Intestinal serotonin and fluoxetine exposure modulate bacterial colonization in the gut


The gut microbiota regulates levels of serotonin (5-hydroxytryptamine (5-HT)) in the intestinal epithelium and lumen1,2,3,4,5. 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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Fig. 1: Elevating intestinal 5-HT enriches spore-forming bacteria in the gut.
Fig. 2: T. sanguinis takes up 5-HT, which is inhibited by the SSRI fluoxetine.
Fig. 3: 5-HT and the SSRI fluoxetine regulate gene expression and intestinal colonization of T. sanguinis.
Fig. 4: T. sanguinis colonization regulates host lipid metabolism.

Data availability

Data generated or analysed during this study are included in this published article and its Supplementary Information files. Structural modelling files that support the findings of this study are available from Zenodo with the identifier 10.5281/zenodo.3266444. The 16S rDNA sequencing data that support the findings of this study are available from the Qiita database with study IDs 12585, 12596 and 12597, and are also available in the Supplementary Tables. Bacterial transcriptomic data that support the findings of this study are available in Gene Expression Omnibus repository with the accession number GSE133810 and are also available in the Supplementary Tables. Intestinal transcriptomic data that support the findings of this study are available in the Gene Expression Omnibus repository with the accession number GSE133809 and are also available in the Supplementary Tables.


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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.

Author information

T.C.F. performed the bacteriology, sequencing experiments and data analysis. C.D.G.L. and A.V. assisted with the bacteriology experiments. T.C.F., H.E.V. and G.N.P. performed the mouse experiments. A.A.A., N.G.R. and L.R.F. performed the structural modelling. J.M. and T.R. generated the gnotobiotic mice. L.R.F. and E.Y.H. contributed to the data analysis. T.C.F., L.R.F. and E.Y.H. supervised the study. T.C.F. and E.Y.H. wrote the manuscript. All authors reviewed and edited the final version of the text.

Correspondence to Thomas C. Fung or Elaine Y. Hsiao.

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Competing interests

The authors declare no competing interests. Findings regarding the host effect of T. sanguinis reported in the manuscript are the subject of a provisional patent application (US 62/815,760), owned by UCLA.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–19.

Reporting Summary

Supplementary Tables

Supplementary Tables 1–11.

Supplementary Dataset 1

Protein structural model of CUW_0748 from T. sanguinis MOL361, based on the available structure of human SERT (Protein Data Bank entry 5i6x chain A).

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