Implications of microbe-derived ɣ-aminobutyric acid (GABA) in gut and brain barrier integrity and GABAergic signaling in Alzheimer's disease

Abstract

The gut microbial ecosystem communicates bidirectionally with the brain in what is known as the gut-microbiome-brain axis. Bidirectional signaling occurs through several pathways including signaling via the vagus nerve, circulation of microbial metabolites, and immune activation. Alterations in the gut microbiota are implicated in Alzheimer's disease (AD), a progressive neurodegenerative disease. Perturbations in gut microbial communities may affect pathways within the gut-microbiome-brain axis through altered production of microbial metabolites including ɣ-aminobutyric acid (GABA), the primary inhibitory mammalian neurotransmitter. GABA has been shown to act on gut integrity through modulation of gut mucins and tight junction proteins and may be involved in vagus nerve signal inhibition. The GABAergic signaling pathway has been shown to be dysregulated in AD, and may be responsive to interventions. Gut microbial production of GABA is of recent interest in neurological disorders, including AD. Bacteroides and Lactic Acid Bacteria (LAB), including Lactobacillus, are predominant producers of GABA. This review highlights how temporal alterations in gut microbial communities associated with AD may affect the GABAergic signaling pathway, intestinal barrier integrity, and AD-associated inflammation.

Keywords: Alzheimer’s disease; Bacteroides; GABA; Lactobacillus; blood brain barrier; gut microbiota; gut-microbiome-brain axis; tight junctions.

Figure 1.

The gut mucus layer in AD is damaged by increased GABA-producing microbes in the context of a disease-associated microbiome. Damage to the mucus allows closer proximity of microbes and their metabolites to gut epithelial cells, damaging tight junction proteins and stimulating inflammation.

Figure 2.

GABA-producing bacteria enriched in the disease-associated gut microbiome increase the local concentration of GABA. GABA inhibits the vagus nerve in the gut and afferent signaling to the brain downregulates the release of norepinephrine. Norepinephrine is responsible for inhibiting microglia activation and subsequent microgliosis.