Editors' ChoiceMicrobiome

“Yabba-GABA-Doo”: Meet the microbiome

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Science Translational Medicine  02 Jan 2019:
Vol. 11, Issue 473, eaaw0528
DOI: 10.1126/scitranslmed.aaw0528

Abstract

The microbiome is an important regulator of GABA, which has implications for major depressive disorder.

The human microbiome has been linked to neurologic diseases, such as Parkinson’s disease and depression, but little is known about the mechanisms through which microbes might elicit these phenotypes. In a recent manuscript, Strandwitz et al. studied the biosynthesis and metabolism of the neurotransmitter γ-aminobutyric acid (GABA) by human gut microbiota. To identify GABA-active bacteria, the authors plated human fecal samples on rich agar and identified colonies with delayed growth, reflecting a dependence on metabolites produced by neighboring bacteria. The authors then screened “late-growers” for dependency on individual microbes and identified an organism (KLE1738) that required Bacteroides fragilis for growth. Using 16S sequencing, KLE1738 was identified as a member of the Ruminococcaceae family and the first cultured representative of its genus.

Bioassay-guided fractionation of B. fragilis supernatant showed GABA was the metabolite required for in vitro growth of KLE1738. Genome analysis of KLE1738 metabolic pathways confirmed the loss of a key enzyme required for the metabolism of typical sugars, explaining the nutrient dependence of KLE1738 on GABA, which was further confirmed by attempts to grow KLE1738 using other carbon sources and radiolabeled GABA. KLE1738 was then used as a reporter organism to identify other bacteria capable of synthesizing GABA, as inferred by growth of KLE1738 in coculture.

Using their set of GABA-active organisms and genes, the authors queried metagenomic databases to curate a larger set of related microbes and genetic pathways associated with GABA biosynthesis or degradation. This set was then used to interrogate a cohort of 23 patients with major depressive disorder to identify whether GABA-active microbes were associated with changes on functional magnetic resonance imaging. The relative abundance of GABA-active organisms was found to be inversely correlated with functional changes in the default mode network, an area of the brain implicated in depression.

With this study, we can now move from correlative studies of the microbiome in depression and suggest discrete mechanisms through which bacteria can elicit changes in neurologic function. Future studies will need to assess if and how GABA-active microbes modulate phenotypes in model systems as a prelude to human studies in patients with depression. Similarly, it will need to be determined how alterations in GABA production in the intestine might translate into functional changes in the brain.

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