2. Academic Validation
  3. A gut-derived metabolite alters brain activity and anxiety behaviour in mice

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

  • Nature. 2022 Feb;602(7898):647-653. doi: 10.1038/s41586-022-04396-8.
Brittany D Needham 1,  Masanori Funabashi 2 3,  Mark D Adame 4,  Zhuo Wang 5,  Joseph C Boktor 4,  Jillian Haney 6,  Wei-Li Wu 4 7 8,  Claire Rabut 9,  Mark S Ladinsky 4,  Son-Jong Hwang 9,  Yumei Guo 5,  Qiyun Zhu 10 11,  Jessica A Griffiths 4,  Rob Knight 10 12 13,  Pamela J Bjorkman 4,  Mikhail G Shapiro 9,  Daniel H Geschwind 6,  Daniel P Holschneider 5 14 15,  Michael A Fischbach 2,  Sarkis K Mazmanian 16
Affiliations

Affiliations

  • 1 Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA. [email protected].
  • 2 Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA, USA.
  • 3 Translational Research Department, Daiichi Sankyo RD Novare Co Ltd, Tokyo, Japan.
  • 4 Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
  • 5 Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 6 Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA.
  • 7 Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • 8 Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • 9 Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA.
  • 10 Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
  • 11 School of Life Sciences, Arizona State University, Tempe, AZ, USA.
  • 12 Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA, USA.
  • 13 Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA.
  • 14 Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 15 Viterbi School of Engineering, Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA.
  • 16 Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA. [email protected].
PMID: 35165440 DOI: 10.1038/s41586-022-04396-8
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.

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