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

Brittany D. Needham (), Masanori Funabashi, Mark D. Adame, Zhuo Wang, Joseph C. Boktor, Jillian Haney, Wei-Li Wu, Claire Rabut, Mark S. Ladinsky, Son-Jong Hwang, Yumei Guo, Qiyun Zhu, Jessica A. Griffiths, Rob Knight, Pamela J. Bjorkman, Mikhail G. Shapiro, Daniel H. Geschwind, Daniel P. Holschneider, Michael A. Fischbach and Sarkis K. Mazmanian ()
Additional contact information
Brittany D. Needham: California Institute of Technology
Masanori Funabashi: Stanford University
Mark D. Adame: California Institute of Technology
Zhuo Wang: University of Southern California
Joseph C. Boktor: California Institute of Technology
Jillian Haney: University of California Los Angeles
Wei-Li Wu: California Institute of Technology
Claire Rabut: California Institute of Technology
Mark S. Ladinsky: California Institute of Technology
Son-Jong Hwang: California Institute of Technology
Yumei Guo: University of Southern California
Qiyun Zhu: University of California San Diego
Jessica A. Griffiths: California Institute of Technology
Rob Knight: University of California San Diego
Pamela J. Bjorkman: California Institute of Technology
Mikhail G. Shapiro: California Institute of Technology
Daniel H. Geschwind: University of California Los Angeles
Daniel P. Holschneider: University of Southern California
Michael A. Fischbach: Stanford University
Sarkis K. Mazmanian: California Institute of Technology

Nature, 2022, vol. 602, issue 7898, 647-653

Abstract: 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 microbiota1 and gut-derived metabolites are disseminated to all organs, including the brain2. In mice, the gut microbiota impacts behaviour3, modulates neurotransmitter production in the gut and brain4,5, and influences brain development and myelination patterns6,7. 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 neurodevelopment8. 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 outcomes7,9–14. 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.

Date: 2022
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41586-022-04396-8 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:602:y:2022:i:7898:d:10.1038_s41586-022-04396-8

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-022-04396-8

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().