Empirical evidence of the neuroactive potential of the gut on neurochemistry in the gut-brain axis in humans

The gut microbiome produces a wide range of neuroactive metabolites capable of influencing brain neurotransmitter systems. While preclinical studies suggest these microbial pathways modulate cognitive and emotional processes, evidence in humans remains limited. This study investigates the relationship between gut microbiome-derived neuroactive pathways and in vivo brain neurotransmitter concentrations in healthy young females. Using proton magnetic resonance spectroscopy (¹H-MRS), we quantified GABA and glutamate levels in the dorsolateral prefrontal cortex (dlPFC), anterior cingulate cortex (ACC), and inferior occipital gyrus (IOG). Parallel gut microbiome profiling identified functional pathways associated with the synthesis and degradation of GABA, glutamate, short-chain fatty acids, p-cresol, and inositol. We observed significant, region-specific associations between microbial neuroactive pathways and both neurotransmitter concentrations and excitatory/inhibitory (E/I) balance, a key regulator of neuroplasticity and mental health. Notably, microbial GABA synthesis pathways were inversely related to brain glutamate levels in the dlPFC, while glutamate synthesis pathways correlated with GABA levels in the ACC. Additional pathways, including p-cresol and SCFA metabolism, showed region-dependent relationships with brain neurochemistry and E/I ratios. These neurochemical findings were complemented by associations between the same microbial pathways and psychological outcomes, including anxiety, depressive symptoms, and sleep quality. These findings provide new evidence of gut-derived metabolic influence on human brain neurotransmitter dynamics and mental wellbeing, highlighting the gut-brain axis as a promising target for microbiome-based interventions supporting cognitive resilience and emotional health.