The DOI matches its Crossref record; 55 of the 55 references it cites were found in a registry or an index.
GABA-modulating bacteria of the human gut microbiota
Open accessAbstract
The gut microbiota affects many important host functions, including the immune response and the nervous system1. However, while substantial progress has been made in growing diverse microorganisms of the microbiota2, 23–65% of species residing in the human gut remain uncultured3,4, which is an obstacle for understanding their biological roles. A likely reason for this unculturability is the absence in artificial media of key growth factors that are provided by neighbouring bacteria in situ5,6. In the present study, we used co-culture to isolate KLE1738, which required the presence of Bacteroides fragilis to grow. Bioassay-driven purification of B. fragilis supernatant led to the isolation of the growth factor, which, surprisingly, is the major inhibitory neurotransmitter GABA (γ-aminobutyric acid). GABA was the only tested nutrient that supported the growth of KLE1738, and a genome analysis supported a GABA-dependent metabolism mechanism. Using growth of KLE1738 as an indicator, we isolated a variety of GABA-producing bacteria, and found that Bacteroides ssp. produced large quantities of GABA. Genome-based metabolic modelling of the human gut microbiota revealed multiple genera with the predicted capability to produce or consume GABA. A transcriptome analysis of human stool samples from healthy individuals showed that GABA-producing pathways are actively expressed by Bacteroides, Parabacteroides and Escherichia species. By coupling 16S ribosmal RNA sequencing with functional magentic resonance imaging in patients with major depressive disorder, a disease associated with an altered GABA-mediated response, we found that the relative abundance levels of faecal Bacteroides are negatively correlated with brain signatures associated with depression. A bacterial strain that requires the neurotransmitter GABA for growth was identified and used to isolate GABA-producing bacteria, including Bacteroides spp., from human stool samples; the relative abundance of Bacteroides was negatively correlated with an altered GABA-mediated response in a depression patient cohort.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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 [37]
In the citing paper
“The GM can metabolize GABA and recent research has shown that certain microbes can produce GABA, required for their growth (235).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [235]
In the citing paper
“Furthermore, abundances of faecal GABA-producers, such as Bacteroides, correlate negatively with brain signatures associated with depression [77].”
From Distinct actions of the fermented beverage kefir on host behaviour, immunity and microbiome gut-brain modules in the mouse (2020) · cites this paper as [77]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
QIIME allows analysis of high-throughput community sequencing data
Caporaso, J. G., Kuczynski, J., Stombaugh, J., Bittinger, K., Bushman, F. D., Costello, E. K., Fierer, N., Peña, A. G., Goodrich, J. K., Gordon, J. I., et al. (2010) · Nature Methods · doi:10.1038/nmeth.f.303 · Cited by 34,887
Self-citationHamilton, M. (1960) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.23.1.56 · Cited by 32,817
RAxML version 8: a tool for phylogenetic analysis and post-analysis of large phylogenies
Stamatakis, A. (2014) · Bioinformatics · doi:10.1093/bioinformatics/btu033 · Cited by 32,291
KEGG: Kyoto Encyclopedia of Genes and Genomes
Ogata, H., Goto, S., Sato, K., Fujibuchi, W., Bono, H., & Kanehisa, M. (1999) · Nucleic Acids Research · doi:10.1093/nar/27.1.29 · Cited by 31,232
Prodigal: prokaryotic gene recognition and translation initiation site identification
Hyatt, D., Chen, G.-L., LoCascio, P. F., Land, M., Larimer, F. W., & Hauser, L. (2010) · BMC Bioinformatics · doi:10.1186/1471-2105-11-119 · Cited by 12,692
The RAST Server: Rapid Annotations using Subsystems Technology
Aziz, R. K., Bartels, D., Best, A. A., DeJongh, M., Disz, T. L., Edwards, R. A., Formsma, K., Gerdes, S., Glass, E. M., Kubal, M., et al. (2008) · BMC Genomics · doi:10.1186/1471-2164-9-75 · Cited by 11,893
Haas, B. J., Papanicolaou, A., Yassour, M., Grabherr, M., Blood, P. D., Bowden, J., Couger, M. B., Eccles, D., Li, B., Lieber, M., et al. (2013) · Nature Protocols · doi:10.1038/nprot.2013.084 · Cited by 8,464
Functional connectivity in the resting brain: a network analysis of the default mode hypothesis
Greicius, M. D., Krasnow, B., Reiss, A. L., & Menon, V. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0135058100 · Cited by 6,358
UniProt: a hub for protein information
The UniProt Consortium (2015) · Nucleic Acids Research · doi:10.1093/nar/gku989 · Cited by 5,106
Bravo, J. A., Forsythe, P., Chew, M. V., Escaravage, E., Savignac, H. M., Dinan, T. G., Bienenstock, J., & Cryan, J. F. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1102999108 · Cited by 3,888
Yarza, P., Yilmaz, P., Pruesse, E., Glöckner, F. O., Ludwig, W., SCHLEIFER, K. H., Whitman, W. B., Euzéby, J. P., Amann, R., & Rossello-Mora, R. A. (2014) · Nature Reviews Microbiology · doi:10.1038/nrmicro3330 · Cited by 2,651
Greicius, M. D., Flores, B. H., Menon, V., Glover, G. H., Solvason, H. B., Kenna, H., Reiss, A. L., & Schatzberg, A. F. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.09.020 · Cited by 2,214
Interactions between the microbiota, immune and nervous systems in health and disease
Fung, T. C., Olson, C. A., & Hsiao, E. Y. (2017) · Nature Neuroscience · doi:10.1038/nn.4476 · Cited by 1,900
Deblur Rapidly Resolves Single-Nucleotide Community Sequence Patterns
Amir, A., McDonald, D., Navas-Molina, J. A., Kopylova, E., Morton, J. T., Zech Xu, Z., Kightley, E. P., Thompson, L. R., Hyde, E. R., Gonzalez, A., et al. (2017) · mSystems · doi:10.1128/msystems.00191-16 · Cited by 1,881
Self-citationDecoding subject-driven cognitive states with whole-brain connectivity patterns
Shirer, W. R., Ryali, S., Rykhlevskaia, E., Menon, V., & Greicius, M. D. (2012) · Cerebral Cortex · doi:10.1093/cercor/bhr099 · Cited by 1,843
Prefrontal-Subcortical Pathways Mediating Successful Emotion Regulation
Wager, T. D., Davidson, M. L., Hughes, B. L., Lindquist, M. A., & Ochsner, K. N. (2008) · Neuron · doi:10.1016/j.neuron.2008.09.006 · Cited by 1,761
Improvements to PATRIC, the all-bacterial Bioinformatics Database and Analysis Resource Center
Wattam, A. R., Davis, J. J., Assaf, R., Boisvert, S., Brettin, T. S., Bun, C., Conrad, N. R., Dietrich, E. M., Disz, T. L., Gabbard, J. L., et al. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw1017 · Cited by 1,635
KBase: The United States Department of Energy Systems Biology Knowledgebase
(2018) · doi:10.1038/nbt.4163 · Cited by 1,624
The default mode network and self-referential processes in depression
Sheline, Y. I., Barch, D. M., Price, J. L., Rundle, M. M., Vaishnavi, S. N., Snyder, A. Z., Mintun, M. A., Wang, S., Coalson, R. S., & Raichle, M. E. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0812686106 · Cited by 1,480
Deutscher, J., Francke, C., & Postma, P. W. (2006) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00024-06 · Cited by 1,411
Kitagawa, M., Ara, T., Arifuzzaman, M., Ioka-Nakamichi, T., Inamoto, E., Toyonaga, H., & Mori, H. (2006) · DNA Research · doi:10.1093/dnares/dsi012 · Cited by 1,388
Culturing of ‘unculturable’ human microbiota reveals novel taxa and extensive sporulation
Browne, H. P., Forster, S. C., Anonye, B. O., Kumar, N., Neville, B. A., Stares, M. D., Goulding, D., & Lawley, T. D. (2016) · Nature · doi:10.1038/nature17645 · Cited by 1,299
γ-Aminobutyric acid production by culturable bacteria from the human intestine
Barrett, E., Ross, R. P., O'Toole, P. W., Fitzgerald, G. F., & Stanton, C. (2012) · Journal of Applied Microbiology · doi:10.1111/j.1365-2672.2012.05344.x · Cited by 1,156
Depression: Perspectives from Affective Neuroscience
Davidson, R. J., Pizzagalli, D., Nitschke, J. B., & Putnam, K. (2002) · Annual Review of Psychology · doi:10.1146/annurev.psych.53.100901.135148 · Cited by 1,138
Kootte, R. S., Levin, E., Salojärvi, J., Smits, L. P., Hartstra, A. V., Udayappan, S. D., Hermes, G., Bouter, K. E., Koopen, A. M., Holst, J. J., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.09.008 · Cited by 1,039
The GABAergic deficit hypothesis of major depressive disorder
Luscher, B., Shen, Q., & Sahir, N. (2011) · Molecular Psychiatry · doi:10.1038/mp.2010.120 · Cited by 934
American Gut: an Open Platform for Citizen-Science Microbiome Research
McDonalda, D., Hyde, E., Debelius, J. W., Morton, J. T., Gonzalez, A., Ackermann, G., Aksenov, A. A., Behsaz, B., Brennan, C., Chen, Y., et al. (2018) · doi:10.1101/277970 · Cited by 878
Self-citationLagier, J., Hugon, P., Khelaifia, S., Fournier, P., Scola, B. L., & Raoult, D. (2015) · Clinical Microbiology Reviews · doi:10.1128/cmr.00014-14 · Cited by 876
Goodman, A. L., Kallstrom, G., Faith, J. J., Reyes, A., Moore, A. M., Dantas, G. A., & Gordon, J. I. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1102938108 · Cited by 781
Anterior Prefrontal Function and the Limits of Human Decision-Making
Koechlin, É., & Hyafil, A. (2007) · Science · doi:10.1126/science.1142995 · Cited by 776
Default mode network mechanisms of transcranial magnetic stimulation in depression
Liston, C., Chen, A. C., Zebley, B. D., Drysdale, A. T., Gordon, R., Leuchter, B., Voss, H. U., Casey, B. J., Etkin, A., & Dubin, M. J. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.01.023 · Cited by 763
Self-citationIntraluminal pH of the human gastrointestinal tract.
Fallingborg, J. (1999) · PubMed · Cited by 630
Lagkouvardos, I., Joseph, D., Kapfhammer, M., Giritli, S., Horn, M., Haller, D., & Clavel, T. (2016) · Scientific Reports · doi:10.1038/srep33721 · Cited by 507
Chang, C., & Glover, G. H. (2009) · NeuroImage · doi:10.1016/j.neuroimage.2009.05.012 · Cited by 503
Siderophores from Neighboring Organisms Promote the Growth of Uncultured Bacteria
Donofrio, A. E., Crawford, J. M., Stewart, E. J., Witt, K., Gavrish, E., Epstein, S. S., Clardy, J., & Lewis, K. (2010) · Chemistry & Biology · doi:10.1016/j.chembiol.2010.02.010 · Cited by 457
Self-citationRole of glutamate metabolism in bacterial responses towards acid and other stresses
Feehily, C., & Karatzas, K. A. G. (2012) · Journal of Applied Microbiology · doi:10.1111/j.1365-2672.2012.05434.x · Cited by 457
GABA ‐producing Bifidobacterium dentium modulates visceral sensitivity in the intestine
Pokusaeva, K., Johnson, C., Luk, B., Uribe, G., Fu, Y., Oezguen, N., Matsunami, R. K., Lugo, M., Major, A., Mori‐Akiyama, Y., et al. (2017) · Neurogastroenterology & Motility · doi:10.1111/nmo.12904 · Cited by 337
Janik, R., Thomason, L. A. M., Stanisz, A. M., Forsythe, P., Bienenstock, J., & Stanisz, G. J. (2016) · NeuroImage · doi:10.1016/j.neuroimage.2015.11.018 · Cited by 283
The Kyoto Encyclopedia of Genes and Genomes—KEGG
Wixon, J., & Kell, D. B. (2000) · Yeast · doi:10.1002/(sici)1097-0061(200004)17:1 · Cited by 278
Diet, genetics, and the gut microbiome drive dynamic changes in plasma metabolites
Fujisaka, S., Avila-Pacheco, J., Soto, M., Kostic, A., Dreyfuss, J. M., Pan, H., Ussar, S., Altindis, E., Li, N., Bry, L., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.02.060 · Cited by 231
Tillisch, K., Mayer, E. A., Gupta, A., Gill, Z., Brazeilles, R., Le Nevé, B., van Hylckama Vlieg, J. E. T., Guyonnet, D., Derrien, M., & Labus, J. S. (2017) · Psychosomatic Medicine · doi:10.1097/psy.0000000000000493 · Cited by 185
Hassan, A. M., Mancano, G., Kashofer, K., Fröhlich, E. E., Matak, A., Mayerhofer, R., Reichmann, F., Olivares, M., Neyrinck, A. M., Delzenne, N. M., et al. (2019) · Nutritional Neuroscience · doi:10.1080/1028415x.2018.1465713 · Cited by 166
The “Most Wanted” Taxa from the Human Microbiome for Whole Genome Sequencing
Fodor, A. A., DeSantis, T. Z., Wylie, K. M., Badger, J. H., Ye, Y., Hepburn, T. A., Hu, P., Sodergren, E. J., Liolios, K., Huot, H., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0041294 · Cited by 134
Carlier, J.-P., Bedora-Faure, M., K'ouas, G., Alauzet, C., & Mory, F. (2009) · INTERNATIONAL JOURNAL OF SYSTEMATIC AND EVOLUTIONARY MICROBIOLOGY · doi:10.1099/ijs.0.016725-0 · Cited by 128
Kläring, K., Hanske, L., Bui, T. P. N., Charrier, C., Blaut, M., Haller, D., Plugge, C. M., & Clavel, T. (2013) · INTERNATIONAL JOURNAL OF SYSTEMATIC AND EVOLUTIONARY MICROBIOLOGY · doi:10.1099/ijs.0.051441-0 · Cited by 127
Wixon, J. (2000) · Yeast · doi:10.1002/1097-0061(20000930)17:3 · Cited by 125
Quinones are growth factors for the human gut microbiota
Fenn, K., Strandwitz, P., Stewart, E. J., Dimise, E. J., Rubin, S., Gurubacharya, S., Clardy, J., & Lewis, K. (2017) · Microbiome · doi:10.1186/s40168-017-0380-5 · Cited by 108
Self-citationCultured microbes represent a substantial fraction of the human and mouse gut microbiota
Lagkouvardos, I., Overmann, J., & Clavel, T. (2017) · Gut Microbes · doi:10.1080/19490976.2017.1320468 · Cited by 104
Correcting for Microbial Blooms in Fecal Samples during Room-Temperature Shipping
Amir, A., McDonald, D. T., Navas-Molina, J. A., Debelius, J. W., Morton, J. T., Hyde, E. R., Robbins‐Pianka, A., & Knight, R. D. (2017) · mSystems · doi:10.1128/msystems.00199-16 · Cited by 98
Self-citationSubmerged fermentation of Lactobacillus rhamnosus YS9 for γ-aminobutyric acid (GABA) production
Lin, Q. (2013) · Brazilian Journal of Microbiology · doi:10.1590/s1517-83822013000100028 · Cited by 81
Matsumoto, M., Ooga, T., Kibe, R., Aiba, Y., Koga, Y., & Benno, Y. (2017) · PLoS ONE · doi:10.1371/journal.pone.0169207 · Cited by 80
Hardman, J. K., & Stadtman, T. C. (1960) · Journal of Bacteriology · doi:10.1128/jb.79.4.544-548.1960 · Cited by 60
Ni, Y., Li, J., & Panagiotou, G. (2015) · mBio · doi:10.1128/mbio.01263-15 · Cited by 39
γ-Aminobutyric acid production in small and large intestine of normal and germfree Wistar rats
van Berlo, C. L. H., de Jonge, H. R., van den Bogaard, A. E. J. M., van Eijk, H. M. H., Janssen, M., & Soeters, P. B. (1987) · Gastroenterology · doi:10.1016/0016-5085(87)90908-5 · Cited by 24
Measurement of Taxonomic Criteria [ Abridged ]
Sneath, P. H. A. (1972) · Proceedings of the Royal Society of Medicine · doi:10.1177/003591577206501017 · Cited by 3
Research works printed but not linked: 1
- Sneath, P. H. Principles of bacterial taxonomy. Proc. R. Soc. Med. 65, 851–852 (1972).
Cited by
Sorted by citations
Cryan, J. F., O'Riordan, K. J., Cowan, C. S. M., Sandhu, K. V., Bastiaanssen, T. F. S., Boehme, M., Codagnone, M. G., Cussotto, S., Fulling, C., Golubeva, A. V., et al. (2019) · Physiological Reviews · doi:10.1152/physrev.00018.2018 · Cited by 5,286
The gut microbiota–brain axis in behaviour and brain disorders
Morais, L. H., Schreiber, H. L., & Mazmanian, S. K. (2021) · Nature Reviews Microbiology · doi:10.1038/s41579-020-00460-0 · Cited by 2,149
Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
Loh, J. S., Mak, W. Q., Tan, L. K. S., Ng, C. X., Chan, H. H., Yeow, S. H., Foo, J. B., Ong, Y. S., How, C. W., & Khaw, K. Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01743-1 · Cited by 1,193
Chen, Y., Xu, J., & Chen, Y. (2021) · Nutrients · doi:10.3390/nu13062099 · Cited by 917
“Besides short-chain fatty acids and bile acids, recent studies show that the metabolites produced by the gut microbiota also include some neurotransmitters such as glutamate, GABA, serotonin, and dopamine [19,29,32].”
BackgroundInfluentialFord, A. C., Mahadeva, S., Carbone, F., Lacy, B. E., & Talley, N. J. (2020) · The Lancet · doi:10.1016/s0140-6736(20)30469-4 · Cited by 587
Metadata
- Authors
- Strandwitz, P., Kim, K. H., Terekhova, D., Liu, J. K., Sharma, A., Levering, J., McDonald, D., Dietrich, D., Ramadhar, T. R., Lekbua, A., Mroue, N., Liston, C., Stewart, E. J., Dubin, M. J., Zengler, K., Knight, R., Gilbert, J. A., Clardy, J., & Lewis, K.
- Affiliations
- Northeastern University (US)
- Harvard University (US)
- Weill Cornell Medicine (US)
- University of California San Diego (US)
- Argonne National Laboratory (US)
- Corresponding author
- Strandwitz, Philip
- Lewis, Kim
- ORCID
- Venue
- Nature Microbiology
- Published
- 2018-12-10
- Volume
- 4
- Issue
- 3
- Pages
- 396-403
- ISSN
- 2058-5276 (ISSN-L)
- PMC
- PMC6384127
- OpenAlex
- W2902161130
- Semantic Scholar
- e557d4ef36b36019dcd3ba0973119440d4426bca
- Cited by
- 1,170
- References
- 55
- Citations by year
- 2026: 153 · 2025: 187 · 2024: 225 · 2023: 176 · 2022: 141 · 2021: 131 · 2020: 110 · 2019: 46
- FWCI
- 26.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Microbiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health
- Faculty of Arts and Sciences
- National Human Genome Research Institute (R01HG005824)
- National Institute of General Medical Sciences (F32GM108415)
- National Institute of Allergy and Infectious Diseases (R01AI122286)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
- Life Sciences › Agricultural and Biological Sciences › Plant Science › GABA and Rice Research
- Keywords
- GABA, gut microbiota, Bacteroides, GABA-producing bacteria, bacterial growth factors, co-culture, Bacteroides fragilis, Parabacteroides, Escherichia, major depressive disorder, functional MRI, neurotransmitter metabolism, uncultured bacteria
- MeSH terms
- Gastrointestinal Microbiome, Whole Genome Sequencing, Adult, Aged, Bacteria, Bacteroides, Brain, Depression, Depressive Disorder, Major, Major Depressive Disorder, Feces, Female, gamma-Aminobutyric Acid, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Cohort Studies, Gene Expression Profiling, Gastrointestinal Tract, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
