A gut-derived metabolite alters brain activity and anxiety behaviour in mice
- 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.
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 and gut-derived metabolites are disseminated to all organs, including the brain. In mice, the gut microbiota impacts behaviour, modulates neurotransmitter production in the gut and brain, and influences brain development and myelination patterns. 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. 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. 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.
© 2022 Nature Publishing Group. Received 11 June 2020; Accepted 02 January 2022; Published 14 February 2022. We thank the members of the Mazmanian laboratory for evaluating the manuscript; S. Reisman and L. Chapman (Caltech) for synthesizing 4EPS; the staff at the Caltech Kavli Nanoscience Institute for help with maintaining the TF30 electron microscope, and the Gordon and Betty Moore and Beckman Foundations for gifts to Caltech to support electron microscopy. This work was supported by funds from the Center for Environmental Microbial Interactions to B.D.N., National Science Foundation MRI grant 1920364 for Bruker console upgrading, the Human Frontier Science Program (grant no. LT000217/2020-C) to C.R., the National Institutes of Health (NIH) (2 P50 GM082545-08) to P.J.B., the Ministry of Science and Technology in Taiwan (MOST107-2320-B-006-072-MY3; MOST108-2321-B-006-025-MY2) to W.-L.W., and the Heritage Medical Research Institute, L. and B. Fetter, and the NIH (MH100556 and AG063744) to S.K.M. Data availability: All data analysed for this study are included in this published Article and its Supplementary Information. Additional 2DG data are available online (https://gin.g-node.org/bneedham/Needham_Nature_2022). The WoL database annotation files are publicly available at GitHub (https://biocore.github.io/wol/download). The Greengenes database is publicly available online (https://greengenes.secondgenome.com/). Source data are provided with this paper. Code availability: Custom scripts used in the fUSi analysis are available at GitHub (https://github.com/brittanyneedham/Needham_Nature2022). Author Contributions: Conceptualization: B.D.N. and S.K.M. Methodology: B.D.N., M.F., M.D.A., Z.W., W.-L.W., J.H., M.S.L., J.A.G., C.R., S.-J.H. and D.P.H. Formal analysis: B.D.N., M.D.A., Z.W. and J.H. Investigation: B.D.N., M.F., M.D.A., Z.W., W.-L.W., J.C.B., C.R., J.H., S.-J.H., Q.Z., M.S.L. and Y.G. Biochemical pathway investigation and strain engineering: M.F. and M.A.F. Gene abundance analysis: Q.Z., J.C.B. and R.K. fUSi imaging: C.R., J.C.B., B.D.N. and M.G.S. 2DG analysis: Z.W., B.D.N., Y.G. and D.P.H. QuantSeq analysis: J.H., W.-L.W., B.D.N. and D.H.G. Oligodendrocyte characterization: B.D.N., M.D.A., J.C.B., M.S.L. and J.A.G. ET: M.S.L., B.D.N. and M.D.A. MRI/diffusion tensor imaging: S.-J.H. and B.D.N. Animal behaviour: B.D.N. and M.D.A. Resources: P.J.B., D.G., D.P.H., M.A.F., R.K., M.G.S. and S.K.M. Writing original draft: B.D.N. Writing review and editing: B.D.N., M.F., M.D.A., Z.W., W.-L.W., J.H., M.S.L., J.A.G., D.P.H., M.A.F. and S.K.M. Visualization: B.D.N., M.F., M.D.A., Z.W., W.-L.W., J.H., J.C.B., C.R., S.-J.H., M.S.L. and M.A.F. Supervision: S.K.M. Project administration: B.D.N. Funding acquisition: B.D.N., W.-L.W., P.J.B. and S.K.M. Competing interests: S.K.M. has financial interests in Axial Biotherapeutics. The other authors declare no competing interests. Peer review information: Nature thanks Gabriel Corfas, Jane Foster, Robert Quinn and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Supplemental Material - 41586_2022_4396_Fig10_ESM.webp
Supplemental Material - 41586_2022_4396_Fig11_ESM.webp
Supplemental Material - 41586_2022_4396_Fig12_ESM.webp
Supplemental Material - 41586_2022_4396_Fig13_ESM.webp
Supplemental Material - 41586_2022_4396_Fig14_ESM.webp
Supplemental Material - 41586_2022_4396_Fig5_ESM.webp
Supplemental Material - 41586_2022_4396_Fig6_ESM.webp
Supplemental Material - 41586_2022_4396_Fig7_ESM.webp
Supplemental Material - 41586_2022_4396_Fig8_ESM.webp
Supplemental Material - 41586_2022_4396_Fig9_ESM.webp
Supplemental Material - 41586_2022_4396_MOESM10_ESM.xlsx
Supplemental Material - 41586_2022_4396_MOESM11_ESM.xlsx
Supplemental Material - 41586_2022_4396_MOESM12_ESM.xlsx
Supplemental Material - 41586_2022_4396_MOESM13_ESM.xlsx
Supplemental Material - 41586_2022_4396_MOESM14_ESM.xlsx
Supplemental Material - 41586_2022_4396_MOESM15_ESM.xlsx
Supplemental Material - 41586_2022_4396_MOESM16_ESM.xlsx
Supplemental Material - 41586_2022_4396_MOESM1_ESM.pdf
Supplemental Material - 41586_2022_4396_MOESM2_ESM.pdf
Supplemental Material - 41586_2022_4396_MOESM3_ESM.xlsx
Supplemental Material - 41586_2022_4396_MOESM4_ESM.xlsx
Supplemental Material - 41586_2022_4396_MOESM5_ESM.xlsx
Supplemental Material - 41586_2022_4396_MOESM6_ESM.xlsx
Supplemental Material - 41586_2022_4396_MOESM7_ESM.xlsx
Supplemental Material - 41586_2022_4396_MOESM8_ESM.xlsx
Supplemental Material - 41586_2022_4396_MOESM9_ESM.xlsx
Accepted Version - nihms-1798333.pdf
||4.4 MB||Preview Download|
||6.2 MB||Preview Download|
||4.8 MB||Preview Download|