Resumen: Intestinal serotonergic system is a key modulator of intestinal homeostasis; however, its regulation is still unclear. Toll-like receptor 9 (TLR9), an innate immune receptor, detects different external agents in the intestine, preserving intestinal integrity. Since little is known about TLR9 role in the intestine, our aim was to address the potential regulation between TLR9 and intestinal serotonergic system. Caco-2/TC7 cell line and intestinal tract of Tlr9−/− mice were used in this study. Serotonin uptake studies were performed, and molecular expression of different serotonergic components was analyzed by western blot and real-time PCR. Our results show that TLR9 activation inhibits serotonin transporter activity and expression, involving p38/MAPK and ERK/MAPK intracellular pathways, and reciprocally, serotonin increases TLR9 expression. Supporting this interaction, serotonin transporter, serotonin receptors and serotonin producer enzymes were found altered in intestinal tract of Tlr9−/− mice. We conclude that TLR9 could contribute to intestinal homeostasis by modulation of intestinal serotonergic system. Idioma: Inglés DOI: 10.1007/s13105-022-00897-2 Año: 2022 Publicado en: Journal of Physiology and Biochemistry 78 (2022), 689–701 ISSN: 1138-7548 Factor impacto JCR: 3.4 (2022) Categ. JCR: PHYSIOLOGY rank: 25 / 79 = 0.316 (2022) - Q2 - T1 Categ. JCR: BIOCHEMISTRY & MOLECULAR BIOLOGY rank: 158 / 285 = 0.554 (2022) - Q3 - T2 Factor impacto CITESCORE: 7.5 - Medicine (Q1) - Biochemistry, Genetics and Molecular Biology (Q2)