Gut microbiota (GM) metabolites modulate host brain physiology via the gut-brain axis. This study investigated the relationship between GM, neurotransmitters, and brain function using a high-sugar, high-fat (HSHF) diet to induce GM dysbiosis in mice. The HSHF diet caused intestinal damage, altered neurotransmitter metabolism in the gut and brain, impacted brain function, and modified brain circRNA profiles. Trimethylamine-N-oxide (TMAO), a GM byproduct, degraded some circRNAs, with the basal GM level influencing choline's conversion to TMAO. Altering a single bacterial strain's abundance affected neurotransmitter secretion. The findings suggest a novel link between metabolism, brain circRNAs, and GM, expanding the "microbiome-transcriptome" linkage library and providing insights into the gut-brain axis. This could aid in identifying therapeutic markers and mechanistic solutions for various pathologies.
