When we think of serotonin, we almost instantly imagine the brain’s “molecule of happiness”—a central chemical messenger governing our mood, sleep, and emotional wellbeing. Yet, this conventional picture overlooks a fascinating
biological reality: approximately 95% of the body’s serotonin is manufactured not in the brain, but in the gastrointestinal tract.
Produced primarily by specialized lining cells known as enterochromaffin cells, enteric serotonin serves as a vital
biological conductor, regulating intestinal development, digestive motility, and local inflammatory responses.
For decades, clinical research studied the central nervous system and the enteric nervous system—often dubbed our “second brain”—in strict silos. However, emerging scientific evidence demonstrates that these two systems engage in
continuous, bidirectional dialogue through the gut-brain axis. This complex communication network relies on the vagus nerve, systemic immune circulating factors, and the gut microbiota, with serotonin acting as a primary molecular
dialect.
In a comprehensive review published in the Spanish Journal of Psychiatry and Mental Health, our collaborative research consortium examined how disturbances in enteric serotonin signaling drive the onset and progression of
devastating brain disorders, specifically Parkinson’s disease and major depression. Both conditions are heavily characterized by debilitating gastrointestinal co-pathologies, such as chronic constipation and dysmotility, which frequently plague patients years before classic motor tremors or depressive mood symptoms emerge.
Our collaborative findings shed light on three critical interconnected mechanisms. First, enteric serotonin signaling plays a pivotal role in regulating the accumulation of misfolded α-synuclein—the toxic protein hallmark of Parkinson’s disease. Pathological α-synuclein can aggregate within intestinal epithelial cells and potentially migrate via enteric nerves upward to the brain. Second, systemic imbalances in tryptophan metabolism (the essential amino acid building block of serotonin) alter the gut microbiota, depriving both the gut and the brain of vital neuroprotective support. Third, local gut neuroinflammation
can propagate systemically, disrupting neural circuits and exacerbating both mood and motor deterioration.
The societal and clinical implications of these insights are profound.
By shifting our gaze from the brain to the gut, we open an entirely new frontier for early medical intervention. Recognizing enteric serotonin as a systemic bridge connecting the digestive tract, immune defenses, and central neural circuitry means that future therapies for depression and Parkinson’s disease may not need to cross the blood-brain barrier. Instead, targeting gut microbiota, local inflammatory pathways, and intestinal serotonin receptors could halt these disabling conditions at their gastrointestinal point of origin.
References
Sancho-Alonso M, Sarriés-Serrano U, Miquel-Rio L, Yanes Castilla C, Paz V, Meana JJ, Perello M,
Bortolozzi A. New insights into the effects of serotonin on Parkinson’s disease and depression
through its role in the gastrointestinal tract. Span J Psychiatry Ment Health. 2025 Jul-Sep;18(3):
216-227. DOI: 10.1016/j.sjpmh.2024.07.002.
Principal Investigator & Group Leader, Systems
Neuropharmacology Group.
Affiliations: Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC); Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Biomedical Research Networking Center for Mental Health (CIBERSAM-ISCIII), Barcelona, Spain.