Abstract
BackgroundOf the many neurotransmitters in humans, gamma-aminobutyric acid (GABA) shows potential for improving several mental health indications such as stress and anxiety. The microbiota-gut-brain axis is an important pathway for GABAergic effects, as microbially-secreted GABA within the gut can affect host mental health outcomes. Understanding the molecular characteristics of GABA production by microbes within the gut can offer insight to novel therapies for mental health.ResultsThree strains of Levilactobacillus brevis with syntenous glutamate decarboxylase (GAD) operons were evaluated for overall growth, glutamate utilization, and GABA production in typical synthetic growth media supplemented with monosodium glutamate (MSG). Levilactobacillus brevis Lbr-6108™ (Lbr-6108), formerly known as L. brevis DPC 6108, and Levilactobacillus brevis Lbr-35 ™ (Lbr-35) had similar growth profiles but differed significantly in GABA secretion and acid resistance. Lbr-6108 produced GABA early within the growth phase and produced significantly more GABA than Lbr-35 and the type strain Levilactobacillus brevis ATCC 14869 after the stationary phase. The global gene expression during GABA production at several timepoints was determined by RNA sequencing. The GAD operon, responsible for GABA production and secretion, activated in Lbr-6108 after only 6 h of fermentation and continued throughout the stationary phase. Furthermore, Lbr-6108 activated many different acid resistance mechanisms concurrently, which contribute to acid tolerance and energy production. In contrast, Lbr-35, which has a genetically similar GAD operon, including two copies of the GAD gene, showed no upregulation of the GAD operon, even when cultured with MSG.ConclusionsThis study is the first to evaluate whole transcriptome changes in Levilactobacillus brevis during GABA production in different growth phases. The concurrent expression of multiple acid-resistance mechanisms reveals niche-specific metabolic functionality between common human commensals and highlights the complex regulation of GABA metabolism in this important microbial species. Furthermore, the increased and rapid GABA production of Lbr-6108 highlights the strain’s potential as a therapeutic and the overall value of screening microbes for effector molecule output.
Highlights
Of the many neurotransmitters in humans, gamma-aminobutyric acid (GABA) shows potential for improving several mental health indications such as stress and anxiety
In lactic acid bacteria (LAB), gamma-aminobutyric acid (GABA) is produced by glutamate decarboxylation encoded by the glutamate decarboxylase or glutamic acid decarboxylase (GAD) operon
The GAD operon consists of three important elements responsible for GABA secretion in bacteria: the positive transcriptional regulator encoded by GAD operon together with transcriptional regulator (gadR) gene, the glutamate/GABA antiporter encoded by gadC gene, and the glutamate decarboxylase enzyme encoded either by gadA or gadB genes [2, 3]
Summary
Of the many neurotransmitters in humans, gamma-aminobutyric acid (GABA) shows potential for improving several mental health indications such as stress and anxiety. In lactic acid bacteria (LAB), gamma-aminobutyric acid (GABA) is produced by glutamate decarboxylation encoded by the glutamate decarboxylase or glutamic acid decarboxylase (GAD) operon. The GAD operon consists of three important elements responsible for GABA secretion in bacteria: the positive transcriptional regulator encoded by gadR gene, the glutamate/GABA antiporter encoded by gadC gene, and the glutamate decarboxylase enzyme encoded either by gadA or gadB genes [2, 3]. While most GAD systems in LAB have one GABA producing gad (A or B) gene, Levilactobacillus brevis is the only known species that encodes two biochemically identical isoforms of the GAD enzyme [3, 4]. The GAD operon includes gadR, which positively regulates GABA production in a glutamate-dependent manner and is essential for GABA conversion from glutamate [5]
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