Donor Microbiota Metabolic Capacity Determines Engraftment Dynamics and Modulates Gut–Brain Signaling in Recipient Mice

This study performs patient-to-mouse fecal microbiota transplantation (FMT) as an experimental platform to investigate gut-brain axis alterations with potential relevance to psychiatric disorders, integrating metabolic modeling with measured metabolites and multi-layer molecular profiling. Microbial communities of a stool sample associated with bipolar disorder (BD) displayed a reduced ecological diversity and diminished metabolic potential, particularly within glutamate, aspartate, and GABA biosynthetic pathways. Upon transplantation with BD patient microbiota, recipient mice displayed a markedly altered microbiome characterized by loss of Akkermansia and expansion of Alloprevotella, alongside disruptions in amino acid and carbohydrate metabolism not evident in mice colonized by a healthy donor microbiota. Metabolic microbiome alterations in BD-recipient mice were also correlated to reduced glutathione levels in gut tissue, likely indicating increased oxidative stress, and decreased mRNA expression of key enteroendocrine hormones, including peptide YY and glucagon. Brain metabolomic profiling of BD-recipient mice revealed significant depletion of glycine, choline, and methionine levels connected to anxiety-like phenotypes in elevated plus-maze and light-dark box behavioral tests. Akkermansia abundance positively correlated with physical activity and exploratory behavior, highlighting an important role of this taxon in gut-brain signaling. Collectively, these findings identify distinct microbial, metabolic, and neurobehavioral signatures transmittable from humans to mice via FMT and demonstrate that differences in donor microbiome diversity and metabolic capacity shape engraftment dynamics in recipient mice, which contribute to differences in gut-brain signaling.