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Serotonin, tryptophan metabolism and the brain-gut-microbiome axis

12/31/2017

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​Something for 2018 ~ Gut instinct is bidirectional
 
Serotonin, tryptophan metabolism and the brain-gut-microbiome axis
Behavioural Brain Research
15 January 2015: Pages 32-48
S.M. O’Mahony, et al
 
The Abstract as Poem
(Or, A Microbiota Ode to the Brain-Gut Axis)
 
The brain-gut axis is
 a bidirectional communication system
 between the central nervous system
 and the gastrointestinal tract.
 
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.
 
Here’s to Buttressed Happy Guts in 2018!
 
*Next Up: 1 February 2018 and a 2020 Update.
 
Posted by Bryan W. Brickner
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Serotonin (5-HT) System, Obesity and Energy Homeostasis

8/13/2015

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PictureSerotonin Receptor (by S Janhichen)





We have a homeostatic serotonin update today from PubMed (June 2015) with the starring principal receptor, 5-HT2CR, in energy action:


Abstract
The central 5-hydroxytryptamine (5-HT; serotonin) system represents a fundamental component of the brain's control of energy homeostasis.

Medications targeting the 5-HT pathway have been at the forefront of obesity treatment for the past 15 years.

Pharmacological agents targeting 5-HT receptors (5-HTR), in combination with genetic models of 5-HTR manipulation, have uncovered a role for specific 5-HTRs in energy balance and reveal the 5-HT2 C R as the principal 5-HTR mediating this homeostatic process.

Capitalising on this neurophysiological machinery, 5-HT2 C R agonists improve obesity and glycaemic control in patient populations.

The underlying therapeutic mechanism has been probed using model systems and appears to be achieved primarily through 5-HT2 C R modulation of the brain melanocortin circuit via activation of pro-opiomelanocortin neurones signalling at melanocortin4 receptors.

Thus, 5-HT2 C R agonists offer a means to improve obesity and type 2 diabetes, which are conditions that now represent global challenges to human health.

5-hydroxytryptamine medications for the treatment of obesity.
Burke LK, Heisler LK.
J Neuroendocrinol. 2015 Jun;27(6):389-98. doi: 10.1111/jne.12287.
PMID: 25925636
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Next Up: A Hannah Arendt Footnote on Tuesday 18 August.

Posted by Bryan W. Brickner

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Homeostasis: Equinox Serotonin (5HT) Headache Stories

9/20/2014

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PictureHomeostatic Life Light (2014)






The Cannabis Papers: A citizen’s guide to cannabinoids (2011)
By Publius

Headache Edition ~ Autumnal Equinox


Equinox and Homeostasis are mid-point extremes and today’s serotonin system science looks at 5-HT (5-hydroxytryptamine) and its role in modulating another extreme, the brain: specifically, headaches. Below are five (brief) science stories from the National Institutes of Health (PubMed). The serotonin brain tales include: pro-cognitive 5-HT4 receptors, mitigating medication overuse, abnormal headache chronicity, (red) wine interference mechanisms, and new cluster headache horizons.

Autumnal Equinox Health Everyone!

1. Serotonin 5-HT4 Receptors ~ Pro-Cognitive Hippocampal Effects
“Activation of serotonin 5-HT4 receptors has pro-cognitive effects on memory performance. … These results indicate that 5-HT4 receptors are not synthesized by cholinergic cells, and thus would be absent from cholinergic terminals. In contrast, several non-cholinergic cell populations within the basal forebrain and its target hippocampal and cortical areas express these receptors and are thus likely to mediate the enhancement of acetylcholine release elicited by 5-HT4 agonists.”
Serotonin 5-HT4 receptors and forebrain cholinergic system: receptor expression in identified cell populations.
Peñas-Cazorla R, Vilaró MT.
Brain Struct Funct. 2014 Sep 3. [Epub ahead of print]
PMID: 25183542 [PubMed - as supplied by publisher]
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2. Serotonin Metabolism ~ Reversing Anxiety and Depression
“Medication overuse headache (MOH) affects between 1% and 2% of the general population but is present in up to 50% of patients seen in headache centers. … We conclude that headache frequency can be reduced to episodic headache in more than 50% of the patients by simple detoxification and information. Approximately half the patients will not have need for prophylactic medication after withdrawal. Pain perception is altered in patients with MOH but can be restored to a baseline pattern, indicating a reversible mechanism in the central sensitization leading to chronic pain. The great comorbidity with depression and anxiety could be a consequence of the altered serotonin metabolism indicating a reversible and potentially treatable condition.”
Medication overuse headache.
Munksgaard SB, Jensen RH.
Headache. 2014 Jul-Aug;54(7):1251-7. doi: 10.1111/head.12408. Epub 2014 Jul 2.
PMID: 24990298 [PubMed - in process]
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3. Serotonergic Homeostasis ~ Chronic Migraine and Tension-Type Headaches
“The primary aim of this study (TA-CH, Tryptophan Amine in Chronic Headache) was to investigate a possible role of tryptophan (TRP) metabolism in chronic migraine (CM) and chronic tension-type headache (CTTH). … Our results support the hypothesis that TRP metabolism is altered in CM and CTTH patients, leading to a reduction in plasma TRY. As TRY modulates the function of pain matrix serotonergic system, this may affect modulation of incoming nociceptive inputs from the trigeminal endings and posterior horns of the spinal cord. We suggest that these biochemical abnormalities play a role in the chronicity of CM and CTTH.”
Tryptamine levels are low in plasma of chronic migraine and chronic tension-type headache.
D'Andrea G, D'Amico D, Bussone G, Bolner A, Aguggia M, Saracco MG, Galloni E, De Riva V, D'Arrigo A, Colavito D, Leon A, Perini F.
Neurol Sci. 2014 Jul 14. [Epub ahead of print]
PMID: 25016960 [PubMed - as supplied by publisher]
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4. Serotonin Metabolism / Migraines ~ Wine Interference Mechanisms
“Wine, and specifically red wine, is a migraine trigger. Non-migraineurs may have headache attacks with wine ingestion as well. The reasons for that triggering potential are uncertain, but the presence of phenolic flavonoid radicals and the potential for interfering with the central serotonin metabolism are probably the underlying mechanisms of the relationship between wine and headache. Further controlled studies are necessary to enlighten this traditional belief.”
Wine and headache.
Krymchantowski AV, da Cunha Jevoux C.
Headache. 2014 Jun;54(6):967-75. doi: 10.1111/head.12365. Epub 2014 May 6.
PMID: 24801068 [PubMed - in process]
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5. Serotonin Homeostasis ~ New Migraine and Cluster Headache Horizons
“Migraine and cluster headache are primary headache disorders commonly encountered in clinical practice. … This article will highlight several of the new treatments that are currently under investigation including novel delivery mechanisms of already existing medications, calcitonin gene-related peptide (CGRP) receptor antagonists, antibodies to CGRP and its receptor, serotonin receptor agonists, transient receptor potential vanilloid receptor modulators, orexin receptor antagonists, glial cell modulators, and neuromodulation.”
New treatments for headache.
Vollbracht S, Rapoport AM.
Neurol Sci. 2014 May;35 Suppl 1:89-97. doi: 10.1007/s10072-014-1747-z.
PMID: 24867844 [PubMed - in process]
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Serotonin Video: The Truth about Depression BBC Full Documentary 2013
~
Posted by Bryan W. Brickner

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Homeostatic Cannabinoid Science ~ Publius’ World Cup Edition

7/6/2014

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PictureThe Cannabis Papers by Publius (2011)






The Cannabis Papers: A citizen’s guide to cannabinoids (2011)
By Publius


A World (Cup) of Cannabinoids: Fielders Edition

Today’s science roundup looks at ten articles on how the cannabinoid system (CS) modulates our health and homeostasis; the line-up links to 2014 CS PubMed articles: four directly on homeostasis, two on the circulatory system, two on the central nervous system, and one each on our digestive and respiratory systems.

I. CNS (Pediatric Brain Injury) and the CS
“Paediatric traumatic brain injury (TBI) is a leading cause of death and disability. Previous studies showed neuroprotection after TBI by (endo)cannabinoid mechanisms, suggesting involvement of cannabinoid receptors (CBR). … The results may provide explanation for the neuroprotective properties of cannabinoid ligands and future therapeutic strategies of TBI.”
Early increase of cannabinoid receptor density after experimental traumatic brain injury in the newborn piglet.
Donat CK, Fischer F, Walter B, Deuther-Conrad W, Brodhun M, Bauer R, Brust P.
Acta Neurobiol Exp (Wars). 2014;74(2):197-210.
PMID: 24993629 [PubMed - in process]
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II. Digestive System (Irritable Bowel Syndrome) and the CS
“The activation of the ATP ion-gated channels, voltage-gated sodium (Nav) and calcium (Cav) channels, as well as the activation of protease-activated receptors (PAR2), transient receptor potential vanilloide-1, serotonin, cannabinoids and cholecystokinin are involved in the genesis of visceral hypersensitivity in IBS.”
Main ion channels and receptors associated with visceral hypersensitivity in irritable bowel syndrome.
de Carvalho Rocha HA, Dantas BP, Rolim TL, Costa BA, de Medeiros AC.
Ann Gastroenterol. 2014;27(3):200-206. Review.
PMID: 24976114 [PubMed - as supplied by publisher] Free PMC Article
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III. Respiratory System (Paraquat and Acute Lung Injury) and the CS
“Paraquat [PQ], a widely used herbicide, is well known to exhibit oxidative stress and lung injury. … The results suggested that activating CB2 receptor exerted protective activity against PQ-induced ALI [Acute Lung Injury], and it potentially contributed to the suppression of the activation of MAPKs and NF- κ B pathways.”
CB2 Receptor Activation Ameliorates the Proinflammatory Activity in Acute Lung Injury Induced by Paraquat.
Liu Z, Wang Y, Zhao H, Zheng Q, Xiao L, Zhao M.
Biomed Res Int. 2014;2014:971750. doi: 10.1155/2014/971750. Epub 2014 May 22.
PMID: 24963491 [PubMed - in process] Free PMC Article
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IV. Homeostasis (Indole Quinuclidine Analogs) and the CS
“Therefore, indole quinuclidines are a novel structural class of compounds exhibiting high affinity and a range of intrinsic activity at cannabinoid type-1 and type-2 receptors.”
Characterization of the intrinsic activity for a novel class of cannabinoid receptor ligands: Indole quinuclidine analogs.
Franks LN, Ford BM, Madadi NR, Penthala NR, Crooks PA, Prather PL.
Eur J Pharmacol. 2014 Aug 15;737:140-8. doi: 10.1016/j.ejphar.2014.05.007. Epub 2014 May 20.
PMID: 24858620 [PubMed - in process]
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V. Circulatory System (Ischemic Heart Disease) and the CS
“Ischemic heart disease is associated with inflammation, interstitial fibrosis and ventricular dysfunction prior to the development of heart failure. … Therefore, the endocannabinoid-CB2 receptor axis plays a key role in cardioprotection during the initial phase of ischemic cardiomyopathy development.”
The endocannabinoid-CB2 receptor axis protects the ischemic heart at the early stage of cardiomyopathy.
Duerr GD, Heinemann JC, Suchan G, Kolobara E, Wenzel D, Geisen C, Matthey M, Passe-Tietjen K, Mahmud W, Ghanem A, Tiemann K, Alferink J, Burgdorf S, Buchalla R, Zimmer A, Lutz B, Welz A, Fleischmann BK, Dewald O.
Basic Res Cardiol. 2014 Jul;109(4):425. doi: 10.1007/s00395-014-0425-x. Epub 2014 Jul 1.
PMID: 24980781 [PubMed - in process]
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VI. Homeostasis, Endocannabinoid Deficiencies and the CS
“Subsequent research has confirmed that underlying endocannabinoid deficiencies indeed play a role in migraine, fibromyalgia, irritable bowel syndrome and a growing list of other medical conditions. Clinical experience is bearing this out. Further research and especially, clinical trials will further demonstrate the usefulness of medical cannabis. As legal barriers fall and scientific bias fades this will become more apparent.”
Clinical endocannabinoid deficiency (CECD) revisited: Can this concept explain the therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions?
Smith SC, Wagner MS.
Neuro Endocrinol Lett. 2014 Jun 30;35(3):198-201. [Epub ahead of print]
PMID: 24977967 [PubMed - as supplied by publisher]
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VII. Homeostasis (Epilepsy, Neuronal Plasticity) and the CS
“Synaptic communication requires constant adjustments of pre- and postsynaptic efficacies. In addition to synaptic long-term plasticity, the presynaptic machinery underlies homeostatic regulations which prevent out of range transmitter release. In this mini-review we will discuss the relevance of selected presynaptic mechanisms to epilepsy including voltage- and ligand-gated ion channels as well as cannabinoid and adenosine receptor signaling.”
Presynaptic mechanisms of neuronal plasticity and their role in epilepsy.
Meier J, Semtner M, Winkelmann A, Wolfart J.
Front Cell Neurosci. 2014 Jun 17;8:164. doi: 10.3389/fncel.2014.00164. eCollection 2014. Review.
PMID: 24987332 [PubMed]
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VIII. Homeostasis (Turning Agonists into Antagonists) and the CS
“However, we discovered that bivalency has an influence on the effect at both cannabinoid receptors. Moreover, we found out that the spacer length and the attachment position altered the efficacy of the bivalent ligands at the receptors by turning agonists into antagonists and inverse agonists.”
Synthesis and biological evaluation of bivalent cannabinoid receptor ligands based on hCB2R selective benzimidazoles reveal unexpected intrinsic properties.
Nimczick M, Pemp D, Darras FH, Chen X, Heilmann J, Decker M.
Bioorg Med Chem. 2014 Jun 13. pii: S0968-0896(14)00454-4. doi: 10.1016/j.bmc.2014.06.008. [Epub ahead of print]
PMID: 24984935 [PubMed - as supplied by publisher]
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IX. Circulatory System (Blood Vessels-Heart) and the CS
“2-Arachidonoylglycerol [2-AG] plays an important role in the regulation of the circulatory system via direct and/or indirect, through their metabolites, effects on blood vessels and/or heart. Accumulating evidence reveals that 2-AG is involved in the pathogenesis of various shocks and atherosclerosis.”
Role of endocannabinoid 2-arachidonoylglycerol in the physiology and pathophysiology of the cardiovascular system.
Karabowicz P, Grzęda E, Baranowska-Kuczko M, Malinowska B.
Postepy Hig Med Dosw (Online). 2014 Jun 12;68(0):814-27.
PMID: 24934539 [PubMed - in process]
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X. CNS (Brain Mitochondria) and the CS
“Our results show that the use of appropriate controls and quantifications allows detecting mtCB1 receptor with CB1 receptor antibodies, and that, if mitochondrial fractions are enriched and purified, CB1 receptor agonists reliably decrease respiration in brain mitochondria.”
Cannabinoid control of brain bioenergetics: Exploring the subcellular localization of the CB1 receptor.
Hebert-Chatelain E, Reguero L, Puente N, Lutz B, Chaouloff F, Rossignol R, Piazza PV, Benard G, Grandes P, Marsicano G.
Mol Metab. 2014 Apr 2;3(4):495-504. doi: 10.1016/j.molmet.2014.03.007. eCollection 2014 Jul.
PMID: 24944910 [PubMed] Free PMC Article
Related citations

See also: Alzheimer’s, Cancer and Homeostatic Cannabinoid Science

Bonus Video: Homeostasis

Posted by Bryan W. Brickner


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Solstice Serotonin (5HTP) Science Stories

6/20/2014

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PictureLife ~ circa 2014






Serotonin activation was our topic on 19 April 2014; it’s serotonin life sciences today with the precursor 5-HTP (5-hydroxytryptophan) in highlight. 

Below are four (brief) science stories from the National Institutes of Health (PubMed). Shortened titles should suffice to suggest the main themes: Therapeutic 5-HTP, Hot Flash and Breast Cancer Reduction, Irritable Bowels, and Morphine’s Efficacy. The links and quotes are from PubMed (1998-2014).

Healthy Solstice Everyone!
~.~
Therapeutic 5-HTP Has Been Shown … (1998)
“5-Hydroxytryptophan (5-HTP) is the intermediate metabolite of the essential amino acid L-tryptophan (LT) in the biosynthesis of serotonin. Intestinal absorption of 5-HTP does not require the presence of a transport molecule, and is not affected by the presence of other amino acids; therefore it may be taken with meals without reducing its effectiveness. … Therapeutic administration of 5-HTP has been shown to be effective in treating a wide variety of conditions, including depression, fibromyalgia, binge eating associated with obesity, chronic headaches, and insomnia.”
5-Hydroxytryptophan: a clinically-effective serotonin precursor.
Birdsall TC.
Altern Med Rev. 1998 Aug;3(4):271-80. Review.
PMID: 9727088 [PubMed - indexed for MEDLINE] Free Article
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Hot Flash (and Breast Cancer) Reduction: a hypothesis (2005)
“This would be particularly desirable for menopausal women with breast cancer or with risks of breast cancer. This article discusses the background information on hot flashes, SSRIs, tryptophan, and 5HTP, and possible clinical application of 5HTP for menopausal women with breast cancer risk.”
The potential of 5-hydryoxytryptophan for hot flash reduction: a hypothesis.
Curcio JJ, Kim LS, Wollner D, Pockaj BA.
Altern Med Rev. 2005 Sep;10(3):216-21.
PMID: 16164376 [PubMed - indexed for MEDLINE] Free Article
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A Serotonin-mediated Mechanism in Bowels (2014)
“Oral 5-HTP induced alterations in mucosal 5-HT metabolism. In healthy controls, a reinforcement of the intestinal barrier was seen whereas such reaction was absent in IBS [irritable bowel syndrome] patients. This could indicate the presence of a serotonin-mediated mechanism aimed to reinforce intestinal barrier function, which seems to dysfunction in IBS patients.”
Serotonergic reinforcement of intestinal barrier function is impaired in irritable bowel syndrome.
Keszthelyi D, Troost FJ, Jonkers DM, van Eijk HM, Lindsey PJ, Dekker J, Buurman WA, Masclee AA.
Aliment Pharmacol Ther. 2014 Jun 18. doi: 10.1111/apt.12842. [Epub ahead of print]
PMID: 24943480 [PubMed - as supplied by publisher]
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Serotonin and Morphine’s Efficacy (2014)
“Systemic administration of morphine increases 5-HT levels in the spinal cord, and the increase in 5-HT contributes to morphine-induced analgesia in the normal state but attenuates that in neuropathic pain through spinal 5-HT3 receptors. The plasticity of the descending serotonergic system may contribute to the reduced efficacy of systemic morphine in neuropathic pain.”
Peripheral Nerve Injury Reduces Analgesic Effects of Systemic Morphine via Spinal 5-Hydroxytryptamine 3 Receptors.
Kimura M, Obata H, Saito S.
Anesthesiology. 2014 Jun 2. [Epub ahead of print]
PMID: 24887968 [PubMed - as supplied by publisher]
Related citations

VIDEO:
5HTP benefit and side effects of 5htp, dosage, anxiety, weight loss, sleep

BONUS VIDEO: Serotonin/Binaural Beats
5-HTP secretion for happiness binaural beats, intensity WARNING

~ Posted by Bryan W. Brickner ~


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    Author

    Brickner has a 1997 political science doctorate from Purdue University, cofounded Illinois NORML in 2001, and was a 2007 National NORML Cannabis Advocate Awardee. He is also publisher and coauthor of the 2011 book banned by the Illinois Department of Corrections – The Cannabis Papers: A Citizen’s Guide to Cannabinoids.

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