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.
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The 16S rRNA sequence and genome data for KLE1738 are available from the NCBI (MH636586 and PRJNA482656, respectively). The American Gut sequence data are available from the EBI under accession ERP012803. fMRI data are available at the discretion of M.J.D. All other data that support the findings of this study are available from the corresponding author upon request.
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The authors would like to thank S. Rubin for help with the cultivation of KLE1738, and J. Wang of the Small Molecule Mass Spectrometry Facility, a Harvard Faculty of Arts and Science (FAS) Division of Science Core Facility, for analysing the GC/MS samples. This work was supported by grants R01HG005824 to K.L., R01GM086158 to J.C. and F32GM108415 to T.R.R.
P.S. and K.L. declare competing financial interests as they are founders of Holobiome, Inc. All other authors have no competing interests.
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Strandwitz, P., Kim, K.H., Terekhova, D. et al. GABA-modulating bacteria of the human gut microbiota. Nat Microbiol 4, 396–403 (2019). https://doi.org/10.1038/s41564-018-0307-3
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