Prof. Ki Hyun KIM (School of Pharmacy) and his co-researchers in Northeastern University and Harvard Medical School have recently published a significant article, titled “GABA-modulating bacteria of the human gut microbiota” in the world-renowned international journal, Nature Microbiology (Impact Factor 14.174).
□ The gut microbiota affects many important host functions, including the immune response and the nerve system. However, while substantial progress has been made in growing diverse microorganisms of the microbiota, 23–65% of species residing in the human gut remain uncultured, which is an obstacle for understanding their biological roles. A likely reason for this unculturation is the absence in artificial medium of key growth factors that are provided by neighbouring bacteria in situ.
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). Surprisingly, 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 diseases associated with depression.
The research is evaluated to be the first case of integrated research between human gut microorganism cultivation and natural product chemistry. It is expected to propose potential in the development of new therapeutic and preventive agents to treat depression using GABA-modulating bacteria.
*Thesis title: GABA-modulating bacteria of the human gut microbiota, Nature Microbiology, 4, 396–403 (2019) (doi.org/10.1038/s41564-018-0307-3).