From the gut to the brain, mechanisms and clinical applications of γ-aminobutyric acid (GABA) on the treatment of anxiety and insomnia

Abstract

Anxiety and insomnia are prevalent global mood disorders, and affect approximately 4 and 10 out of every 100 individuals, respectively. Common abnormal brain activity and altered neural circuitries are detected in patients with anxiety disorders and insomnia, suggesting overlapping pathogenesis in these two disorders. Promisingly, GABA from dietary supplements and GABA produced by gut microbiota have shown significant treatment effects in anxiety and insomnia. This review summarizes neurological mechanisms causing anxiety and insomnia, reveals cellular pathways transferring GABA from the gut to the brain, and delivers the therapeutic potential of gut derived GABA for anxiety and insomnia. Moreover, this review proposes emerging therapeutic strategies utilizing engineered GABA-producing bacteria to target anxiety and insomnia, and highlights the potential of live biotherapeutics as novel interventions for mood disorders.

Keywords: GABA; anxiety; genetic engineered bacteria; gut microbiota; insomnia; probiotics.

Figure 1

Structure and production of GABA. (A) The production diagram of GABA. With the assistance of pyridoxal phosphate, the glutamate decarboxylase (GAD) enzyme is transformed into an active structure and then converts L-Glu into GABA. L-Glu, GABA, and Pyridoxal phosphate are illustrated by PubChem. White ball: the hydrogen atom; red ball: the oxygen atom; gray ball: the carbon atom; blue ball: the nitrogen atom; yellow ball: the phosphorus atom. (B) The diagram of GABA’s production by gut microbiota. The genome of many bacteria carries the gadB and gadC genes. The gadB is a type of GAD in (A), and functions in the same manner as GAD. GABA produced by gadB can be transported extracellularly through gadC. Meanwhile, the raw material L-Glu can also enter the cell through gadC, and this process can consume H⁺ ions outside the environment.

Figure 2

Diagram of GABA receptors’ workflow and GABA’s conversion balance. (A) GABA_A receptors’ workflow and the balance among GABA, glutamine and glutamate. GABA neurons can convert the absorbed glutamine into glutamate, and then into GABA. Subsequently, GABA is excreted and acts on the next neuron. Upon the binding of GABA to the GABA_A receptor, it prompts the opening of chloride ion channels within the receptor, thereby giving rise to either the inward or outward flow of chloride ions. The predominant direction of movement is the inward flow. (B) GABA_B receptors’ workflow. GABA_B receptors are capable of anchoring to Ca²⁺ and K⁺ channels on the cell membrane. Through the dynamic modulation of the closure of these ion channels, it restricts the influx of Ca²⁺ and augments the influx of K⁺, thereby attaining an inhibitory hyperpolarized state of the membrane potential.

Figure 3

The mechanism of gut derived GABA on human body. Two sources gut derived GABA: one is obtained through direct oral intake or via food, and the other is generated by the gut microbiota. Subsequently, GABA will directly act on the gut microbiota and have a direct impact on its metabolism. A significant portion will also be absorbed by the gut, enter the bloodstream, or act on enteric neurons and the vagus nerve. GABA that acts on the enteric nerves and vagus nerve can be transmitted through neural signals and affect the brain. GABA that enters the bloodstream may eventually interact with the brain by crossing the blood–brain barrier.

Figure 4

Exogenous GABA intestinal absorption pathway. (A) GABA intestinal absorption diagram: Initially, GABA is taken up by intestinal epithelial cells. Then, it diverges into three pathways: bloodstream entry, interaction with enteric neurons, and connection with the vagus nerve. (B) GABA intestinal transport: GABA crosses the small intestine membrane via the PAT protein on the basolateral side and exits through a probable SLC family protein on the apical side. (C) GABA integrates into the blood circulation: GABA penetrates the fenestrated capillaries within the intestinal lining to join the bloodstream. (D) GABA binds to receptors: GABA interacts with GABA receptors on intestinal neurons and the vagus nerve, as previously described, to exert its effects.