Exploring the impact of a high-fat diet on the serotonin signaling in gut-brain axis

Serotonin is a critical neurotransmitter that regulates a wide range of physiological, neurological, and behavioral functions. While peripheral serotonin, primarily produced in the gut, modulates gastrointestinal motility and vascular tone, central serotonin that is synthesized in the brain governs processes such as food intake, emotion regulation, memory, learning, and sexual behavior. Chronic consumption of a high-fat diet (HFD) disrupts serotonin signaling across the gut, brain, and the gut-brain axis, which supports bidirectional communication between these systems. Although the underlying mechanisms remain incompletely understood, this review explores how HFD alters serotonin signaling in both the gut and the brain. We report that HFD triggers pathway-specific changes that elevate serotonin levels in the gut while eliciting region-specific effects in the brain. HFD increases serotonin biosynthesis in the brain's raphe nuclei; however, enhanced 5-HT1A autoreceptor activity within these nuclei inhibits serotonin release to downstream projection areas. Coupled with increased serotonin degradation in these regions, this results in reduced serotonin levels in the hippocampus and hypothalamus. Additionally, our findings highlight a central role for microbial metabolites in mediating HFD-induced serotonergic dysfunction. Notably, short-chain fatty acids produced by gut microbiota, significantly contribute to the dysregulation of serotonin release and signaling under HFD conditions. Understanding these mechanisms may reveal new therapeutic strategies for managing serotonergic dysfunctions associated with gastrointestinal disorders, mood disturbances, and obesity-related complications.