Resumen: Serotonin is a key neuromodulator of intestinal physiology. Serotonin transporter (SERT) is responsible for serotonin uptake, modulating its availability and consequently, serotonergic signalling. Recently, microbiota has been described to affect intestinal homeostasis through microbiota recognition receptors (TLRs). In fact,TLRs activation seems to regulate intestinal serotonergic system. However, whether intestinal microbiota can modulate SERT by short-chain fatty acids (SCFA) is unknown. Microbiota-derived short-chain fatty acids such as acetate, propionate and butyrate, are important metabolites from non-digestible dietary fibers bacterial fermentation. These metabolites have been shown to maintain intestinal homeostasis through protecting epithelial barrier integrity, promoting IgA production and regulating T-cell differentiation. In this study human enterocyte-like Caco-2/TC7 cells were used as intestinal epithelial cells model, which expresses serotonin transporter. Caco-2/TC7 cells were treated for 24 h with different concentrations of acetate, propionate and butyrate and then, and 5-HT uptake was measured. SERT molecular expression was analysed by measuring both, mRNA levels by real-time PCR and protein expression by western blotting. Our results show that the treatment with SCFA modulates SERT function and expression, in a different way for each fatty acid. Consequently, a different production of SCFA by microbiota could differently modulate SERT and affect to serotonergic signalling and intestinal physiology. Our study contributes to growing evidence about the key role of microbiota on host physiology regulation, and it opens a cutting-edge opportunity of microbiota modulation to balance serotonergic signalling alterations. Idioma: Inglés DOI: 10.1002/2211-5463.13206 Año: 2021 Publicado en: FEBS openbio 11 (2021), 46-47 ISSN: 2211-5463 Factor impacto JCR: 2.792 (2021) Categ. JCR: BIOCHEMISTRY & MOLECULAR BIOLOGY rank: 232 / 297 = 0.781 (2021) - Q4 - T3 Factor impacto CITESCORE: 3.9 - Biochemistry, Genetics and Molecular Biology (Q3)