Study of the physiological functions of serotonin

Iron and Immunity (IRONY)
Metabolism and endocrinology

Research on serotonin (5-hydroxytryptamine or 5-HT) has primarily focused on its role as a neurotransmitter in the central nervous system. Yet only a small percentage of 5-HT (∼5%) is synthesized in the brain. In fact, the enterochromaffin cells of the intestine produce more than 95% of the body's 5-HT.
Since the discovery of a second gene responsible for the synthesis of 5-HT (Côté et al., PNAS 2003, Walther et al., Science 2003), numerous studies indicate that 5-HT has functions that go well beyond those of a neurotransmitter. To clarify, in vivo, these functions, we generated a mouse model invalidated for the tryptophan hydroxylase gene (Tph1), responsible for the synthesis of 5-HT outside the central nervous system and thus identified new functions of 5-HT in peripheral tissues.
We have recently demonstrated in cohorts of patients with myelodysplastic syndromes, that reduced levels of 5-HT are associated with various types of anemia and disorders related to iron homeostasis (Sibon et al., Cell Reports 2019 ; Coman et al., BioRxiv 2023). In addition, the pharmacological modulation of the serotonergic system allowed to regulate iron deficiency anemia.
Our research aims to better understand the role played by peripheral 5-HT in the regulation of erythropoiesis and iron homeostasis in normal and pathological conditions.

Project members

Nolwenn MORRIS PhD student

Benoît GENDROT PhD student

Guillemette FOUQUET Contract researcher

Project

Axis 1. Serotonin and iron homeostasis

Iron is essential to central biological processes of all living organisms. Yet, a deficiency or an excess can be harmful for the organism which faces a double challenge to ensure that an adequate amount of iron is absorbed to satisfy biological needs and avoid toxicity. Despite years of public health efforts, abnormalities of iron homeostasis—i.e. insufficient or excess iron—still affect more than 25% of the world’s population and occur in people of any age, ethnicity, or gender. Iron overload plays a major role in free radical pathology and associated tissue damage and organ failure (heart, liver…). While iron deficiency and for example, maternal iron deficiency remains prevalent, accounting for half of the anemia burden in pregnant women worldwide. The consequences are serious, both for the mother and her developing fetus, and many studies have shown that maternal iron deficiency doubles the risk of preterm delivery.
Iron metabolism and erythropoiesis are closely linked. Erythropoiesis, the fine-tuned process by which red blood cells are produced in the bone marrow, depends on oxygen and iron availability for proper hemoglobin synthesis.
Until recently, little was known regarding the mechanism of action of 5-HT during hematopoiesis or iron homeostasis. It was long ago hypothesized that 5-HT had an erythropoietic effect in mice through stimulation of the 5-HT2 receptor family (Proc Soc Exp Biol Med 1971), while in vitro studies published fifty years ago suggested a role for 5-HT in iron absorption (Arch Int Pharmacodyn, 1965).
We provided evidence that manipulation of the serotonergic system for the coordination of iron homeostasis with erythropoiesis could counter the vicious cycle of ineffective erythropoiesis and iron overload seen, for example, in patients with myelodysplastic syndromes (Sibon et al., Cell Reports 2019). We further demonstrated that gut derived 5-HT serves as an essential sensor and regulator for iron homeostasis. Precisely, in healthy individuals, there is a negative correlation between 5-HT and hepcidin levels and 5-HT can directly repress hepcidin expression in a human hepatocyte cell line. Using the Tph1−/− mouse model, we determined that 5-HT produced in enterochromaffin cells suppresses liver hepcidin synthesis through a 5‑HT2B receptor signaling, independently of any other known hepcidin regulators, including bone marrow signals (Coman et al., BioRxiv 2023).

We hypothesize that gut-derived 5-HT is a novel key regulator of intracellular iron homeostasis. Our research questions are to:

Define the molecular/cellular mechanism(s) played by 5-HT on intracellular iron homeostasis and erythropoiesis;
Reveal the importance of 5-HT in iron overload diseases.

Axis 2. Serotonin and embryogenesis

5-HT is a powerful mitogen and has been shown to promote neuro development (Vitalis et al., Dev Neurosc 2003) and angiogenesis (Nemecek et al., PNAS 1986). During embryonic development in mice, where the mitogenic action of 5-HT is particularly important, studies have reported the presence of components of the serotonergic system suggesting that 5-HT is needed by the embryo before the latter is capable of synthesizing it (Zamani et al., FEBS Lett 2012).
Our published data argue for a role played by maternally derived 5-HT during development (Côté et al., PNAS 2007), whereas others suggest a role played by placental derived 5-HT for proper embryonic development. Whether 5-HT is of maternal (paracrine) or placental (autocrine) origin during embryonic development—and whether an interaction between these two sources exists—is still a subject of debate.

We hypothesize that 5-HT is essential for adequate trans-placental iron transfer to prevent fetal iron deficiency.

Our research questions are to:

Demonstrate that 5-HT is a new local key regulator of iron homoeostasis in cells of the placenta;
Demonstrate the existence of a cross-talk between maternally derived 5-HT and placental 5-HT as a mechanism to regulate iron homoeostasis thereby challenging the classic dogma of exclusive fetal control over the iron transfer process.