Serotonin, tryptophan metabolism and the brain- gut- microbiome axis. Highlights. Serotonin functions as a key neurotransmitter at both terminals of this network. Accumulating evidence points to a critical role for the gut microbiome in regulating normal functioning of this axis. In particular, it is becoming clear that the microbial influence on tryptophan metabolism and the serotonergic system may be an important node in such regulation. There is also substantial overlap between behaviours influenced by the gut microbiota and those which rely on intact serotonergic neurotransmission. The developing serotonergic system may be vulnerable to differential microbial colonisation patterns prior to the emergence of a stable adult- like gut microbiota. At the other extreme of life, the decreased diversity and stability of the gut microbiota may dictate serotonin- related health problems in the elderly. The mechanisms underpinning this crosstalk require further elaboration but may be related to the ability of the gut microbiota to control host tryptophan metabolism along the kynurenine pathway, thereby simultaneously reducing the fraction available for serotonin synthesis and increasing the production of neuroactive metabolites. The enzymes of this pathway are immune and stress- responsive, both systems which buttress the brain- gut axis. In addition, there are neural processes in the gastrointestinal tract which can be influenced by local alterations in serotonin concentrations with subsequent relay of signals along the scaffolding of the brain- gut axis to influence CNS neurotransmission. Therapeutic targeting of the gut microbiota might be a viable treatment strategy for serotonin- related brain- gut axis disorders. Abbreviations. CNS, central nervous system; ENS, enteric nervous system; BBB, blood- brain- barrier; 5- HTP, 5- hydroxytryptophan; TPH, tryptophan hydroxylase; TDO, tryptophan- 2,3- dioxygenase; IDO, indoleamine- 2,3- dioxygenase; AAAD, aromatic amino acid decarboxylase; NMDA, N- methyl- d- aspartate; ATD, acute tryptophan depletion; SSRIs, selective serotonin reuptake inhibitors; TLR, toll- like receptor; IBS, irritable bowel syndrome; IAA, indole 3- acetic acid; EC, enterochromaffin cell; ERK, extracellular signal- regulated kinase; GABA, gamma- aminobutyric acid; TCA, tricyclic antidepressant; HPA axis, hypothalamic pituitary adrenal axis; SHRP, stress hypo- responsive period; EPAN, extrinsic primary afferent neuron. Keywords. Tryptophan; Serotonin; Microbiome; Kynurenine; Pain; Anxiety. Introduction. Tryptophan and its metabolite serotonin have an expansive physiological repertoire, making them fundamental to health and there are numerous associations between alterations in this system and disease . A growing body of data is also pointing to the influence of this system far beyond the traditional focus on its signalling pathways in the central nervous system (CNS) (see Reviews in this Special Issue). Moreover, emerging data implicates the gut microbiome in the regulation of brain and behaviour in general with a specific emphasis on its impact on tryptophan metabolism and the serotonergic system. Research in this area builds on the principles of the brain- gut axis concept (see Fig. ENS) and the CNS . Recently, it has become clear that the gut microbiome is a critical component of this axis and one which exerts control at multiple levels, not just locally in the gastrointestinal tract . Using a variety of preclinical strategies, it has been established that manipulating the composition of the gut microbiota across the lifespan or altering the trajectory of microbial colonisation of the gastrointestinal tract early in life influences the availability of tryptophan. In tandem and possibly related to this capacity, this research has also illuminated a role for the gut microbiota in serotonergic signalling at the level of the CNS. There is also a substantial overlap between many of the behaviours underpinned by serotonergic signalling and those which are influenced by alterations in the composition, diversity or stability of the microbiota. This topic contains 420 study abstracts on Neurodegenerative Diseases indicating that the following substances may be helpful: Curcumin, Vitamin B-12, and Ginkgo biloba.Taken together, it seems plausible that the gut microbiota can either directly or indirectly recruit tryptophan metabolism and serotonergic signalling within the framework of the brain- gut axis to modulate host behaviour. Recreational drug use is the use of a psychoactive drug to alter one's mental state in a way that modifies emotions, perceptions, and feelings for recreational purposes. Resveratrol is a polyphenolic compound naturally found in peanuts, grapes, red wine, and some berries. Is Cannabis Really That Bad? Though some studies point to negative consequences of pot use in adolescents, data on marijuana’s dangers are mixed. CROI: Impressions from CROI - Pablo Tebas, MD University of Pennsylvania.
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June 2017
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