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Nat Microbiol. 2018 Dec 10. doi: 10.1038/s41564-018-0307-3. [Epub ahead of print]

GABA-modulating bacteria of the human gut microbiota.

Author information

1
Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA, USA. p.strandwitz@northeastern.edu.
2
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
3
School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
4
Department of Psychiatry and Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, USA.
5
Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, CA, USA.
6
Department of Surgery, University of Chicago, Chicago, IL, USA.
7
Biosciences Division (BIO), Argonne National Laboratory, Argonne, IL, USA.
8
Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA.
9
Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
10
Department of Chemistry, Howard University, Washington, DC, USA.
11
Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA, USA.
12
Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA, USA.
13
Marine Biological Laboratory, Woods Hole, MA, USA.
14
Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA, USA. k.lewis@neu.edu.

Abstract

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.

PMID:
30531975
DOI:
10.1038/s41564-018-0307-3

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