Gut-to-brain neuromodulation by synthetic butyrate-producing commensal bacteria

Siyao Wang; Xuwei Zhou; Yanchang Ma; Shuyi Zhang; Xu Gong; Baoyan Zhang; Jiarui Zhou; Guo-Qiang Chen; Wei Shi; Yun Yang

doi:10.59717/j.xinn-life.2024.100082

The Innovation Life > 2024 Vol. 2 > No. 3 > 100082

Next Article Previous Article

REPORT Open Access

Cite PDF

Gut-to-brain neuromodulation by synthetic butyrate-producing commensal bacteria

1.
Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Engineering Medicine, Beihang University, Beijing 100083, China
2.
Key Laboratory of Big Data-Based Precision Medicine, Ministry of Industry and Information Technology, Beihang University, Beijing 100083, China
3.
School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China
4.
Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China
5.
MOE Key Lab of Industrial Biocatalysis, Department of Chemical Engineering, Tsinghua University, Beijing 100084, China
6.
Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
7.
These authors contributed equally

Show all affliationsShow less

More Information

Corresponding authors: yangyun0731@buaa.edu.cn (Y.Y.); shiweilab@buaa.edu.cn (W.S.)
Received Date: 31 May 2024

Accepted Date: 15 July 2024

Published Online: 12 August 2024

The Innovation Life 2(3), https://doi.org/10.59717/j.xinn-life.2024.100082 | Cite this article

GRAPHICAL ABSTRACT

GRAPHICAL ABSTRACT

PUBLIC SUMMARY

PUBLIC SUMMARY
1. Synthetic butyrate-overproducing commensal bacteria ameliorate murine depression.
  
  Gut butyrate functions by regulating paraventricular thalamic nucleus (PVT) via a gut-brain neural pathway.
  
  Gut butyrate triggers the neural circuit as a role of free fatty acid receptor 3 (FFAR3) agonist.
  
  Synthetic living delivery bacteria provide a new avenue for non-invasive neuromodulation technology.

ABSTRACT

ABSTRACT

Previous studies have revealed the existence of gut epithelial-neuronal synapses and an array of neuroactive bacterial metabolites, highlighting the potential of gut chemicals in stimulating gut-to-brain neurotransmission. However, bacterial metabolite-focused studies in murine models frequently apply systemic administration of the chemicals, and the illustrated gut-to-brain signals are generally through humoral pathways, probably distinct from the physiological working mechanism, since many bacterial metabolites could not cross the blood-brain barrier in primates. Limited by delivery approach, research on gut-to-brain neurotransmission pathway regulated by gut bacterial metabolites is sparse. To address this challenge, engineered commensal bacteria were harnessed for gut delivery of bacterial metabolites with physiological biogeography. In murine model of depression, the synthetic butyrate-overproducing Escherichia coli Nissle 1917 (EcN) significantly attenuates depressive-like syndromes. The aberrantly activated paraventricular thalamus (PVT) is modulated by gut butyrate via a gut-to-brain neurotransmission route, which is illuminated for the first time. We provide a paradigm for dissecting gut-to-brain neurotransmission pathways regulated by gut bacterial metabolites, and point out a new avenue for non-invasive gut-to-brain neuromodulation by oral administration of metabolically engineered commensal bacteria, without the dependence on external devices or surgery.

FullText(HTML)

REFERENCES

[1]	San-Juan, D., Davila-Rodriguez, D.O., Jimenez, C.R., et al. (2019). Neuromodulation techniques for status epilepticus: A review. Brain Stimul. 12: 835−844. DOI: 10.1016/j.brs.2019.04.005. View in Article CrossRef Google Scholar
[2]	Lozano, A.M. and Lipsman, N. (2013). Probing and regulating dysfunctional circuits using deep brain stimulation. Neuron 77: 406−424. DOI: 10.1016/j.neuron.2013.01.020. View in Article CrossRef Google Scholar
[3]	Krauss, J.K., Lipsman, N., Aziz, T., et al. (2021). Technology of deep brain stimulation: Current status and future directions. Nat. Rev. Neurol. 17: 75−87. DOI: 10.1038/s41582-020-00426-z. View in Article CrossRef Google Scholar
[4]	Rossini, P.M., Burke, D., Chen, R., et al. (2015). Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: Basic principles and procedures for routine clinical and research application. An updated report from an i.F.C.N. Committee. Clin. Neurophysiol. 126: 1071−1107. DOI: 10.1016/j.clinph.2015.02.001. View in Article CrossRef Google Scholar
[5]	Lozano, A.M. (2017). Waving hello to noninvasive deep-brain stimulation. N. Engl. J. Med. 377: 1096−1098. DOI: 10.1056/NEJMcibr1707165. View in Article CrossRef Google Scholar
[6]	Grossman, N., Bono, D., Dedic, N., et al. (2017). Noninvasive deep brain stimulation via temporally interfering electric fields. Cell 169 :1029-1041 e1016. DOI: 10.1016/j.cell.2017.05.024. View in Article Google Scholar
[7]	Liu, L., Huh, J.R., and Shah, K. (2022). Microbiota and the gut-brain-axis: Implications for new therapeutic design in the CNS. EBioMedicine 77: 103908. DOI: 10.1016/j.ebiom.2022.103908. View in Article CrossRef Google Scholar
[8]	Strandwitz, P., Kim, K.H., Terekhova, D., et al. (2019). Gaba-modulating bacteria of the human gut microbiota. Nat. Microbiol. 4: 396−403. DOI: 10.1038/s41564-018-0307-3. View in Article CrossRef Google Scholar
[9]	Valles-Colomer, M., Falony, G., Darzi, Y., et al. (2019). The neuroactive potential of the human gut microbiota in quality of life and depression. Nat. Microbiol. 4: 623−632. DOI: 10.1038/s41564-018-0337-x. View in Article CrossRef Google Scholar
[10]	Liu, R.T., Rowan-Nash, A.D., Sheehan, A.E., et al. (2020). Reductions in anti-inflammatory gut bacteria are associated with depression in a sample of young adults. Brain, Behav., Immun. 88: 308−324. DOI: 10.1016/j.bbi.2020.03.026. View in Article CrossRef Google Scholar
[11]	Suez, J. and Elinav, E. (2017). The path towards microbiome-based metabolite treatment. Nat. Microbiol. 2 : 17075. DOI: ARTN 1707510.1038/nmicrobiol.2017.75. View in Article Google Scholar
[12]	Li, T., Fang, J., Tang, S., et al. (2022). PM(2.5) exposure associated with microbiota gut-brain axis: Multi-omics mechanistic implications from the bape study. The Innovation 3 :100213. DOI: 10.1016/j.xinn.2022.100213. View in Article Google Scholar
[13]	Cook, T.M., Gavini, C.K., Jesse, J., et al. (2021). Vagal neuron expression of the microbiota-derived metabolite receptor, free fatty acid receptor (FFAR3), is necessary for normal feeding behavior. Mol. Metab. 54: 101350. DOI: 10.1016/j.molmet.2021.101350. View in Article CrossRef Google Scholar
[14]	Yu, K.B. and Hsiao, E.Y. (2021). Roles for the gut microbiota in regulating neuronal feeding circuits. J. Clin. Invest. 131: e143772. DOI: ARTN e14377210.1172/JCI143772. DOI: 10.1172/JCI143772. View in Article CrossRef Google Scholar
[15]	Wang, Y., Zhan, G.F., Cai, Z.W., et al. (2021). Vagus nerve stimulation in brain diseases: Therapeutic applications and biological mechanisms. Neurosci. Biobehav. Rev. 127: 37−53. DOI: 10.1016/j.neubiorev.2021.04.018. View in Article CrossRef Google Scholar
[16]	Ahmed, H., Leyrolle, Q., Koistinen, V., et al. (2022). Microbiota-derived metabolites as drivers of gut-brain communication. Gut Microbes 14: 2102878. DOI: 10.1080/19490976.2022.2102878. View in Article CrossRef Google Scholar
[17]	Simpson, C.A., Diaz-Arteche, C., Eliby, D., et al. (2021). The gut microbiota in anxiety and depression - a systematic review. Clin. Psychol. Rev. 83: 101943. DOI: 10.1016/j.cpr.2020.101943. View in Article CrossRef Google Scholar
[18]	Dalile, B., Van Oudenhove, L., Vervliet, B., et al. (2019). The role of short-chain fatty acids in microbiota-gut-brain communication. Nat. Rev. Gastroenterol. Hepatol. 16: 461−478. DOI: 10.1038/s41575-019-0157-3. View in Article CrossRef Google Scholar
[19]	Morais, L.H., Schreiber, H.L.t., and Mazmanian, S.K. (2021). The gut microbiota-brain axis in behaviour and brain disorders. Nat. Rev. Microbiol. 19: 241−255. DOI: 10.1038/s41579-020-00460-0. View in Article CrossRef Google Scholar
[20]	Gong, X., Geng, H., Yang, Y., et al. (2023). Metabolic engineering of commensal bacteria for gut butyrate delivery and dissection of host-microbe interaction. Metab. Eng. 80: 94−106. DOI: 10.1016/j.ymben.2023.09.008. View in Article CrossRef Google Scholar
[21]	Tian, M., Ma, Z., and Yang, G.Z. (2024). Micro/nanosystems for controllable drug delivery to the brain. The Innovation 5: 100548. DOI: 10.1016/j.xinn.2023.100548. View in Article CrossRef Google Scholar
[22]	Siopi, E., Chevalier, G., Katsimpardi, L., et al. (2020). Changes in gut microbiota by chronic stress impair the efficacy of fluoxetine. Cell. Rep. 30 : 3682-3690. DOI: 10.1016/j.celrep.2020.02.099. View in Article Google Scholar
[23]	Nollet, M., Hicks, H., McCarthy, A.P., et al. (2019). Rem sleep's unique associations with corticosterone regulation, apoptotic pathways, and behavior in chronic stress in mice. Proc. Natl. Acad. Sci. USA. 116: 2733−2742. DOI: 10.1073/pnas.1816456116. View in Article CrossRef Google Scholar
[24]	Goswami, C., Iwasaki, Y., and Yada, T. (2018). Short-chain fatty acids suppress food intake by activating vagal afferent neurons. J. Nutr. Biochem. 57: 130−135. DOI: 10.1016/j.jnutbio.2018.03.009. View in Article CrossRef Google Scholar
[25]	Li, K., Zhou, T., Liao, L., et al. (2013). Betacamkii in lateral habenula mediates core symptoms of depression. Science 341: 1016−1020. DOI: 10.1126/science.1240729. View in Article CrossRef Google Scholar
[26]	Cui, Y., Yang, Y., Ni, Z., et al. (2018). Astroglial kir4.1 in the lateral habenula drives neuronal bursts in depression. Nature 554 : 323-327. DOI: 10.1038/nature25752. View in Article Google Scholar
[27]	He, J.G., Zhou, H.Y., Xue, S.G., et al. (2021). Transcription factor twist1 integrates dendritic remodeling and chronic stress to promote depressive-like behaviors. Biol. Psychiatry 89: 615−626. DOI: 10.1016/j.biopsych.2020.09.003. View in Article CrossRef Google Scholar
[28]	Zhao, D., Liu, C., Cui, M., et al. (2021). The paraventricular thalamus input to central amygdala controls depression-related behaviors. Exp. Neurol. 342: 113744. DOI: 10.1016/j.expneurol.2021.113744. View in Article CrossRef Google Scholar
[29]	Wu, W.L., Adame, M.D., Liou, C.W., et al. (2021). Microbiota regulate social behaviour via stress response neurons in the brain. Nature 595: 409−414. DOI: 10.1038/s41586-021-03669-y. View in Article CrossRef Google Scholar
[30]	Franklin, K.B. and Paxinos, G. (2001). The mouse brain in stereotaxic coordinates (Academic Press). View in Article Google Scholar
[31]	Chen, J., Cheng, M., Wang, L., et al. (2020). A vagal-nts neural pathway that stimulates feeding. Curr. Biol. 30:3986-3998 e3985. DOI: 10.1016/j.cub.2020.07.084. View in Article Google Scholar
[32]	Fan, Z.X., Chang, J.R., Liang, Y.L., et al. (2023). Neural mechanism underlying depressive-like state associated with social status loss. Cell 186: 560−576. DOI: 10.1016/j.cell.2022.12.033. View in Article CrossRef Google Scholar
[33]	Nestler, E.J. (2015). ∆FosB: A transcriptional regulator of stress and antidepressant responses. Eur. J. Pharmacol. 753: 66−72. DOI: 10.1016/j.ejphar.2014.10.034. View in Article CrossRef Google Scholar
[34]	Iglesias, A.G. and Flagel, S.B. (2021). The paraventricular thalamus as a critical node of motivated behavior via the hypothalamic-thalamic-striatal circuit. Front. Integr. Neurosci. 15 : 706713. DOI: 10.3389/fnint.2021.706713. View in Article Google Scholar
[35]	Browning, K.N. and Travagli, R.A. (2019). Central control of gastrointestinal motility. Curr. Opin. Endocrinol Diabetes Obes. 26: 11−16. DOI: 10.1097/MED.0000000000000449. View in Article CrossRef Google Scholar
[36]	Zhu, Y.J., Wienecke, C.F.R., Nachtrab, G., et al. (2016). A thalamic input to the nucleus accumbens mediates opiate dependence. Nature 530: 219−222. DOI: 10.1038/nature16954. View in Article CrossRef Google Scholar
[37]	Penzo, M.A., Robert, V., Tucciarone, J., et al. (2015). The paraventricular thalamus controls a central amygdala fear circuit. Nature 519: 455−459. DOI: 10.1038/nature13978. View in Article CrossRef Google Scholar
[38]	Hai, J., Kawabata, F., Uchida, K., et al. (2020). Intragastric administration of amg517, a trpv1 antagonist, enhanced activity-dependent energy metabolism via capsaicin-sensitive sensory nerves in mice. Biosci. Biotechnol. Biochem. 84: 2121−2127. DOI: 10.1080/09168451.2020.1789836. View in Article CrossRef Google Scholar
[39]	Nohr, M.K., Egerod, K.L., Christiansen, S.H., et al. (2015). Expression of the short chain fatty acid receptor GPR41/FFAR3 in autonomic and somatic sensory ganglia. Neuroscience 290: 126−137. DOI: 10.1016/j.neuroscience.2015.01.040. View in Article CrossRef Google Scholar
[40]	Brown, A.J., Goldsworthy, S.M., Barnes, A.A., et al. (2003). The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J. Biol. Chem. 278: 11312−11319. DOI: 10.1074/jbc.M211609200. View in Article CrossRef Google Scholar
[41]	Fan, S., Guo, W., Xiao, D., et al. (2023). Microbiota-gut-brain axis drives overeating disorders. Cell Metab. 35 : 2011-2027. DOI: 10.1016/j.cmet.2023.09.005. View in Article Google Scholar
[42]	Shi, H., Ge, X., Ma, X., et al. (2021). A fiber-deprived diet causes cognitive impairment and hippocampal microglia-mediated synaptic loss through the gut microbiota and metabolites. Microbiome 9: 223. DOI: 10.1186/s40168-021-01172-0. View in Article CrossRef Google Scholar
[43]	Stilling, R.M., van de Wouw, M., Clarke, G., et al. (2016). The neuropharmacology of butyrate: The bread and butter of the microbiota-gut-brain axis. Neurochem. Int. 99: 110−132. DOI: 10.1016/j.neuint.2016.06.011. View in Article CrossRef Google Scholar
[44]	Boets, E., Deroover, L., Houben, E., et al. (2015). Quantification of in vivo colonic short chain fatty acid production from inulin. Nutrients 7: 8916−8929. DOI: 10.3390/nu7115440. View in Article CrossRef Google Scholar
[45]	Beaumont, E., Campbell, R.P., Andresen, M.C., et al. (2017). Cervical vagus nerve stimulation augments spontaneous discharge in second- and higher-order sensory neurons in the rat nucleus of the solitary tract. Am. J. Physiol. Heart Circ. Physiol. 313: H354−H367. DOI: 10.1152/ajpheart.00070.2017. View in Article CrossRef Google Scholar
[46]	Ruggiero, D.A., Underwood, M.D., Mann, J.J., et al. (2000). The human nucleus of the solitary tract: Visceral pathways revealed with an "in vitro" postmortem tracing method. J. Auton. Nerv. Syst. 79: 181−190. DOI: 10.1016/s0165-1838(99)00097-1. View in Article CrossRef Google Scholar
[47]	Frangos, E., Ellrich, J., and Komisaruk, B.R. (2015). Non-invasive access to the vagus nerve central projections via electrical stimulation of the external ear: Fmri evidence in humans. Brain Stimul. 8: 624−636. DOI: 10.1016/j.brs.2014.11.018. View in Article CrossRef Google Scholar
[48]	Kasahara, T., Takata, A., Kato, T.M., et al. (2016). Depression-like episodes in mice harboring mtdna deletions in paraventricular thalamus. Mol. Psychiatry 21: 39−48. DOI: 10.1038/mp.2015.156. View in Article CrossRef Google Scholar
[49]	Needham, B.D., Kaddurah-Daouk, R., and Mazmanian, S.K. (2020). Gut microbial molecules in behavioural and neurodegenerative conditions. Nat. Rev. Neurosci. 21: 717−731. DOI: 10.1038/s41583-020-00381-0. View in Article CrossRef Google Scholar
[50]	Krautkramer, K.A., Fan, J., and Backhed, F. (2021). Gut microbial metabolites as multi-kingdom intermediates. Nat. Rev. Microbiol. 19: 77−94. DOI: 10.1038/s41579-020-0438-4. View in Article CrossRef Google Scholar
[51]	Hou, Y.F., Shan, C., Zhuang, S.Y., et al. (2021). Gut microbiota-derived propionate mediates the neuroprotective effect of osteocalcin in a mouse model of parkinson's disease. Microbiome 9: 34. DOI: ARTN 3410.1186/s40168-020-00988-6. DOI: 10.1186/s40168-020-00988-6. View in Article CrossRef Google Scholar
[52]	Dohnalova, L., Lundgren, P., Carty, J.R.E., et al. (2022). A microbiome-dependent gut-brain pathway regulates motivation for exercise. Nature 612: 739−747. DOI: 10.1038/s41586-022-05525-z. View in Article CrossRef Google Scholar
[53]	Bellono, N.W., Bayrer, J.R., Leitch, D.B., et al. (2017). Enterochromaffin cells are gut chemosensors that couple to sensory neural pathways. Cell 170: 185−198. DOI: 10.1016/j.cell.2017.05.034. View in Article CrossRef Google Scholar
[54]	Kaelberer, M.M., Buchanan, K.L., Klein, M.E., et al. (2018). A gut-brain neural circuit for nutrient sensory transduction. Science 361: eaat5236. DOI: 10.1126/science.aat5236. View in Article CrossRef Google Scholar

CITED BY

ABOUT THIS ARTICLE

Cite this article:

Wang S., Zhou X., Ma Y., et al., (2024). Gut-to-brain neuromodulation by synthetic butyrate-producing commensal bacteria. The Innovation Life 2(3): 100082. https://doi.org/10.59717/j.xinn-life.2024.100082

Wang S., Zhou X., Ma Y., et al., (2024). Gut-to-brain neuromodulation by synthetic butyrate-producing commensal bacteria. The Innovation Life 2(3): 100082. https://doi.org/10.59717/j.xinn-life.2024.100082

Welcome!

To request copyright permission to republish or share portions of our works, please visit Copyright Clearance Center's (CCC) Marketplace website at marketplace.copyright.com.

Standard PDF

Extended PDF

Figures(6)

Article Metrics

Article views(2925) PDF downloads(1081) Cited by(0)

Relative Articles

Article Contents

ABOUT THIS ARTICLE

Gut-to-brain neuromodulation by synthetic butyrate-producing commensal bacteria

GRAPHICAL ABSTRACT

PUBLIC SUMMARY

ABSTRACT