Serotonin regulates hepcidin expression via a gut-liver axis

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Coman, T. | Falabrègue, M. | Rossignol, J. | Bonneau, P. | Djebar, M. | Bigorgne, A. | Mathieu, J | Foretz, Marc | Puy, H. | Peoc’h, K. | Logeart, D. | Cohen-Solal, A. | Launay, J.-M. | Maroteaux, L. | Peyssonnaux, C. | Hermine, O. | Côté, F.

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Abstract Liver hepcidin, is well recognized as the central hormone of systemic iron regulation. Although serotonin is most recognized as a brain neurotransmitter, prodigious quantities are synthesized in gut enterochromaffin cells and several lines of evidence, also identified the gut as an essential sensor and regulator of iron homeostasis. Using a mouse model deficient for peripheral serotonin (Tph1 KO), we identified gut-derived serotonin as a key physiological factor in hepcidin regulation. Serotonin represses hepcidin’s through a 5HT2B receptor-dependent pathway, independently of any other known hepcidin regulators, including bone marrow signals. This regulation is conserved in humans and shows physiological significance as a negative correlation between serotonin and hepcidin levels was observed in a cohort of healthy individuals. Moreover, in pathological situation such as acute heart failure, where iron deficiency has a negative prognostic impact, we provide evidence that an increase in serotonin level seems necessary to repress hepcidin level, to increase iron availability.

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