Human-Derived Bifidobacterium dentium Modulates the Mammalian Serotonergic System and Gut–Brain Axis
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BACKGROUND & AIMS: The human gut microbiota can regulate production of serotonin (5-hydroxytryptamine [5-HT]) from enterochromaffin cells. However, the mechanisms underlying microbial-induced serotonin signaling are not well understood. METHODS: Adult germ-free mice were treated with sterile media, live Bifidobacterium dentium, heat-killed B dentium, or live Bacteroides ovatus. Mouse and human enteroids were used to assess the effects of B dentium metabolites on 5-HT release from enterochromaffin cells. In vitro and in vivo short-chain fatty acids and 5-HT levels were assessed by mass spectrometry. Expression of tryptophan hydroxylase, short-chain fatty acid receptor free fatty acid receptor 2, 5-HT receptors, and the 5-HT re-uptake transporter (serotonin transporter) were assessed by quantitative polymerase chain reaction and immunostaining. RNA in situ hybridization assessed 5-HT-receptor expression in the brain, and 5-HT-receptor-dependent behavior was evaluated using the marble burying test. RESULTS: B dentium mono-associated mice showed increased fecal acetate. This finding corresponded with increased intestinal 5-HT concentrations and increased expression of 5-HT receptors 2a, 4, and serotonin transporter. These effects were absent in B ovatus-treated mice. Application of acetate and B dentium-secreted products stimulated 5-HT release in mouse and human enteroids. In situ hybridization of brain tissue also showed significantly increased hippocampal expression of 5-HT-receptor 2a in B dentium-treated mice relative to germ-free controls. Functionally, B dentium colonization normalized species-typical repetitive and anxiety-like behaviors previously shown to be linked to 5-HT-receptor 2a. CONCLUSIONS: These data suggest that B dentium, and the bacterial metabolite acetate, are capable of regulating key components of the serotonergic system in multiple host tissues, and are associated with a functional change in adult behavior.
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Gut microbiota is capable of producing or stimulating the production of neurotransmitters, including serotonin, dopamine, and γ-aminobutyric acid (GABA).
“Studies have shown that gut microbiota is capable of producing or stimulating the production of neurotransmitters, including serotonin,33–35 dopamine,36 and γ-aminobutyric acid (GABA).37”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [35]
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References 156 · Cited by 164
- Authors
- Engevik, M. A., Luck, B., Visuthranukul, C., Ihekweazu, F. D., Engevik, A. C., Shi, Z., Danhof, H. A., Chang-Graham, A. L., Hall, A., Endres, B. T., Haidacher, S. J., Horvath, T. D., Haag, A. M., Devaraj, S., Garey, K. W., Britton, R. A., Hyser, J. M., Shroyer, N. F., & Versalovic, J.
- Affiliations
- Baylor College of Medicine (US)
- Chulalongkorn University (TH)
- Vanderbilt University Medical Center (US)
- University of Houston (US)
- Corresponding author
- Versalovic, James
- ORCID
- Venue
- Cellular and Molecular Gastroenterology and Hepatology
- Publisher
- Elsevier BV
- Published
- 2021
- Volume
- 11
- Issue
- 1
- Pages
- 221-248
- ISSN
- 2352-345X (ISSN-L)
- PMC
- PMC7683275
- OpenAlex
- W3048590350
- Cited by
- 164
- References
- 156
- Citations by year
- 2026: 23 · 2025: 34 · 2024: 29 · 2023: 26 · 2022: 32 · 2021: 18 · 2020: 1 · 2017: 1
- FWCI
- 6.25
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cellular and Molecular Gastroenterology and Hepatology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of Allergy and Infectious Diseases
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
- Keywords
- Bifidobacterium dentium, gut microbiota, serotonin, serotonergic system, gut-brain axis, enterochromaffin cells, acetate, short-chain fatty acids, tryptophan hydroxylase, 5-HT2A receptor, serotonin transporter, Bacteroides ovatus, anxiety-like behavior, repetitive behavior, hippocampus, enteroids, germ-free mice
- MeSH terms
- Gastrointestinal Microbiome, Host Microbial Interactions, Acetates, Brain-Gut Axis, Animals, Behavior, Animal, Bifidobacterium, Enterochromaffin Cells, Germ-Free Life, Humans, Intestinal Mucosa, Organoids, Receptors, Serotonin, Serotonin, Cell Culture Techniques, Models, Animal, Mice
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