Evaluating the Effects of Intestinal Bacteria’s Production of GABA Neurotransmitter on an Animal Model of Multiple Sclerosis

Abstract

Abstract Past studies show that the production of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, by gut bacteria is decreased in patients with multiple sclerosis (MS). Furthermore, the administration of GABAergic compounds ameliorates the progression of experimental autoimmune encephalomyelitis (EAE), a murine model of MS. We investigated whether modifying the microbiota of mice with GABA-producing bacteria reduced the severity of EAE. We genetically modified a Lactococcus lactis with increased copies of the genes encoding the enzyme glutamic acid decarboxylase (GAD), which synthesizes GABA, and the GABA/glutamate antiporter (GadC). This modified L. lactis strain (GAD-L. lactis) produced significantly increased GABA, measured by ELISA, compared to control L. lactis strain, with an unmodified plasmid (P-L. lactis). These strains were compared with sham treatment as probiotic treatments against EAE. EAE-induced C57BL/6 mice were divided into three groups: sham group (EAE induced, treated with autoclaved media; n = 10); EAE mice treated with P-L. lactis (n = 10); and EAE mice treated with GAD-L. lactis (n = 10). The treatments occurred five times a week via oral gavage (5 x 108 CFU/mouse). The oral administration of GAD-L. lactis significantly reduced the severity of EAE and body weight loss during disease, compared to both the P-L. lactis and sham groups. Our results indicate that oral treatment with a probiotic strain that produces enhanced GABA levels protects against the progression of CNS demyelination. Immunophenotyping studies will help us understand the mechanism of action of GAD-L. lactis and its potential as a novel approach to treat autoimmune disorders.