Intestinal serotonin and fluoxetine exposure modulate bacterial colonization in the gut

Thomas C. Fung; Helen E. Vuong; Cristopher D.G. Luna; Geoffrey N. Pronovost; Antoniya A. Aleksandrova; Noah G. Riley; Anastasia Vavilina; Julianne McGinn; Tomiko Rendon; Lucy R. Forrest; Elaine Y. Hsiao

doi:10.1038/s41564-019-0540-4

Intestinal serotonin and fluoxetine exposure modulate bacterial colonization in the gut

Thomas C. Fung
, Helen E. Vuong
, Cristopher D.G. Luna
, Geoffrey N. Pronovost
, Antoniya A. Aleksandrova
, Noah G. Riley
, Anastasia Vavilina
, Julianne McGinn
, Tomiko Rendon
, Lucy R. Forrest
, Elaine Y. Hsiao

Neonatology (Pediatrics)

Research output: Contribution to journal › Letter › peer-review

406 Scopus citations

Abstract

The gut microbiota regulates levels of serotonin (5-hydroxytryptamine (5-HT)) in the intestinal epithelium and lumen^1–5. However, whether 5-HT plays a functional role in bacteria from the gut microbiota remains unknown. We demonstrate that elevating levels of intestinal lumenal 5-HT by oral supplementation or genetic deficiency in the host 5-HT transporter (SERT) increases the relative abundance of spore-forming members of the gut microbiota, which were previously reported to promote host 5-HT biosynthesis. Within this microbial community, we identify Turicibacter sanguinis as a gut bacterium that expresses a neurotransmitter sodium symporter-related protein with sequence and structural homology to mammalian SERT. T. sanguinis imports 5-HT through a mechanism that is inhibited by the selective 5-HT reuptake inhibitor fluoxetine. 5-HT reduces the expression of sporulation factors and membrane transporters in T. sanguinis, which is reversed by fluoxetine exposure. Treating T. sanguinis with 5-HT or fluoxetine modulates its competitive colonization in the gastrointestinal tract of antibiotic-treated mice. In addition, fluoxetine reduces the membership of T. sanguinis in the gut microbiota of conventionally colonized mice. Host association with T. sanguinis alters intestinal expression of multiple gene pathways, including those important for lipid and steroid metabolism, with corresponding reductions in host systemic triglyceride levels and inguinal adipocyte size. Together, these findings support the notion that select bacteria indigenous to the gut microbiota signal bidirectionally with the host serotonergic system to promote their fitness in the intestine.

Original language	English (US)
Pages (from-to)	2064-2073
Number of pages	10
Journal	Nature Microbiology
Volume	4
Issue number	12
DOIs	https://doi.org/10.1038/s41564-019-0540-4
State	Published - Dec 1 2019

Bibliographical note

Funding Information:
We thank members of the Hsiao Laboratory and G. Donaldson for critical review of the manuscript; R. Kaback (UCLA), D. Yang and E. Gouaux (Vollum Institute, OHSU), K. C. Huang (Stanford), M. Quick and J. Javitch (Columbia University) for helpful advice; J. Murowski, D. Nusbaum and J. Yano (UCLA) for assistance with the initial pilot experiments; Y. Wang and J. F. Miller (UCLA) for providing Bacteroides strains and expression constructs; K. Williams (UCLA Lipidomic Core Facility) for performing lipidomic measurements; P. Bradley and R. Gunsalus (UCLA) for facilitating the radioisotope experiments; and G. Karsenty (Columbia), Y. Tintut (UCLA) and F. Bäckhed (University of Gothernburg) for providing the Tph1 mice and tissue samples. Support for this research was provided by the NIH Director’s Early Independence Award (5DP5OD017924) to E.Y.H., Klingenstein-Simons Award to E.Y.H., Packard Fellowship in Science and Engineering to E.Y.H., UCLA Postdocs’ Longitudinal Investment in Faculty Training Award (K12 GM106996) to H.E.V., Ruth L. Kirschstein National Research Service Award (AI007323) to G.N.P. and Division of Intramural Research of the NIH (National Institute of Neurological Disorders and Stroke) to L.R.F. All data and materials used to understand and assess the conclusions of this research are available in the main text and Supplementary Materials.

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© 2019, The Author(s), under exclusive licence to Springer Nature Limited.

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@article{82c1923a104a42b286aa1d99d0926a99,

title = "Intestinal serotonin and fluoxetine exposure modulate bacterial colonization in the gut",

abstract = "The gut microbiota regulates levels of serotonin (5-hydroxytryptamine (5-HT)) in the intestinal epithelium and lumen1{\textendash}5. However, whether 5-HT plays a functional role in bacteria from the gut microbiota remains unknown. We demonstrate that elevating levels of intestinal lumenal 5-HT by oral supplementation or genetic deficiency in the host 5-HT transporter (SERT) increases the relative abundance of spore-forming members of the gut microbiota, which were previously reported to promote host 5-HT biosynthesis. Within this microbial community, we identify Turicibacter sanguinis as a gut bacterium that expresses a neurotransmitter sodium symporter-related protein with sequence and structural homology to mammalian SERT. T. sanguinis imports 5-HT through a mechanism that is inhibited by the selective 5-HT reuptake inhibitor fluoxetine. 5-HT reduces the expression of sporulation factors and membrane transporters in T. sanguinis, which is reversed by fluoxetine exposure. Treating T. sanguinis with 5-HT or fluoxetine modulates its competitive colonization in the gastrointestinal tract of antibiotic-treated mice. In addition, fluoxetine reduces the membership of T. sanguinis in the gut microbiota of conventionally colonized mice. Host association with T. sanguinis alters intestinal expression of multiple gene pathways, including those important for lipid and steroid metabolism, with corresponding reductions in host systemic triglyceride levels and inguinal adipocyte size. Together, these findings support the notion that select bacteria indigenous to the gut microbiota signal bidirectionally with the host serotonergic system to promote their fitness in the intestine.",

author = "Fung, \{Thomas C.\} and Vuong, \{Helen E.\} and Luna, \{Cristopher D.G.\} and Pronovost, \{Geoffrey N.\} and Aleksandrova, \{Antoniya A.\} and Riley, \{Noah G.\} and Anastasia Vavilina and Julianne McGinn and Tomiko Rendon and Forrest, \{Lucy R.\} and Hsiao, \{Elaine Y.\}",

note = "Funding Information: We thank members of the Hsiao Laboratory and G. Donaldson for critical review of the manuscript; R. Kaback (UCLA), D. Yang and E. Gouaux (Vollum Institute, OHSU), K. C. Huang (Stanford), M. Quick and J. Javitch (Columbia University) for helpful advice; J. Murowski, D. Nusbaum and J. Yano (UCLA) for assistance with the initial pilot experiments; Y. Wang and J. F. Miller (UCLA) for providing Bacteroides strains and expression constructs; K. Williams (UCLA Lipidomic Core Facility) for performing lipidomic measurements; P. Bradley and R. Gunsalus (UCLA) for facilitating the radioisotope experiments; and G. Karsenty (Columbia), Y. Tintut (UCLA) and F. B{\"a}ckhed (University of Gothernburg) for providing the Tph1 mice and tissue samples. Support for this research was provided by the NIH Director{\textquoteright}s Early Independence Award (5DP5OD017924) to E.Y.H., Klingenstein-Simons Award to E.Y.H., Packard Fellowship in Science and Engineering to E.Y.H., UCLA Postdocs{\textquoteright} Longitudinal Investment in Faculty Training Award (K12 GM106996) to H.E.V., Ruth L. Kirschstein National Research Service Award (AI007323) to G.N.P. and Division of Intramural Research of the NIH (National Institute of Neurological Disorders and Stroke) to L.R.F. All data and materials used to understand and assess the conclusions of this research are available in the main text and Supplementary Materials. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",

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doi = "10.1038/s41564-019-0540-4",

language = "English (US)",

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T1 - Intestinal serotonin and fluoxetine exposure modulate bacterial colonization in the gut

AU - Fung, Thomas C.

AU - Vuong, Helen E.

AU - Luna, Cristopher D.G.

AU - Pronovost, Geoffrey N.

AU - Aleksandrova, Antoniya A.

AU - Riley, Noah G.

AU - Vavilina, Anastasia

AU - McGinn, Julianne

AU - Rendon, Tomiko

AU - Forrest, Lucy R.

AU - Hsiao, Elaine Y.

N1 - Funding Information: We thank members of the Hsiao Laboratory and G. Donaldson for critical review of the manuscript; R. Kaback (UCLA), D. Yang and E. Gouaux (Vollum Institute, OHSU), K. C. Huang (Stanford), M. Quick and J. Javitch (Columbia University) for helpful advice; J. Murowski, D. Nusbaum and J. Yano (UCLA) for assistance with the initial pilot experiments; Y. Wang and J. F. Miller (UCLA) for providing Bacteroides strains and expression constructs; K. Williams (UCLA Lipidomic Core Facility) for performing lipidomic measurements; P. Bradley and R. Gunsalus (UCLA) for facilitating the radioisotope experiments; and G. Karsenty (Columbia), Y. Tintut (UCLA) and F. Bäckhed (University of Gothernburg) for providing the Tph1 mice and tissue samples. Support for this research was provided by the NIH Director’s Early Independence Award (5DP5OD017924) to E.Y.H., Klingenstein-Simons Award to E.Y.H., Packard Fellowship in Science and Engineering to E.Y.H., UCLA Postdocs’ Longitudinal Investment in Faculty Training Award (K12 GM106996) to H.E.V., Ruth L. Kirschstein National Research Service Award (AI007323) to G.N.P. and Division of Intramural Research of the NIH (National Institute of Neurological Disorders and Stroke) to L.R.F. All data and materials used to understand and assess the conclusions of this research are available in the main text and Supplementary Materials. Publisher Copyright: © 2019, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - The gut microbiota regulates levels of serotonin (5-hydroxytryptamine (5-HT)) in the intestinal epithelium and lumen1–5. However, whether 5-HT plays a functional role in bacteria from the gut microbiota remains unknown. We demonstrate that elevating levels of intestinal lumenal 5-HT by oral supplementation or genetic deficiency in the host 5-HT transporter (SERT) increases the relative abundance of spore-forming members of the gut microbiota, which were previously reported to promote host 5-HT biosynthesis. Within this microbial community, we identify Turicibacter sanguinis as a gut bacterium that expresses a neurotransmitter sodium symporter-related protein with sequence and structural homology to mammalian SERT. T. sanguinis imports 5-HT through a mechanism that is inhibited by the selective 5-HT reuptake inhibitor fluoxetine. 5-HT reduces the expression of sporulation factors and membrane transporters in T. sanguinis, which is reversed by fluoxetine exposure. Treating T. sanguinis with 5-HT or fluoxetine modulates its competitive colonization in the gastrointestinal tract of antibiotic-treated mice. In addition, fluoxetine reduces the membership of T. sanguinis in the gut microbiota of conventionally colonized mice. Host association with T. sanguinis alters intestinal expression of multiple gene pathways, including those important for lipid and steroid metabolism, with corresponding reductions in host systemic triglyceride levels and inguinal adipocyte size. Together, these findings support the notion that select bacteria indigenous to the gut microbiota signal bidirectionally with the host serotonergic system to promote their fitness in the intestine.

AB - The gut microbiota regulates levels of serotonin (5-hydroxytryptamine (5-HT)) in the intestinal epithelium and lumen1–5. However, whether 5-HT plays a functional role in bacteria from the gut microbiota remains unknown. We demonstrate that elevating levels of intestinal lumenal 5-HT by oral supplementation or genetic deficiency in the host 5-HT transporter (SERT) increases the relative abundance of spore-forming members of the gut microbiota, which were previously reported to promote host 5-HT biosynthesis. Within this microbial community, we identify Turicibacter sanguinis as a gut bacterium that expresses a neurotransmitter sodium symporter-related protein with sequence and structural homology to mammalian SERT. T. sanguinis imports 5-HT through a mechanism that is inhibited by the selective 5-HT reuptake inhibitor fluoxetine. 5-HT reduces the expression of sporulation factors and membrane transporters in T. sanguinis, which is reversed by fluoxetine exposure. Treating T. sanguinis with 5-HT or fluoxetine modulates its competitive colonization in the gastrointestinal tract of antibiotic-treated mice. In addition, fluoxetine reduces the membership of T. sanguinis in the gut microbiota of conventionally colonized mice. Host association with T. sanguinis alters intestinal expression of multiple gene pathways, including those important for lipid and steroid metabolism, with corresponding reductions in host systemic triglyceride levels and inguinal adipocyte size. Together, these findings support the notion that select bacteria indigenous to the gut microbiota signal bidirectionally with the host serotonergic system to promote their fitness in the intestine.

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UR - https://www.scopus.com/pages/publications/85072113647#tab=citedBy

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JO - Nature Microbiology

JF - Nature Microbiology

IS - 12

ER -

Intestinal serotonin and fluoxetine exposure modulate bacterial colonization in the gut

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