brain activity and anxiety behaviour in mice

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