Empirical evidence for gut microbial influence on human brain neurochemistry via the gut–brain axis

The gut microbiome produces metabolites with potential neuroactive properties, many of which act locally within the gut. While preclinical studies suggest these microbial pathways can influence cognitive and emotional processes, human evidence remains limited. This study investigates associations between gut microbiome-derived neuroactive functional potential 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 metagenomic profiling characterised microbial functional potential for pathways related to the synthesis and degradation of GABA, glutamate, short-chain fatty acids (SCFAs), p-cresol, and inositol. Region-specific associations were observed between these microbial pathways and cortical GABA and glutamate levels, including excitatory/inhibitory (E/I) balance, a key marker of neuroplasticity and mental health. Notably, microbial glutamate degradation and inositol synthesis potential were associated with IOG E/I balance, while additional pathways including GABA metabolism, p-cresol production, and SCFA synthesis showed distinct associations across regions. Exploratory analyses also identified links between microbial functional potential and anxiety, depressive symptoms, and sleep quality. Together, these findings provide new human evidence that variation in microbial functional potential corresponds with regional cortical neurochemistry and psychological wellbeing, highlighting the gut-brain axis as a promising avenue for mechanistically informed microbiome-based- interventions.