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

Serotonin is a vital neurotransmitter that influences numerous physiological, neurological, and behavioral functions. Peripheral serotonin, mainly produced in the gastrointestinal tract, regulates motility and vascular tone, while central serotonin, synthesized in the brain, governs food intake, emotional regulation, memory, learning, and sexual behavior. Chronic high-fat diet (HFD) consumption has been shown to disrupt serotonin signaling within the gut, brain, and the gut-brain axis, which facilitates bidirectional communication between these systems.

This review elucidates the pathway-specific alterations induced by HFD on serotonin signaling, revealing an increase in serotonin levels within the gut alongside region-specific effects in the brain. Specifically, HFD enhances serotonin biosynthesis in the raphe nuclei of the brain; however, heightened activity of 5-HT1A autoreceptors in these nuclei inhibits serotonin release to downstream areas, compounded by increased serotonin degradation. Consequently, there is a notable reduction in serotonin concentrations within the hippocampus and hypothalamus.

Furthermore, the review emphasizes the significant role of microbial metabolites, particularly short-chain fatty acids produced by gut microbiota, in mediating HFD-induced serotonergic dysfunction. These findings suggest that understanding the mechanisms underlying serotonergic dysregulation may pave the way for novel therapeutic strategies aimed at addressing gastrointestinal disorders, mood disturbances, and obesity-related complications. [NPID: Gastrointestinal Disorders, serotonin, neurotransmitter, gastrointestinal tract, HFD, high-fat diet, signaling, gut-brain axis, hippocampus]

Year: 2025

Reference: Gray, T., Fasina, Y. O., Harrison, S. H., Chang, E. M., Chang, A. Y., Maldonado-Devincci, A., & Han, J. (2025). Exploring the impact of a high-fat diet on the serotonin signaling in gut-brain axis. Nutritional neuroscience, 1–15. Advance online publication. https://doi.org/10.1080/1028415X.2025.2539320

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