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Journal ArticleDOI

5-Hydroxytryptamine (serotonin) in the gastrointestinal tract.

01 Feb 2013-Current Opinion in Endocrinology, Diabetes and Obesity (Curr Opin Endocrinol Diabetes Obes)-Vol. 20, Iss: 1, pp 14-21
TL;DR: New studies show that enteric 5-HT is a polyfunctional signalling molecule, acting both in developing and mature animals as a neurotransmitter paracrine factor, endocrine hormone and growth factor.
Abstract: Purpose of reviewAlthough the gut contains most of the body's 5-hydroxytryptamine (5-HT), many of its most important functions have recently been discovered. This review summarizes and directs attention to this new burst of knowledge.Recent findingsEnteroendocrine cells have classically been regarde

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Citations
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Journal ArticleDOI
TL;DR: Therapeutic targeting of the gut microbiota might be a viable treatment strategy for serotonin-related brain-gut axis disorders.

1,201 citations

Journal ArticleDOI
TL;DR: Gut microbiota acting through SCFAs are important determinants of enteric 5‐HT production and homeostasis through an effect of short‐chain fatty acids on enterochromaffin cells.
Abstract: Gut microbiota alterations have been described in several diseases with altered gastrointestinal (GI) motility, and awareness is increasing regarding the role of the gut microbiome in modulating GI function. Serotonin [5-hydroxytryptamine (5-HT)] is a key regulator of GI motility and secretion. To determine the relationship among gut microbes, colonic contractility, and host serotonergic gene expression, we evaluated mice that were germ-free (GF) or humanized (HM; ex-GF colonized with human gut microbiota). 5-HT reduced contractile duration in both GF and HM colons. Microbiota from HM and conventionally raised (CR) mice significantly increased colonic mRNAs Tph1 [(tryptophan hydroxylase) 1, rate limiting for mucosal 5-HT synthesis; P < 0.01] and chromogranin A (neuroendocrine secretion; P < 0.01), with no effect on monoamine oxidase A (serotonin catabolism), serotonin receptor 5-HT4, or mouse serotonin transporter. HM and CR mice also had increased colonic Tph1 protein (P < 0.05) and 5-HT concentrations (GF, 17 ± 3 ng/mg; HM, 25 ± 2 ng/mg; and CR, 35 ± 3 ng/mg; P < 0.05). Enterochromaffin (EC) cell numbers (cells producing 5-HT) were unchanged. Short-chain fatty acids (SCFAs) promoted TPH1 transcription in BON cells (human EC cell model). Thus, gut microbiota acting through SCFAs are important determinants of enteric 5-HT production and homeostasis.

774 citations


Cites background from "5-Hydroxytryptamine (serotonin) in ..."

  • ...90%) in the human body is produced by enterochromaffin (EC) cells of the gut, where it is synthesized by the rate-limiting enzyme tryptophan hydroxylase (Tph/TPH) 1, and stored in secretory granules prior to release (3)....

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Journal ArticleDOI
TL;DR: Emerging evidence that the microbiome extends its influence to the brain via various pathways connecting the gut to the central nervous system is highlighted.

754 citations


Cites background from "5-Hydroxytryptamine (serotonin) in ..."

  • ...%) is produced by enterochromaffin cells in the gut (Gershon, 2013)....

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Journal ArticleDOI
28 Jul 2017-Science
TL;DR: The modulation of tryptophan-kynurenine metabolism using lifestyle and pharmacological interventions could help prevent and treat several diseases with underlying inflammatory mechanisms, including metabolic, oncologic, and mental health disorders.
Abstract: BACKGROUND The essential amino acid tryptophan is a substrate for the generation of several bioactive compounds with important physiological roles. Only a small fraction of ingested tryptophan is used in anabolic processes, whereas the large majority is metabolized along the kynurenine pathway of tryptophan degradation. This pathway generates a range of metabolites, collectively known as kynurenines, involved in inflammation, immune response, and excitatory neurotransmission. Kynurenines have been linked to several psychiatric and mental health disorders such as depression and schizophrenia. In addition, due to the close relationship between kynurenine metabolism and inflammatory responses, kynurenines are emerging as recognized players in a variety of diseases such as diabetes and cancer. Because the levels of enzymes of the kynurenine pathway in peripheral tissues tend to be much higher than in the brain, their contribution to the kynurenine pathway can have both local and systemic consequences. Due to their characteristics, kynurenine and its metabolites have the right profile to fill the role of mediators of interorgan communication. ADVANCES Understanding how the tryptophan-kynurenine pathway is regulated in different tissues, and the diverse biological activities of its metabolites, has become of interest to many areas of science. The bioavailability of tryptophan can be affected by factors that range from gut microbiome composition to systemic inflammatory signals. Gut-resident bacteria can directly absorb tryptophan and thus limit its availability to the host organism. The resulting metabolites can have local effects on both microbiome and host cells and even mediate interspecies communication. In addition, the biochemical fate of absorbed tryptophan will be affected by cross-talk with other nutrients and even by individual fitness, because skeletal muscle has recently been shown to contribute to kynurenine metabolism. With exercise training, skeletal muscle increases the expression of kynurenine aminotransferase enzymes and shifts peripheral kynurenine metabolism toward the production of kynurenic acid. As a consequence, alleviating the accumulation of kynurenine in the central nervous system can positively affect mental health, such as reducing stress-induced depressive symptoms. The kynurenine pathway is highly regulated in the immune system, where it promotes immunosuppression in response to inflammation or infection. Kynurenine reduces the activity of natural killer cells, dendritic cells, or proliferating T cells, whereas kynurenic acid promotes monocyte extravasation and controls cytokine release. Perturbations in the kynurenine pathway have been linked to several diseases. High kynurenine levels can increase the proliferation and migratory capacity of cancer cells and help tumors escape immune surveillance. Kynurenine metabolites have been proposed as markers of type 2 diabetes and may interfere at some level with either insulin secretion or its action on target cells. Kynurenines can signal through different tissue-specific extra- and intracellular receptors in a network of events that integrates nutritional and environmental cues with individual health and fitness. OUTLOOK The modulation of tryptophan-kynurenine metabolism using lifestyle and pharmacological interventions could help prevent and treat several diseases with underlying inflammatory mechanisms, including metabolic, oncologic, and mental health disorders. In this context, and considering the substantial effect that the gut microbiome can have on preabsorptive tryptophan metabolism, it is tempting to envision the use of probiotic-based therapies. The discovery that aerobic exercise training can reduce kynurenine levels in circulation and in the central nervous system could have important implications for the development of future generations of antidepressant medications. This again stresses the many advantages of remaining physically active throughout life. Understanding the multiple levels of control of the kynurenine pathway could help predict susceptibility to disease linked to environmental and dietary signals.

689 citations


Cites background from "5-Hydroxytryptamine (serotonin) in ..."

  • ...Thus, the extent of Trp use by bacteria, its dietary supply, and local turnover by the GIT can have far-reaching implications in the development and proper functioning of both the enteric nervous system (ENS) and CNS....

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  • ...Asmuch as 90% of total serotoninproduction (stored in secretory granules) comes from enterochromaffin cells and, to a lesser extent, from serotonergic neurons of the ENS (34)....

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Journal ArticleDOI
TL;DR: Roles of gut microbiome in shaping brain development and neurological function, and the mechanisms by which it can contribute to mental illness are examined; how the insight provided by this new and exciting field of research can inform care and provide a basis for the design of novel, microbiota-targeted, therapies is discussed.
Abstract: The human body hosts an enormous abundance and diversity of microbes, which perform a range of essential and beneficial functions. Our appreciation of the importance of these microbial communities to many aspects of human physiology has grown dramatically in recent years. We know, for example, that animals raised in a germ-free environment exhibit substantially altered immune and metabolic function, while the disruption of commensal microbiota in humans is associated with the development of a growing number of diseases. Evidence is now emerging that, through interactions with the gut–brain axis, the bidirectional communication system between the central nervous system and the gastrointestinal tract, the gut microbiome can also influence neural development, cognition and behaviour, with recent evidence that changes in behaviour alter gut microbiota composition, while modifications of the microbiome can induce depressive-like behaviours. Although an association between enteropathy and certain psychiatric conditions has long been recognized, it now appears that gut microbes represent direct mediators of psychopathology. Here, we examine roles of gut microbiome in shaping brain development and neurological function, and the mechanisms by which it can contribute to mental illness. Further, we discuss how the insight provided by this new and exciting field of research can inform care and provide a basis for the design of novel, microbiota-targeted, therapies.

607 citations

References
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Journal ArticleDOI
03 Jan 2003-Science
TL;DR: The neurotransmitter serotonin [5-hydroxytryptamine (5-HT] is causally involved in multiple central nervous facets of mood control and in regulating sleep, anxiety, alcoholism, drug abuse, food intake, and sexual behavior.
Abstract: The neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] is causally involved in multiple central nervous facets of mood control and in regulating sleep, anxiety, alcoholism, drug abuse, food intake, and sexual behavior ([1][1]). In peripheral tissues, 5-HT regulates vascular tone, gut motility,

1,435 citations

Journal ArticleDOI
TL;DR: Serotonin is an important gastrointestinal signaling molecule as mentioned in this paper, which is used by enterochromaffin (EC) cells to activate intrinsic and extrinsic primary afferent neurons to initiate peristaltic and secretory reflexes and transmit information to the central nervous system.

1,268 citations

Journal ArticleDOI
28 Nov 2008-Cell
TL;DR: It is shown here that Lrp5 inhibits expression of Tph1, the rate-limiting biosynthetic enzyme for serotonin in enterochromaffin cells of the duodenum, and decreasing serotonin blood levels normalizes bone formation and bone mass in L rp5-deficient mice.

751 citations

Journal ArticleDOI
07 Apr 2006-Science
TL;DR: Results suggest that platelet-derived serotonin is involved in the initiation of liver regeneration and blunted in mice lacking tryptophan hydroxylase 1, which is the rate-limiting enzyme for the synthesis of peripheral serotonin.
Abstract: The liver can regenerate its volume after major tissue loss. In a mouse model of liver regeneration, thrombocytopenia, or impaired platelet activity resulted in the failure to initiate cellular proliferation in the liver. Platelets are major carriers of serotonin in the blood. In thrombocytopenic mice, a serotonin agonist reconstituted liver proliferation. The expression of 5-HT2A and 2B subtype serotonin receptors in the liver increased after hepatectomy. Antagonists of 5-HT2A and 2B receptors inhibited liver regeneration. Liver regeneration was also blunted in mice lacking tryptophan hydroxylase 1, which is the rate-limiting enzyme for the synthesis of peripheral serotonin. This failure of regeneration was rescued by reloading serotonin-free platelets with a serotonin precursor molecule. These results suggest that platelet-derived serotonin is involved in the initiation of liver regeneration.

706 citations