Gut Microbiome Modulation of Glutamate Dynamics: Implications for Brain Health and Neurotoxicity

Abstract

The gut-brain axis plays an integral role in maintaining overall health, with growing evidence suggesting its impact on the development of various neuropsychiatric disorders, including depression. This review explores the complex relationship between gut microbiota and glutamate (Glu) regulation, highlighting its effect on brain health, particularly in the context of depression following certain neurological insults. We discuss how microbial populations can either facilitate or limit Glu uptake, influencing its bioavailability and predisposing to neuroinflammation and neurotoxicity. Additionally, we examine the role of gut metabolites and their influence on the blood-brain barrier and neurotransmitter systems involved in mood regulation. The therapeutic potential of microbiome-targeted interventions, such as fecal microbiota transplantation, is also highlighted. While much research has explored the role of Glu in major depressive disorders and other neurological diseases, the contribution of gut microbiota in post-neurological depression remains underexplored. Future research should focus on explaining the mechanisms linking the gut microbiota to neuropsychiatric outcomes, particularly in conditions such as post-stroke depression, post-traumatic brain-injury depression, and epilepsy-associated depression. Systematic reviews and human clinical studies are needed to establish causal relationships and assess the efficacy of microbiome-targeted therapies in improving the neuropsychiatric sequalae after neurological insults.

Keywords: blood–brain barrier; depression; epilepsy; glutamate; gut microbiome; neurodegeneration; stroke; traumatic brain injury.

Figure 1

Brain-to-blood glutamate efflux. (1) In the presence of its enzyme co-substrate pyruvate, GPT catalyzes the reversible conversion of glutamate into its inactive form, 2-ketoglutarate, thereby reducing glutamate levels in the blood. This reduction generates a steep concentration gradient between the extracellular fluid and the blood, enhancing the brain-to-blood glutamate efflux rate. This leads to a reduction in elevated glutamate concentrations in the brain. As long as blood glutamate remains low, this efflux persists. Since the reaction converting glutamate to 2-ketoglutarate is reversible, an accumulation of 2-ketoglutarate can drive the enzyme to regenerate glutamate. (2) To sustain glutamate metabolism, 2-ketoglutarate is further degraded by the enzyme 2-ketoglutarate dehydrogenase. By enhancing the concentration gradient between blood and brain glutamate, the brain-to-blood glutamate transport is expedited, thereby mitigating excitotoxicity, associated with elevated brain glutamate levels. AKG, 2-ketoglutarate; AKGH, 2-ketoglutarate dehydrogenase; ALA, alanine; AST, aspartate; CO₂, carbon dioxide; CoA, Coenzyme A; GLU, glutamate; GOT, glutamate-oxaloacetate transaminase; GPT, glutamate pyruvate transaminase; H⁺, hydrogen ion (proton), NAD⁺, nicotinamide adenine dinucleotide (oxidized form); NADH, nicotinamide adenine dinucleotide (reduced form); OA, oxaloacetate; PYR, pyruvate; succinyl-CoA, succinyl-coenzyme A.

Figure 2

The disruption of the gut–brain axis and glutamate homeostasis during neurological insults. Neurological insults overwhelm regulatory mechanisms, leading to excess glutamate in the brain, which contributes to neuropsychiatric sequelae, oxidative stress, mitochondrial toxicity, cytotoxic edema, and neuronal death. These interconnected pathways highlight the role of the gut–brain axis in mediating systemic and neurological effects during insults to the central nervous system. CSF, cerebral spinal fluid; GPT, glutamate pyruvate transaminase; GOT, glutamic oxaloacetic transaminase; TBI, traumatic brain injury.