"Our findings identify distinctive mucosal microbial signatures in ASD [autism spectrum disorder] children with FGID [functional gastrointestinal disorders] that correlate with cytokine and tryptophan homeostasis."
So said the study results published by Ruth Ann Luna and colleagues [1] who "compared mucosa-associated microbial communities in children with ASD to previous reports characterizing stool in this population" among other things. If you are eating breakfast/lunch/dinner at the time of reading this post, maybe give it a few minutes before reading on...
So rectal biopsies and blood specimens were the samples under investigation and the focus was very much on those children on and off the autism spectrum who also presented with various functional bowel issues. Just before anyone starts to question the ethics of taking biopsies and the like, the authors expand by reporting that participants were "undergoing a lower endoscopy for one of the following symptoms: abdominal pain, altered stool patterns, or painless bright red blood per rectum." In these days of health inequality attached to the label of autism (see here for an example), these were children who were being investigated for their bowel issues and not being unnecessarily subjected to such invasive techniques just for the sake of science.
The various analyses undertaken on those blood and biopsy samples were pretty wide-ranging. Bacterial species present in mucosal samples and their supernatants were included but so researchers also looked at cytokines (various chemical markers linked to immune function among other things) in blood samples and supernatants and levels of "serotonergic metabolites" (chemicals related to the aromatic amino acid tryptophan) pertinent to their "microbiome-neuroimmune signatures" hypothesis testing. Bear in mind that when it comes to the neurotransmitter called serotonin (5-HT), the gut truly is the second brain.
Results: taking into account the relatively small participant numbers included for study - "ASD children with functional GI disorders (ASD-FGID, n=14), as compared to neurotypical (NT) children with (NT-FGID, n=15) and without abdominal pain (NT, n=6)" - there were some interesting, if not unexpected, results to be seen. "Principal component analysis showed clear separation between the ASD-FGID group and the NT-FGID and NT groups" on the basis of the bacterial communities present in those mucosal samples. In the autism group, several mucosa-associated Clostridiales species were predominant as per that noted in other independent findings (see here). Interestingly authors also observed "marked decreases in Dorea and Blautia, as well as Sutterella" species perhaps contrasting with other research in this area (see here). I'll let readers trawl through the other bacterial families talked about in the paper including those potentially linked to the presence of specific functional bowel states derived from questionnaire data from participants.
Looking at any potential associations between mucosal bacterial communities, cytokines and those tryptophan metabolites, researchers also reported some important, if preliminary, observations. So: "Group comparisons revealed that IL-6 [interleukin 6] and tryptophan release by mucosal biopsies was highest in ASD children with abdominal pain, whereas serotonergic metabolites were generally elevated in children with FGIDs." I'd like to see these findings replicated in larger groups before I make anymore of what their potential significance could be but it is intriguing that pain might play some hand in immune signalling and the production of amino acid metabolites. More so when one considers other related research [2].
On the back of a recent post talking about blood-based 'biomarkers' pertinent to more pathological bowel states occurring alongside cases of autism (see here) it is good to see that autism + GI issues is starting to receive a little more scientific attention. It shows that science has moved on from the question 'are bowel symptoms over-represented when it comes to autism?' (answer: yes) and actually started to look at the questions of 'why? and 'how?' The focus on gut bacteria is a worthy cause (see here) and if replicated and found to be important, opens up various intervention options derived from work in other areas of medicine (see here). Indeed, there is a 'watch this space' call for investigations looking at probiotics and autism for example (see here) with the promise of more to come [3]. Oh, and don't forget the good old 'gut-brain axis' when it comes to a possible tie-up between bowel and brain with at least some autism in mind.
But for now, autism, gut disorder, gut bacterial composition, mucosal immune function and little old tryptophan and its metabolites get some well deserved combined research attention...
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[1] Luna RA. et al. Distinct microbiome-neuroimmune signatures correlate with functional abdominal pain in children with autism spectrum disorder. CMGH Cellular and Molecular Gastroenterology and Hepatology. 2016. Dec 11.
[2] Ahmad SF. et al. Imbalance between the anti- and pro-inflammatory milieu in blood leukocytes of autistic children. Mol Immunol. 2016 Dec 24;82:57-65.
[3] Navarro F. et al. Can probiotics benefit children with autism spectrum disorders? World J Gastroenterol. 2016 Dec 14;22(46):10093-10102.
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Luna, R., Oezguen, N., Balderas, M., Venkatachalam, A., Runge, J., Versalovic, J., Veenstra-VanderWeele, J., Anderson, G., Savidge, T., & Williams, K. (2016). Distinct microbiome-neuroimmune signatures correlate with functional abdominal pain in children with autism spectrum disorder CMGH Cellular and Molecular Gastroenterology and Hepatology DOI: 10.1016/j.jcmgh.2016.11.008
Showing posts with label serotonin. Show all posts
Showing posts with label serotonin. Show all posts
Wednesday, 4 January 2017
Thursday, 12 May 2016
Shared genetics? Autism, gastrointestinal issues and serotonin
I note the paper by Kara Gross Margolis and colleagues [1] (open-access available here) has been garnering a few media headlines with the suggestion that: "Gastrointestinal [GI] problems in autistic children may be linked to the same genetic mutations that cause other characteristics of autism spectrum disorder."The study, focusing on the idea that SERT (the serotonin transporter) encoded by the SLC6A4 gene might show some connection to 'some' autism [2], looked to model gastrointestinal (GI) development in a mouse model where SERT function were affected - SERT variant (Ala56). They compared results on various parameters with "those obtained in mice either lacking SERT or treated from gestation to weaning with the selective 5-HT reuptake inhibitor fluoxetine" and wild-type (WT) mice. I should point out that these results were expected to be published around about now and Dr Margolis, a paediatric gastroenterologist, seems to have quite a bit of interest in this whole area.
Results: bearing in mind this was a study of mice, and included only quite a small number of mice, some interesting results are presented: "The ENS [enteric nervous system] was strikingly hypoplastic in SERT Ala56 mice." This 'under-development' of the 'thinking part' of the gut manifested as less neurons being found in various regions of the gut (yes, your gut does house neurons) compared to the other models looked at. The authors suggest that their findings are "consistent with the ideas that defective 5-HT signaling due to the increased 5-HT clearance of SERT Ala56 mice interferes with enteric neurogenesis." 5-HT by the way, is another name for serotonin. Further: "The data are also consistent with the hypothesis that a defect common to the ENS and CNS [central nervous system] could be responsible in ASD [autism spectrum disorder] for comorbid GI disturbances."
They also reported that gut motility - "GI transit time and colonic transit" - was also affected in the SERT Ala56 mice where "slow GI transit [and] diminished peristaltic reflex activity" were more readily present compared to other models. The press release accompanying the study quotes the authors on these points: "Basically, the gut goes slower and the mice were constipated, which is a common complaint in kids with autism." Indeed it is (see here).
And then to quite an interesting piece of information: "The SERT Ala56 mutation decreases crypt epithelial cell proliferation, stunts growth of villi, and decreases mucosal permeability." Decreases mucosal permeability eh? If I'm reading is right (and I'm not expert in this area), all that talk about increased gut permeability (intestinal hyperpermeability) and [some] autism (see here) might have something of a counter-balance under certain circumstances and serotonin (5-HT) might play something of a role...
Finally: "Administration of a 5-HT4 agonist [prucalopride] to Ala56 mice during development prevented Ala56-associated GI perturbations, suggesting that excessive SERT activity leads to inadequate 5-HT4-mediated neurogenesis." The authors caution that although the drug seemed to affect GI issues in the Ala56 mice, this does not necessarily mean that it will do the same in humans carrying the same genetic issue.
Despite the methodological issues associated with this type of study, there are quite a few avenues of further research indicated. Not least is the requirement to identify those people carrying the gain-of-function SERT Ala56 mutation and compare and contrast with other non-carriers in terms of things like gastrointestinal (GI) functions as well as perhaps on other behavioural parameters. This set in the context of functional bowel issues already being suggested to impact on behaviour (see here). The associated idea that offspring of those mice who were treated with the antidepressant fluoxetine during pregnancy might show a distinct pattern of GI issues is also worthy of further study without any big headlines. Accepting that such medication use and risk of offspring autism is still a bit of a scientific hot potato (see here), it looks like a little more science in this area could be indicated.
Music to close, and when following Sunderland Association Football Club, this piece seems particularly apt... (blood pressure starting to return to normal).
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[1] Margolis KG. et al. Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function. J Clin Invest. 2016 Apr 25. pii: 84877.
[2] Muller CL. et al. The serotonin system in autism spectrum disorder: From biomarker to animal models. Neuroscience. 2016 May 3;321:24-41.
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Margolis KG, Li Z, Stevanovic K, Saurman V, Israelyan N, Anderson GM, Snyder I, Veenstra-VanderWeele J, Blakely RD, & Gershon MD (2016). Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function. The Journal of clinical investigation PMID: 27111230
Tuesday, 15 December 2015
Pregnancy antidepressant use and risk of offspring autism (again)
"Use of antidepressants, specifically selective serotonin reuptake inhibitors, during the second and/or third trimester increases the risk of ASD [autism spectrum disorder] in children, even after considering maternal depression."
That was the conclusion reported in the study by Takoua Boukhris and colleagues [1] dealing with a topic which has previously graced the autism research landscape (see here and see here). Detailing the results of a "register-based study of an ongoing population-based cohort, the Québec Pregnancy/Children Cohort" covering data on all pregnancies in Québec (Canada) between 1998 and 2009 (N=145 456 singleton full-term infants born alive and whose mothers were "covered by the Régie de l’assurance maladie du Québec drug plan for at least 12 months before and during pregnancy"), the Boukhris results have created quite the media stir.
Among the 140,000+ infants followed up, just over 1000 were eventually diagnosed with an autism spectrum disorder (ASD) equating to 0.7% of the population. When researchers looked at those who were prenatally exposed to antidepressants specifically during the second or third trimester of pregnancy, the rate of ASD was calculated at 1.2%. When also controlling for potentially confounding variables such as a maternal history of depression, the elevated risk of offspring autism persisted. Ergo, there may be more to see when it comes to antidepressant use during pregnancy and offspring developmental outcomes. I might also direct readers to an editorial discussing the findings [2].
Most of the media on this latest paper have been quite sensible about the findings. They've for example, pointed out that other research studies have reported slightly less in the way of any connection between pregnancy antidepressant use and offspring autism (see here) as well as putting the results into some context with the idea of what 'elevated risk' might actually translate into (see here). That also antidepressant use during pregnancy is not normally entered into lightly without good reason is something else that I'd bring into proceedings as per other research talking about other pregnancy medication use and potentially elevated risk to offspring outcomes (see here).
The authors do suggest that more research is required to build on their findings and "to specifically assess the risk of ASD associated with antidepressant types and dosages during pregnancy." I would agree that we do need more data on this possible association (including that from animal models and related studies) in order to ascertain whether specific medicine formulations might be more strongly involved and onwards the possible mechanism(s) of effect. I'm not necessarily sold on the idea that serotonin chemistry is specifically the be-all-and-end-all of any effect on the unborn child given what we are starting to realise about the wide-ranging effects of various medicines outside of that listed on the package insert (see here). I am willing however to entertain the idea that the further reaches of tryptophan metabolism might eventually come into the frame (see here). We await further studies.
Music now, and with the imminent launch of a certain Russian Soyuz rocket, a song for Tim...
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[1] Boukhris T. et al. Antidepressant Use During Pregnancy and the Risk of Autism Spectrum Disorder in Children. JAMA Pediatrics. 2015. Dec 14.
[2] King BH. Assessing Risk of Autism Spectrum Disorder in Children After Antidepressant Use During Pregnancy. JAMA Pediatrics. Dec 14.
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Boukhris, T., Sheehy, O., Mottron, L., & Bérard, A. (2015). Antidepressant Use During Pregnancy and the Risk of Autism Spectrum Disorder in Children JAMA Pediatrics DOI: 10.1001/jamapediatrics.2015.3356
That was the conclusion reported in the study by Takoua Boukhris and colleagues [1] dealing with a topic which has previously graced the autism research landscape (see here and see here). Detailing the results of a "register-based study of an ongoing population-based cohort, the Québec Pregnancy/Children Cohort" covering data on all pregnancies in Québec (Canada) between 1998 and 2009 (N=145 456 singleton full-term infants born alive and whose mothers were "covered by the Régie de l’assurance maladie du Québec drug plan for at least 12 months before and during pregnancy"), the Boukhris results have created quite the media stir.
Among the 140,000+ infants followed up, just over 1000 were eventually diagnosed with an autism spectrum disorder (ASD) equating to 0.7% of the population. When researchers looked at those who were prenatally exposed to antidepressants specifically during the second or third trimester of pregnancy, the rate of ASD was calculated at 1.2%. When also controlling for potentially confounding variables such as a maternal history of depression, the elevated risk of offspring autism persisted. Ergo, there may be more to see when it comes to antidepressant use during pregnancy and offspring developmental outcomes. I might also direct readers to an editorial discussing the findings [2].
Most of the media on this latest paper have been quite sensible about the findings. They've for example, pointed out that other research studies have reported slightly less in the way of any connection between pregnancy antidepressant use and offspring autism (see here) as well as putting the results into some context with the idea of what 'elevated risk' might actually translate into (see here). That also antidepressant use during pregnancy is not normally entered into lightly without good reason is something else that I'd bring into proceedings as per other research talking about other pregnancy medication use and potentially elevated risk to offspring outcomes (see here).
The authors do suggest that more research is required to build on their findings and "to specifically assess the risk of ASD associated with antidepressant types and dosages during pregnancy." I would agree that we do need more data on this possible association (including that from animal models and related studies) in order to ascertain whether specific medicine formulations might be more strongly involved and onwards the possible mechanism(s) of effect. I'm not necessarily sold on the idea that serotonin chemistry is specifically the be-all-and-end-all of any effect on the unborn child given what we are starting to realise about the wide-ranging effects of various medicines outside of that listed on the package insert (see here). I am willing however to entertain the idea that the further reaches of tryptophan metabolism might eventually come into the frame (see here). We await further studies.
Music now, and with the imminent launch of a certain Russian Soyuz rocket, a song for Tim...
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[1] Boukhris T. et al. Antidepressant Use During Pregnancy and the Risk of Autism Spectrum Disorder in Children. JAMA Pediatrics. 2015. Dec 14.
[2] King BH. Assessing Risk of Autism Spectrum Disorder in Children After Antidepressant Use During Pregnancy. JAMA Pediatrics. Dec 14.
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Boukhris, T., Sheehy, O., Mottron, L., & Bérard, A. (2015). Antidepressant Use During Pregnancy and the Risk of Autism Spectrum Disorder in Children JAMA Pediatrics DOI: 10.1001/jamapediatrics.2015.3356
Friday, 3 July 2015
Vitamin D metabolic gene variants and risk for autism
I was really rather happy to see the "preliminary evidence" reported by Rebecca Schmidt and colleagues [1] when it came to examining whether selected vitamin D metabolic gene variants might show linkage to autism spectrum disorder (ASD) based on data derived from the CHARGE initiative.For quite a while now I've discussed the various peer-reviewed science on the topic of vitamin D deficiency / insufficiency with autism in mind on this blog (see here and see here for example). Specifically, how a diagnosis of ASD seems to offer little protection against issues with vitamin D appearing and what that could mean for important issues such as bone health (see here) for example.
A key component that seemed to be missing from the growing volume of research looking at vitamin D and autism was some discussion about whether the genetics of vitamin production and usage might offer some further clues to how vitamin D might more directly be 'linked' to [some] autism. Schmidt et al have started to put some flesh on to the scientific bones in this area following their previous research discussions on vits and SNPs with autism in mind (see here) .
So: "Maternal, paternal, and child DNA samples for 384 (81%) families of children with ASD and 234 (83%) families of TD [typically developing] children were genotyped for: TaqI, BsmI, FokI, and Cdx2 in the vitamin D receptor (VDR) gene, and CYP27B1 rs4646536, GC rs4588, and CYP2R1 rs10741657." In effect, researchers looked for potential genetic 'issues' with the vitamin D receptor (VDR) gene that have previously been linked to various health issues. They found some potentially interesting information including: "Paternal VDR TaqI homozygous variant genotype was significantly associated with ASD in case-control analysis." Homozygous by the way, refers to the concept of zygosity and the fact we have pairs of chromosomes. Further: "A significant association between decreased ASD risk and child CYP2R1 AA-genotype was found in hybrid log-linear analysis."
This is early days research insofar as the genetics of vitamin D and autism only being mentioned once before in the research literature as per the report from Yan and colleagues [2]. I'm excited at the Schmidt data but am not going to go all out on this very preliminary inspection of vitamin D receptor gene functioning without further large-scale replication and validation studies being carried out including discussions on things like cognitive ability in light of other recent data [3]. Whilst we are however, on the topic of vitamin D and its potential extra-skeletal activities, I'm minded to also bring in the paper by Kaneko and colleagues [4] and their results implying that "vitamin D affects brain serotonin concentrations" with mention of autism among other labels. Reporting on a particularly interesting enzyme - tryptophan hydroxylase (TPH)2 - which has an important role in serotonin metabolism (see here) I'll be watching closely on how vitamin D research with autism in mind also develops in this area.
And then there are the Raftery results [5] to bring to your attention putting further scientific flesh on to the bones about the possibility of a relationship between vitamin D levels and intestinal permeability (see here). Given what has been mentioned about 'leaky gut' and autism in the peer-reviewed literature so far (see here) one might also add this to further investigations in this area...
Music: I am the Monarch of the Sea.
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[1] Schmidt RJ. et al. Selected vitamin D metabolic gene variants and risk for autism spectrum disorder in the CHARGE Study. Early Hum Dev. 2015 Jun 11;91(8):483-489.
[2] Yan J. et al. Vitamin D receptor variants in 192 patients with schizophrenia and other psychiatric diseases. Neurosci Lett. 2005 May 20-27;380(1-2):37-41.
[3] Jorde R. et al. Vitamin D and cognitive function: The Tromsø Study. J Neurol Sci. 2015 Jun 7. pii: S0022-510X(15)00350-0.
[4] Kaneko I. et al. 1,25-Dihydroxyvitamin D regulates expression of the tryptophan hydroxylase 2 and leptin genes: implication for behavioral influences of vitamin D. FASEB J. 2015 Jun 12. pii: fj.14-269811.
[5] Raftery T. et al. Effects of vitamin D supplementation on intestinal permeability, cathelicidin and disease markers in Crohn's disease: Results from a randomised double-blind placebo-controlled study. United European Gastroenterol J. 2015 Jun;3(3):294-302.
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Schmidt RJ, Hansen RL, Hartiala J, Allayee H, Sconberg JL, Schmidt LC, Volk HE, & Tassone F (2015). Selected vitamin D metabolic gene variants and risk for autism spectrum disorder in the CHARGE Study. Early human development, 91 (8), 483-489 PMID: 26073892
Tuesday, 25 November 2014
Serotonin - melatonin (and the in-betweeners) linked to autism
The paper by Pagan and colleagues [1] (open-access) looking at "serotonin, melatonin and the intermediate N-acetylserotonin (NAS) in a large cohort of patients with ASD [autism spectrum disorder] and their relatives" set the old grey-pink matter into action recently. Not only because I have some real interest in the starting material for these compounds - the aromatic amino acid known as tryptophan - but because this research group included some quite important analysis of the enzymes involved in the reaction from serotonin to melatonin with autism in mind.
Just before heading into the paper and the details, I'm gonna draw your attention to the picture shown to the right (hand drawn by yours truly) which was originally included in a blog post on something called 5-hydroxytryptophan (5-HTP). As you can see, the source material tryptophan eventually cascades down into various other compounds with serotonin and melatonin in mind. I might add that this is not the only metabolic fate of tryptophan as, for example, per another important compound set: the kynurenine pathway again talked about on this blog.
Serotonin (5-HT) for those who might not know is a neurotransmitter that represents one of the 'S' in the class of medicines called SSRIs hinting at its relationship to mood regulation among other things. Melatonin by contrast has quite an important role in functions like sleep; although, as has been previously mentioned on this blog, melatonin might be quite the molecular handyperson (see here). Both serotonin and melatonin have some history when it comes to autism research and practice (see here for example).
N-acetylserotonin (NAS) is a slightly less well-known compound when it comes to autism. A quick trawl of PubMed using the search term 'N-Acetylserotonin autism' came up with two other entries at the time of writing. Granted both the Anderson-Maes [2] and Carter and colleagues [3] make for interesting reading for different reasons, but there does seem to be a dearth of research on the possibility of a role for NAS for at least some autism.
Now, back to the Pagan paper and a few pointers even though it is open-access:
I've gone on a little bit in this post but hope that you can see the logic in doing so. Metabolic pathways when it comes to human physiology are pretty complex things affected by all manner of variables including things like enzyme function and the availability of those all-important cofactors (see here for some chatter about BH4 for example). Pagan et al have done a good preliminary job of stitching together some important compounds with autism in mind and particularly their findings in relation to NAS. I personally am looking forward to seeing some independent replication of these findings and perhaps onwards, a little more analysis of some other tryptophan derivatives [5] potentially important to [some] autism...
A little music to close: Mark Ronson - Uptown Funk.
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[1] Pagan C. et al. The serotonin-N-acetylserotonin–melatonin pathway as a biomarker for autism spectrum disorders. Translational Psychiatry. 2014. November 11.
[2] Anderson G. & Maes M. Redox Regulation and the Autistic Spectrum: Role of Tryptophan Catabolites, Immuno-inflammation, Autoimmunity and the Amygdala. Curr Neuropharmacol. 2014 Mar;12(2):148-67.
[3] Carter MD. et al. Quantitation of melatonin and n-acetylserotonin in human plasma by nanoflow LC-MS/MS and electrospray LC-MS/MS. J Mass Spectrom. 2012 Mar;47(3):277-85.
[4] Melke J. et al. Abnormal melatonin synthesis in autism spectrum disorders. Mol Psychiatry. 2008 Jan;13(1):90-8.
[5] Anderson RJ. et al. Identification of indolyl-3-acryloylglycine in the urine of people with autism. J Pharm Pharmacol. 2002 Feb;54(2):295-8.
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Pagan C, Delorme R, Callebert J, Goubran-Botros H, Amsellem F, Drouot X, Boudebesse C, Le Dudal K, Ngo-Nguyen N, Laouamri H, Gillberg C, Leboyer M, Bourgeron T, & Launay JM (2014). The serotonin-N-acetylserotonin-melatonin pathway as a biomarker for autism spectrum disorders. Translational psychiatry, 4 PMID: 25386956
Just before heading into the paper and the details, I'm gonna draw your attention to the picture shown to the right (hand drawn by yours truly) which was originally included in a blog post on something called 5-hydroxytryptophan (5-HTP). As you can see, the source material tryptophan eventually cascades down into various other compounds with serotonin and melatonin in mind. I might add that this is not the only metabolic fate of tryptophan as, for example, per another important compound set: the kynurenine pathway again talked about on this blog.
Serotonin (5-HT) for those who might not know is a neurotransmitter that represents one of the 'S' in the class of medicines called SSRIs hinting at its relationship to mood regulation among other things. Melatonin by contrast has quite an important role in functions like sleep; although, as has been previously mentioned on this blog, melatonin might be quite the molecular handyperson (see here). Both serotonin and melatonin have some history when it comes to autism research and practice (see here for example).
N-acetylserotonin (NAS) is a slightly less well-known compound when it comes to autism. A quick trawl of PubMed using the search term 'N-Acetylserotonin autism' came up with two other entries at the time of writing. Granted both the Anderson-Maes [2] and Carter and colleagues [3] make for interesting reading for different reasons, but there does seem to be a dearth of research on the possibility of a role for NAS for at least some autism.
Now, back to the Pagan paper and a few pointers even though it is open-access:
- The hypothesis: "that (i) the intermediate NAS might also be altered, (ii) alterations of the serotonin-NAS–melatonin pathway might constitute a possible biomarker for a subgroup of individuals with ASD and that (iii) they would be associated with specific clinical profiles."
- Whilst avoiding foods high in tryptophan and/or serotonin such as bananas and chocolate, morning blood samples were provided by "278 patients with ASD, their 506 first-degree relatives (129 unaffected siblings, 199 mothers and 178 fathers) and 416 sex- and age-matched controls" and various parts of the sample assayed for serotonin, melatonin and NAS. The analytical weapons of choice were HPLC (albeit with a rather antiquated method by today's mass spec / NMR standards) and ELISA among other things. A small number of urine samples were also collected and analysed for 6-Sulfatoxymelatonin.
- Results: on the whole, those with autism presented with "elevated whole-blood serotonin" whilst "Plasma melatonin was significantly decreased in individuals with ASD and their relatives compared with controls." These are not surprising results given the research history in this area.
- With slightly more novelty: "the intermediate metabolite NAS, measured in blood platelets, was found to be significantly elevated in individuals with ASD and their relatives compared with controls." Further such elevations in platelet NAS "strongly correlated" with the plasma melatonin findings noted in cases of autism.
- There was potentially also something to see when the results were pooled together in terms of discriminating autism from not-autism but I'll leave it up to you to decide how well their biomarkers functioned.
- Bearing in mind my diagram shown above, the increase in serotonin, increase in NAS but decrease in melatonin might provide some important information about where there may be a metabolic 'block'. In this respect, the authors' analysis of "two enzymes, AANAT [Aralkylamine N-acetyltransferase] and ASMT [N-Acetylserotonin O-methyltransferase] known to form protein complexes with 14-3-3 scaffolding proteins" is also important. Actually, authors looked at 14-3-3 in platelets and reported it/them: "significantly decreased in patients with ASD." Previous work from this group [4] had indicated that ASMT activity to be lower in cases of autism; thus suggesting that problems with this enzyme or the availability of this enzyme converting NAS to melatonin might for example, account for the lower melatonin findings.
I've gone on a little bit in this post but hope that you can see the logic in doing so. Metabolic pathways when it comes to human physiology are pretty complex things affected by all manner of variables including things like enzyme function and the availability of those all-important cofactors (see here for some chatter about BH4 for example). Pagan et al have done a good preliminary job of stitching together some important compounds with autism in mind and particularly their findings in relation to NAS. I personally am looking forward to seeing some independent replication of these findings and perhaps onwards, a little more analysis of some other tryptophan derivatives [5] potentially important to [some] autism...
A little music to close: Mark Ronson - Uptown Funk.
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[1] Pagan C. et al. The serotonin-N-acetylserotonin–melatonin pathway as a biomarker for autism spectrum disorders. Translational Psychiatry. 2014. November 11.
[2] Anderson G. & Maes M. Redox Regulation and the Autistic Spectrum: Role of Tryptophan Catabolites, Immuno-inflammation, Autoimmunity and the Amygdala. Curr Neuropharmacol. 2014 Mar;12(2):148-67.
[3] Carter MD. et al. Quantitation of melatonin and n-acetylserotonin in human plasma by nanoflow LC-MS/MS and electrospray LC-MS/MS. J Mass Spectrom. 2012 Mar;47(3):277-85.
[4] Melke J. et al. Abnormal melatonin synthesis in autism spectrum disorders. Mol Psychiatry. 2008 Jan;13(1):90-8.
[5] Anderson RJ. et al. Identification of indolyl-3-acryloylglycine in the urine of people with autism. J Pharm Pharmacol. 2002 Feb;54(2):295-8.
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Pagan C, Delorme R, Callebert J, Goubran-Botros H, Amsellem F, Drouot X, Boudebesse C, Le Dudal K, Ngo-Nguyen N, Laouamri H, Gillberg C, Leboyer M, Bourgeron T, & Launay JM (2014). The serotonin-N-acetylserotonin-melatonin pathway as a biomarker for autism spectrum disorders. Translational psychiatry, 4 PMID: 25386956
Sunday, 16 December 2012
The hyposerotonemic mouse and autism
Dear readers, please don't be put of this post by the title. All it refers to is a mouse described by Kane and colleagues* (open-access) which was engineered with a null mutation in the TPH2 gene governing the production of tryptophan hydroxylase, a required step in the synthesis of the aromatic amino acid tryptophan to everyone's favourite neurotransmitter, serotonin (or as we Brits like to call it 5-HT). Said mouse was unable to produce serotonin and hence lacked it - hyposerotonemia - despite having all the necessary receptors et al.
Kane and colleagues set about looking at mice "derived from matings of heterozygous (TPH2+/−) males and heterozygous (TPH2+/−) females on a mixed C57BL/6-Sv129 background".
This selective breeding produced offspring who were homozygous for the null mutation, basically carrying the null mutation on both chromosome pairs (TPH2-/-). They then set about testing the TPH2-/- mice on various measures across various ages corresponding to human years (infancy, juvenile, adulthood) and compared results with wild-type pups who were not serotonin deficient.
Their findings? Well, the TPH2-/- mice presented with some interesting developmental features. A delay in hitting certain developmental milestones, transient early brain overgrowth normalising into the equivalent teen years and adulthood, among other things.
When put to various tasks equivalent to looking at some of the core and peripheral features associated with human autism spectrum disorders - a kind of mouse ADOS if you will - the TPH2-/- mice showed some significant differences in their behaviours compared with wild-type mice. So less preference for mother mouse's scent interpreted as the "early signs of a social communication deficit", alongside other socialisation issues and lots of repetitive, compulsive behaviours persisting into mouse adulthood. I'm not going to get to heavily into each individual finding because it's all there in the full-text paper.
The authors conclude: "these results indicate that a hypo-serotonin condition can lead to behavioral traits that are highly characteristic of autism" and certainly I am not going to disagree with them. Yes, you could again use the argument that this was a mouse and not a human being, and the fact us humans are very, very, very complicated creatures by comparison. You could also argue that quite a few of the behaviours described by Kane and colleagues are also associated with other behavioural and psychiatrically-defined conditions and need not be just necessarily construed as autism; depression for example, bearing in mind the timing of presentation. It's a complicated picture of inference and 'ifs and buts' not helped by the mixed bag of research on serotonin and autism.
I remain however interested in these findings and indeed in the whole area of mouse models and autism given previous discussions on the BTBR dangermouse and also how mouse models might be able to translate autism hypotheses into viable murine-based findings. Er, should I mention sulphation and leaky gut here too, or is that old news now? Bearing in mind that those TPH2-/- mice might also carry other mutations and indeed epigenetic differences too, I'll be keeping an eye on the hyposerotonemic mouse research and just how useful it might be to autism research.
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* Kane MJ. et al. Mice genetically depleted of brain serotonin display social impairments, communication deficits and repetitive behaviors: possible relevance to autism. PLoS ONE. 2012; 7: e48975.
----------
Kane MJ, Angoa-Peréz M, Briggs DI, Sykes CE, Francescutti DM, Rosenberg DR, & Kuhn DM (2012). Mice genetically depleted of brain serotonin display social impairments, communication deficits and repetitive behaviors: possible relevance to autism. PloS one, 7 (11) PMID: 23139830
 |
| Meeces to pieces... @ Wikipedia |
This selective breeding produced offspring who were homozygous for the null mutation, basically carrying the null mutation on both chromosome pairs (TPH2-/-). They then set about testing the TPH2-/- mice on various measures across various ages corresponding to human years (infancy, juvenile, adulthood) and compared results with wild-type pups who were not serotonin deficient.
Their findings? Well, the TPH2-/- mice presented with some interesting developmental features. A delay in hitting certain developmental milestones, transient early brain overgrowth normalising into the equivalent teen years and adulthood, among other things.
When put to various tasks equivalent to looking at some of the core and peripheral features associated with human autism spectrum disorders - a kind of mouse ADOS if you will - the TPH2-/- mice showed some significant differences in their behaviours compared with wild-type mice. So less preference for mother mouse's scent interpreted as the "early signs of a social communication deficit", alongside other socialisation issues and lots of repetitive, compulsive behaviours persisting into mouse adulthood. I'm not going to get to heavily into each individual finding because it's all there in the full-text paper.
The authors conclude: "these results indicate that a hypo-serotonin condition can lead to behavioral traits that are highly characteristic of autism" and certainly I am not going to disagree with them. Yes, you could again use the argument that this was a mouse and not a human being, and the fact us humans are very, very, very complicated creatures by comparison. You could also argue that quite a few of the behaviours described by Kane and colleagues are also associated with other behavioural and psychiatrically-defined conditions and need not be just necessarily construed as autism; depression for example, bearing in mind the timing of presentation. It's a complicated picture of inference and 'ifs and buts' not helped by the mixed bag of research on serotonin and autism.
I remain however interested in these findings and indeed in the whole area of mouse models and autism given previous discussions on the BTBR dangermouse and also how mouse models might be able to translate autism hypotheses into viable murine-based findings. Er, should I mention sulphation and leaky gut here too, or is that old news now? Bearing in mind that those TPH2-/- mice might also carry other mutations and indeed epigenetic differences too, I'll be keeping an eye on the hyposerotonemic mouse research and just how useful it might be to autism research.
----------
* Kane MJ. et al. Mice genetically depleted of brain serotonin display social impairments, communication deficits and repetitive behaviors: possible relevance to autism. PLoS ONE. 2012; 7: e48975.
----------
Kane MJ, Angoa-Peréz M, Briggs DI, Sykes CE, Francescutti DM, Rosenberg DR, & Kuhn DM (2012). Mice genetically depleted of brain serotonin display social impairments, communication deficits and repetitive behaviors: possible relevance to autism. PloS one, 7 (11) PMID: 23139830
Monday, 25 June 2012
What's with 5-hydroxytryptophan (5-HTP)?
I might have said it before so please do excuse the repetition, but the aromatic amino acid tryptophan has been of some interest to me down the years. Like most people who have heard or know about tryptophan, the connection with serotonin (5-hydroxytryptamine or 5-HT) seems to be the big attraction when it comes to this very important amino acid and its pretty important effects on biology and daily life.
Putting serotonin slightly to one side for this post, I instead want to talk about another player along the tryptophan - serotonin pathway, 5-hydroxytryptophan (5-HTP) and various lines of study to this important intermediary compound in what is admittedly, a slightly disjointed post.
I was brought to this post by two factors:
Before your eyes start to glaze over and you reach for the 'click away' button, it is probably best if I start at the beginning and briefly show you how things usually go with regards to tryptophan, serotonin and melatonin. So in my very best handwriting (yes, you can perhaps see why I didn't ace certain school exams) and with no expense spared... see figure 1.
In short:
L-Tryptophan is converted to 5-HTP via the enzyme tryptophan hydroxylase, TPH which relies on the cofactors of iron and BH4 for optimal functioning. Keep this cofactor thing in mind.
5-HTP is then converted to serotonin (5-HT) and onwards to various other compounds including 5-hydroxyindoleaceticacid (5-HIAA).
The conversion of 5-HT to melatonin is via the intermediate compound, N-Acetlyserotonin (NAS).
Just before anyone mentions, I have only included the TPH enzyme in my schematic and not the other enzymes involved in the various other reactions so as to keep it simple.
Hopefully you can see from my scribbles the central role tryptophan plays in this important metabolic process and how little issues with components in the pathway can potentially have knock-on effects for downstream metabolites.
So to the title of this post: "What's with 5-hydroxytryptophan?". Well, potentially quite a bit.
The first time I heard about 5-HTP was with reference to the collected data on the potential therapeutic use of the compound in cases of depression as per the Cochrane Review by Shaw and colleagues** (full-text). As per nearly every Cochrane Review I've ever read, the text reads something like, a few trials showing possible effects from [5-HTP] supplementation on depressive symptoms but not enough rigorous study to be able to form a suitable opinion. Don't believe me... well, see the Cochrane Review for GFCF diets for autism (here). Anyway, mention also of the fact that antidepressants already exist to 'treat' depression probably accounts for the drop in research interest in this area in recent years. That and possibly 'peak X' (see here for more details).
Where next?
Sleeping aid. Looking again at the magnificent figure offered to accompany this post, one could perhaps see how sleep could be affected by 5-HTP purely based on melatonin featuring some way down the pathway. The evidence.. well let's just say it needs improving despite some initial attempts (here and here). Additional evidence on any direct effect from 5-HTP administration on melatonin levels is even more scant.
Fibromyalgia. Heading into some pretty interesting territory here with again a dearth of recent investigations on this topic. Caruso and colleagues*** reported some interesting results from a double-blind, placebo-controlled trial of 5-HTP in fibromyalgia (FM) suggestive of positive effects to be had. Other, less controlled trials, also seemed to indicate some improvements in FM symptoms although with side-effects reported. Other than that, reviews and sprinklings of speculation.
Finally autism. Not much more to say aside from the very limited research on 5-HTP supplementation does not (so far) support any resounding changes to presented symptoms as per the paper by Sverd and colleagues****. Evidence has been presented to suggested that 5-HTP administration seemed to do a very good job at raising blood serotonin concentrations in males with autism (here). Whether this finding is (a) transferable to the majority and (b) might relate to issues with the availability of tryptophan as a starting material (in plasma and urine) or indeed the function of TPH (cofactor availability?) are still matters of speculation.
I'm just about done with 5-HTP for now. As per previous posts, the main caveat is that no medical advice or endorsement of anything is given or intended. Hopefully knowing a little bit more about 5-HTP after this post and how we should perhaps not be closing the research door on it just yet, would you be interested to learn that the gut microbiota might very well have an important effect on the serotonergic system*****? Accepting that bacteria and 'the microbiome' is a research area on the rise, one wonders whether 5-HTP might also have a hand in this process.
To finish, the Red Hot Chili Peppers rocked the SoL yesterday evening and so here is one of their finest... Higher Ground. And to the woman sat behind me who told me to sit down... it's a rock concert.
----------
* Emanuele E. et al. An open-label trial of L-5-hydroxytryptophan in subjects with romantic stress.
Neuro Endocrinol Lett. 2010; 31: 663-666.
** Shaw KA. et al. Tryptophan and 5-Hydroxytryptophan for depression. Cochrane Database Syst Rev. 2002: CD003198
*** Caruso I. et al. Double-blind study of 5-hydroxytryptophan versus placebo in the treatment of primary fibromyalgia syndrome. The Journal of International Medical Research. 1990; 18: 201-209.
**** Sverd J. et al. Effects of L-5-hydroxytryptophan in autistic children. J Autism Child Schizophr. 1978;8: 171-180.
***** Clarke G. et al. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manne. Molecular Psychiatry. June 2012.
DOI: 10.1038/mp.2012.77
Putting serotonin slightly to one side for this post, I instead want to talk about another player along the tryptophan - serotonin pathway, 5-hydroxytryptophan (5-HTP) and various lines of study to this important intermediary compound in what is admittedly, a slightly disjointed post.
I was brought to this post by two factors:
- An interesting comment in a LinkedIn discussion about how issues with the production of melatonin observed in some cases of autism might tie into other findings in autism in relation to issues with tetrahydrobiopterin (BH4) for example. Without trying to make connections where there may not be any, it got me thinking about the whole tryptophan - serotonin - melatonin pathway in a little more detail.
- A curious paper which I stumbled upon a while back by Emanuele and colleagues* suggesting that the symptoms of romantic stress defined as "... a recent romantic break-up or reported recent romantic problems" might benefit from a brief dose of 5-HTP both behaviourally and biologically. Curious I know, and not necessarily relevant to this blog; but nevertheless it brought me back to 5-HTP.
Before your eyes start to glaze over and you reach for the 'click away' button, it is probably best if I start at the beginning and briefly show you how things usually go with regards to tryptophan, serotonin and melatonin. So in my very best handwriting (yes, you can perhaps see why I didn't ace certain school exams) and with no expense spared... see figure 1.
 |
| Figure 1: Bless you tryptophan. |
In short:
L-Tryptophan is converted to 5-HTP via the enzyme tryptophan hydroxylase, TPH which relies on the cofactors of iron and BH4 for optimal functioning. Keep this cofactor thing in mind.
5-HTP is then converted to serotonin (5-HT) and onwards to various other compounds including 5-hydroxyindoleaceticacid (5-HIAA).
The conversion of 5-HT to melatonin is via the intermediate compound, N-Acetlyserotonin (NAS).
Just before anyone mentions, I have only included the TPH enzyme in my schematic and not the other enzymes involved in the various other reactions so as to keep it simple.
Hopefully you can see from my scribbles the central role tryptophan plays in this important metabolic process and how little issues with components in the pathway can potentially have knock-on effects for downstream metabolites.
So to the title of this post: "What's with 5-hydroxytryptophan?". Well, potentially quite a bit.
The first time I heard about 5-HTP was with reference to the collected data on the potential therapeutic use of the compound in cases of depression as per the Cochrane Review by Shaw and colleagues** (full-text). As per nearly every Cochrane Review I've ever read, the text reads something like, a few trials showing possible effects from [5-HTP] supplementation on depressive symptoms but not enough rigorous study to be able to form a suitable opinion. Don't believe me... well, see the Cochrane Review for GFCF diets for autism (here). Anyway, mention also of the fact that antidepressants already exist to 'treat' depression probably accounts for the drop in research interest in this area in recent years. That and possibly 'peak X' (see here for more details).
Where next?
Sleeping aid. Looking again at the magnificent figure offered to accompany this post, one could perhaps see how sleep could be affected by 5-HTP purely based on melatonin featuring some way down the pathway. The evidence.. well let's just say it needs improving despite some initial attempts (here and here). Additional evidence on any direct effect from 5-HTP administration on melatonin levels is even more scant.
Fibromyalgia. Heading into some pretty interesting territory here with again a dearth of recent investigations on this topic. Caruso and colleagues*** reported some interesting results from a double-blind, placebo-controlled trial of 5-HTP in fibromyalgia (FM) suggestive of positive effects to be had. Other, less controlled trials, also seemed to indicate some improvements in FM symptoms although with side-effects reported. Other than that, reviews and sprinklings of speculation.
Finally autism. Not much more to say aside from the very limited research on 5-HTP supplementation does not (so far) support any resounding changes to presented symptoms as per the paper by Sverd and colleagues****. Evidence has been presented to suggested that 5-HTP administration seemed to do a very good job at raising blood serotonin concentrations in males with autism (here). Whether this finding is (a) transferable to the majority and (b) might relate to issues with the availability of tryptophan as a starting material (in plasma and urine) or indeed the function of TPH (cofactor availability?) are still matters of speculation.
 |
| The Red Hot Chili Peppers @ Paul Whiteley |
To finish, the Red Hot Chili Peppers rocked the SoL yesterday evening and so here is one of their finest... Higher Ground. And to the woman sat behind me who told me to sit down... it's a rock concert.
----------
* Emanuele E. et al. An open-label trial of L-5-hydroxytryptophan in subjects with romantic stress.
Neuro Endocrinol Lett. 2010; 31: 663-666.
** Shaw KA. et al. Tryptophan and 5-Hydroxytryptophan for depression. Cochrane Database Syst Rev. 2002: CD003198
*** Caruso I. et al. Double-blind study of 5-hydroxytryptophan versus placebo in the treatment of primary fibromyalgia syndrome. The Journal of International Medical Research. 1990; 18: 201-209.
**** Sverd J. et al. Effects of L-5-hydroxytryptophan in autistic children. J Autism Child Schizophr. 1978;8: 171-180.
***** Clarke G. et al. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manne. Molecular Psychiatry. June 2012.
DOI: 10.1038/mp.2012.77
Saturday, 9 June 2012
Melatonin and autism updated
I've covered some of the research on autism, sleep and melatonin previously on this blog. That post was a gentle introduction to to the topic of melatonin which I've decided to upgrade with this latest offering.
Perhaps an introduction first?
Melatonin is an interesting compound synthesized in the pineal gland from another interesting compound, serotonin (5-HT). The intermediate compound formed, N-acetylserotonin (NAS), is itself something which could really do with a lot more investigation given some suggestion of an anti-depressant effect among other things.
I could tell you all about the sleep-wake cycle connection of melatonin but aside from that there are also some other interesting activities of the compound, for example with regards to antioxidants as per this review by Hardeland & Pandi-Perumal* (full-text) from a few years back. I was particularly interested in the connection between melatonin and that old favourite glutathione but am not going to dwell on it.. OK, but not too much.
So what's the story with regards to autism and melatonin?
Well, quite a bit. Generally speaking(!) levels of circulating melatonin and some of its metabolites are noted to be on the low side in cases of autism as per the meta-analysis by Drs Rossignol and Frye**. Even more recent research*** looking at both daytime and night-time levels of the main metabolites of melatonin, 6-sulphatoxymelatonin, confirmed issues with melatonin production to be present in cases of autism. Interestingly also linking production issues with degree of symptom severity.
Why might melatonin production be aberrant in cases of autism?
The big question and I'm afraid that I don't have a big answer. There are a few possibilities: issues with the pineal gland or suprachiasmatic nucleus (the master clock centre), issues with serotonin or the starting material tryptophan, issues with the various reactions in the metabolism of melatonin (or precursors)... take your pick bearing in mind this list is not exhaustive.
I find it particularly interesting that (a) there might be a sensory-perceptual link to the production of melatonin which might be related to melatonin issues in some cases of autism, and (b) acetylation and methylation are required steps in the metabolism of melatonin. I might be making mountains out of molehills again but it strikes me that some people on the autism spectrum aren't exactly flush when it comes to methylation. Just speculating of course.
Supplementation?
Again with the very important caveat about not giving medical advice, melatonin does seem to have quite a good record when it comes to at least some cases of autism spectrum conditions and a few other diagnoses. Sleep and the regulation of sleep is the obvious target of melatonin, which itself can have some pretty important influence on presented behaviour.
Two quite recent trials extended the good news about melatonin: this one from Malow and colleagues**** and this one from Cortesi and colleagues*****. Outside of the CBT data, I was particularly interested in the 'controlled-release' bit of the work by Cortesi and co. given the mechanics of variations in endogenous melatonin production. It strikes me that melatonin is an ideal candidate for some of the newer release technologies being looked at in the world of medicines; such that transdermal patches and the like might have something valuable to offer as per other trials. I might talk about patches and newer methods for medication delivery further at some point in the future.
Having said that, and bearing in mind that lots and lots of different 'medications' have probable biological actions outside of those just intended, melatonin might not be just acting on sleep. I recently read an interesting (and yet again, speculative) review article about melatonin as a molecular 'handyman' by Boga and colleagues****** which does get you thinking about the hows and whys. Even the concept of combination therapy seems to have reached melatonin research.
To finish, something rather sleepy from Mama Cass - 'Dream a little dream of me' (but not literally)... yawn.
* Hardeland R. & Pandi-Perumal SR. Melatonin, a potent agent in antioxidative defense: Actions as a natural food constituent, gastrointestinal factor, drug and prodrug. Nutrition & Metabolism. 2005; 2: 22
DOI: 10.1186/1743-7075-2-22
** Rossignol DA. & Frye RE. Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Developmental Medicine & Child Neurology. 2011; 53: 783-792.
*** Tordjman S. et al. Day and nighttime excretion of 6-sulphatoxymelatonin in adolescents and young adults with autistic disorder. Psychoneuroendocrinology. May 2012.
**** Malow BA. et al. Melatonin for sleep in children with autism: a controlled trial examining dose, tolerability, and outcomes. JADD. December 2011.
***** Cortesi F. et al. Controlled-release melatonin, singly and combined with cognitive behavioural therapy, for persistent insomnia in children with autism spectrum disorders: a randomized placebo-controlled trial. Journal of Sleep Research. May 2012.
****** Boga JA. et al. Beneficial actions of melatonin in the management of viral infections: a new use for this "molecular handyman"? Reviews in Medical Virology. April 2012.
Perhaps an introduction first?
Melatonin is an interesting compound synthesized in the pineal gland from another interesting compound, serotonin (5-HT). The intermediate compound formed, N-acetylserotonin (NAS), is itself something which could really do with a lot more investigation given some suggestion of an anti-depressant effect among other things.
I could tell you all about the sleep-wake cycle connection of melatonin but aside from that there are also some other interesting activities of the compound, for example with regards to antioxidants as per this review by Hardeland & Pandi-Perumal* (full-text) from a few years back. I was particularly interested in the connection between melatonin and that old favourite glutathione but am not going to dwell on it.. OK, but not too much.
So what's the story with regards to autism and melatonin?
Well, quite a bit. Generally speaking(!) levels of circulating melatonin and some of its metabolites are noted to be on the low side in cases of autism as per the meta-analysis by Drs Rossignol and Frye**. Even more recent research*** looking at both daytime and night-time levels of the main metabolites of melatonin, 6-sulphatoxymelatonin, confirmed issues with melatonin production to be present in cases of autism. Interestingly also linking production issues with degree of symptom severity.
Why might melatonin production be aberrant in cases of autism?
The big question and I'm afraid that I don't have a big answer. There are a few possibilities: issues with the pineal gland or suprachiasmatic nucleus (the master clock centre), issues with serotonin or the starting material tryptophan, issues with the various reactions in the metabolism of melatonin (or precursors)... take your pick bearing in mind this list is not exhaustive.
I find it particularly interesting that (a) there might be a sensory-perceptual link to the production of melatonin which might be related to melatonin issues in some cases of autism, and (b) acetylation and methylation are required steps in the metabolism of melatonin. I might be making mountains out of molehills again but it strikes me that some people on the autism spectrum aren't exactly flush when it comes to methylation. Just speculating of course.
Supplementation?
Again with the very important caveat about not giving medical advice, melatonin does seem to have quite a good record when it comes to at least some cases of autism spectrum conditions and a few other diagnoses. Sleep and the regulation of sleep is the obvious target of melatonin, which itself can have some pretty important influence on presented behaviour.
Two quite recent trials extended the good news about melatonin: this one from Malow and colleagues**** and this one from Cortesi and colleagues*****. Outside of the CBT data, I was particularly interested in the 'controlled-release' bit of the work by Cortesi and co. given the mechanics of variations in endogenous melatonin production. It strikes me that melatonin is an ideal candidate for some of the newer release technologies being looked at in the world of medicines; such that transdermal patches and the like might have something valuable to offer as per other trials. I might talk about patches and newer methods for medication delivery further at some point in the future.
Having said that, and bearing in mind that lots and lots of different 'medications' have probable biological actions outside of those just intended, melatonin might not be just acting on sleep. I recently read an interesting (and yet again, speculative) review article about melatonin as a molecular 'handyman' by Boga and colleagues****** which does get you thinking about the hows and whys. Even the concept of combination therapy seems to have reached melatonin research.
To finish, something rather sleepy from Mama Cass - 'Dream a little dream of me' (but not literally)... yawn.
* Hardeland R. & Pandi-Perumal SR. Melatonin, a potent agent in antioxidative defense: Actions as a natural food constituent, gastrointestinal factor, drug and prodrug. Nutrition & Metabolism. 2005; 2: 22
DOI: 10.1186/1743-7075-2-22
** Rossignol DA. & Frye RE. Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Developmental Medicine & Child Neurology. 2011; 53: 783-792.
*** Tordjman S. et al. Day and nighttime excretion of 6-sulphatoxymelatonin in adolescents and young adults with autistic disorder. Psychoneuroendocrinology. May 2012.
**** Malow BA. et al. Melatonin for sleep in children with autism: a controlled trial examining dose, tolerability, and outcomes. JADD. December 2011.
***** Cortesi F. et al. Controlled-release melatonin, singly and combined with cognitive behavioural therapy, for persistent insomnia in children with autism spectrum disorders: a randomized placebo-controlled trial. Journal of Sleep Research. May 2012.
****** Boga JA. et al. Beneficial actions of melatonin in the management of viral infections: a new use for this "molecular handyman"? Reviews in Medical Virology. April 2012.
Thursday, 7 June 2012
Autism's environmental exposome: fish and pharmaceuticals
It's late and it's been a long day but I'm somewhat intrigued by the publication of a paper by Thomas & Klaper* (full-text) recently published in PLoS ONE on unmetabolised psychoactive pharmaceuticals, gene expression in fish and autism.
Intrigued not only because the combination of fish, drugs and autism feature heavily in this paper but also because the findings presented in this study offer some interesting proposals about "autism's environmental exposome" which translated means how environment, and various exposure events in the environment, might be linked to autism.
The paper is full-text but here is a brief summary:
I won't lie to you when I say that I am really quite excited by these findings. Accepting important factors such as the focus being on fish not humans, the quite high amount of exposure over a relatively small time period and the assumption that the 'autism genes' are in fact autism genes, I would certainly like to see some independent replication of this study.
I've talked about environment in relation to autism previously (here) and how things just 'aint what they used to be in terms of our interaction with the chemical environment. Without trying to push too hard an environmental agenda for autism, some cases of autism, or misrepresent what the word 'chemical' actually means (see here), there are some really important considerations to take from this study; not least on how we dispose of our pharmaceuticals and the potential risks attached to (unwitting) exposure to them.
If there are any positive points to come from this study, a primary one is the experimental model and methodology used. So whether replacing UPPs with other chemical components such as those speculatively listed in the 'top 10 hit list' recently discussed might produce similar effects, would be a study worth doing. Indeed thinking back to the chlorination by-products and autistic behaviour paper published last year (here), another important experiment waiting to be done using the fish in a pot gene expression model.
* Thomas MA. & Klaper RD. Psychoactive pharmaceuticals induce fish gene expression profiles associated with human idiopathic autism. PLoS ONE. June 2012
Intrigued not only because the combination of fish, drugs and autism feature heavily in this paper but also because the findings presented in this study offer some interesting proposals about "autism's environmental exposome" which translated means how environment, and various exposure events in the environment, might be linked to autism.
The paper is full-text but here is a brief summary:
- Based on some very logical assumptions about any potential candidate environmental 'trigger' for autism (plausible mechanism, existing in sufficient quantities in the environment, ability to pass from mother to foetus, historical increase in concentration coincident to the rise in autism cases), the authors set about looking at the possibility that pharmaceutical drug residues persistent in the environment may be linked to idiopathic autism - that is autism not secondary to other conditions such as Rett Syndrome (RTT) or Fragile-X syndrome (FXS).
- Allowing for the fact that the use of human participants is not all that ethical in looking at such a relationship, the authors tested mixtures of so-called unmetabolised psychoactive pharmaceuticals (UPPs) on a fish model and the ability of UPPs to induce autism-like gene changes modelled from other data. I might add that gene models of other conditions including ADHD, schizophrenia, depression and bipolar disorder were also included in the analytical mix.
- I can't claim to be an expert on the techniques employed but fish (fathead minnows) were housed in tanks which either contained the UPPs mix made up of a mixture of fluoxetine, venlafaxine and carbamazepine in concentrations described as ".. the highest observed environmental concentrations" compared with control tanks (no pharmaceuticals included). Duration of exposure was over the course of 18 days.
- The authors conducted a "... gene-class analysis of expression patterns induced by the pharmaceutical treatments"; in other words, examining fish brain tissue from exposed animals to see what happened to gene expression as a result of exposure.
- Lo and behold, gene enrichment linked to idiopathic autism came out on top following exposure to UPPs. Gene models of a few other conditions also showed some changes following UPPs exposure but not to the extent or consistency as that noted in autism. The importance of idiopathic autism showing gene enrichment over so-called secondary autism (following cases of RTT or FXS) is not be underestimated given the link to genes already noted in cases of RTT and FXS.
- The authors make the connection between their reported findings and elevated levels of serotonin (5-HT) being implicated in autism spectrum conditions. Further, the proposed connection between maternal SSRI use and elevated offspring autism risk (discussed in this post) also comes into play. The potential added value from this study is that exposure to these classes of medication need not necessarily be voluntary.
I won't lie to you when I say that I am really quite excited by these findings. Accepting important factors such as the focus being on fish not humans, the quite high amount of exposure over a relatively small time period and the assumption that the 'autism genes' are in fact autism genes, I would certainly like to see some independent replication of this study.
I've talked about environment in relation to autism previously (here) and how things just 'aint what they used to be in terms of our interaction with the chemical environment. Without trying to push too hard an environmental agenda for autism, some cases of autism, or misrepresent what the word 'chemical' actually means (see here), there are some really important considerations to take from this study; not least on how we dispose of our pharmaceuticals and the potential risks attached to (unwitting) exposure to them.
If there are any positive points to come from this study, a primary one is the experimental model and methodology used. So whether replacing UPPs with other chemical components such as those speculatively listed in the 'top 10 hit list' recently discussed might produce similar effects, would be a study worth doing. Indeed thinking back to the chlorination by-products and autistic behaviour paper published last year (here), another important experiment waiting to be done using the fish in a pot gene expression model.
* Thomas MA. & Klaper RD. Psychoactive pharmaceuticals induce fish gene expression profiles associated with human idiopathic autism. PLoS ONE. June 2012
Tuesday, 6 March 2012
Of toad skins and psychiatry
 |
| Karma Chameleon @ Paul Whiteley |
Joking aside, there is actually some truth in the potential psychoactive properties of some species of frog/toad as exemplified by the Colorado River toad, whose skin excretes quite a potent cocktail of compounds including 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and bufotenin, both with psychoactive properties. Whether you would actually get a 'high' from oral ingestion of such products is entirely another question and one which I am not all that interested in finding out. I should also add a caveat here just in case anyone stumbled on this post looking for something other than autism research: please don't go licking your friendly neighbourhood amphibians. You might just end up with something rather more unpleasant than you bargained for (see here).
Strange then you might think that a compound found on the skin of a toad might also turn up in human urine samples from people with no evident exposure to such amphibians. Stranger still that elevated levels of that compound were reported in certain groups of people, say diagnosed with autism or schizophrenia. But that's exactly what was found by Emanuele and colleagues* a couple of years back, and not for the first** or second time*** as bufotenin entered the autism research arena. One of the earliest entries I've found mentioning bufotenin (and DMT) and autism is this paper by Piggott**** from 1979.
Bufotenin is an interesting compound in terms of its chemistry and biological effects. It has that famous indole ring so characteristic of the amino acid tryptophan potentially hinting at its chemical relations. Its psychoactive, hallucinogenic effect perhaps warrant its inclusion on various controlled drug schedules around the world. In short, it is quite a character. So why then do elevated levels of this compound appear elevated in the urine of some people with autism and other conditions and what are the potential implications?
Well I don't have a reliable answer for the 'why' question but the chances are that some tryptophan chemistry and perhaps a modicum of bacteria might have some involvement. The words indolethylamine N-methyltransferase (INMT) come up quite a bit in relation to bufotenin bioformation and some suggestion that INMT activity might be heightened in certain psychiatric presentations. I recently discussed the tryptophan-bacteria connection in relation to the production of IAG and autism but who is to say that it just stops there.
As to the implications, well there are a few clues from the Emanuele paper which can be summarised:
- Urinary bufotenin levels were measured in three groups of people: adults with 'severe' autism confirmed by CARS (n=15), adults with schizophrenia (medication free or naive) (n=15) and asymptomatic volunteer control participants (age and gender ratio matched) (n=15) .
- Blinded analysis of samples for bufotenin was via mass spectrometric analysis (coupled to HPLC) using a previously published method. This means that analysis was pretty reliable.
- Compared to controls, mean urinary levels of bufotenin were elevated in both the schizophrenia and autism groups (p<0.001 and p<0.05 respectively). Visually, the distribution of results were more pronounced in the autism group, whereas the schizophrenia group showed less overlap with controls.
- Based on the measurement of adaptive behaviours using the Vineland Adaptive Behaviour Scale (VABS), a significant positive correlation between urinary bufotenin levels and hyperactivity scores on the VABS was observed for the autism group. No correlations with pertinent schedules were observed for the schizophrenia group.
Accepting that participant numbers in this study were low and the degree of overlap between controls and the autism /schizophrenia groups, these are interesting findings. The obvious question based on the VABS hyperactivity connection is whether bufotenin levels have ever been specifically looked at in cases of AD(H)D - the answer: not to my knowledge (well, not according to PubMed). Whether any of the participants with autism (or schizophrenia) were ADHD comorbid, we don't know. Indeed, I am not an expert on VABS (although have reported on it as part of one study) so cannot readily comment on its 'usefulness' and accuracy to measure hyperactivity. It strikes me that future work in this area perhaps needs to utilise more applicable scales looking at things like inattention and impulsivity also.
The next question is what effect elevated levels of bufotenin might have on a person. The short answer is that nobody really knows outside of the more psychedelic observations. Whilst it would be easy to speculate on the 'recreational' actions of the compound, we are perhaps wise to bear in a mind a few points such as: (a) these studies were looking at urine samples and urine content for bufotenin representing the end point of the metabolic journey, and (b) aside from a few trials administering bufotenin to 'volunteers' to look at short-term effects, chronic (long-term) exposure has yet to be properly mapped out. Bear in mind also that some level of this compound were found in just about everyone examined, so there may potentially be some 'function' for this compound in the complicated tapestry that is human biochemistry. This paper even goes so far to say that it may have some intestinal function.
The report by Emanuele and colleagues is not a new publication but nevertheless has been of some interest to me for a while. Those who follow the autism research scene will remember some rumblings a few years back over a patent***** about a certain peptide called dermorphin, normally found on the skin of some species of South American frogs and with quite some opiate potency, which was suggested to show linkage to some case of autism. As it happens, not much more was ever done on the findings aside from mention in this paper on Rett syndrome and some criticism based on the analytical methods and results obtained. Maybe dermorphin and DPP-IV are fodder for a later post.
To finish, and with no connection at all to this post, a tribute to Robert Sherman whose fame some will not have heard of until you hear this piece of music which he penned.
* Emanuele E. et al. Elevated urine levels of bufotenine in patients with autistic spectrum disorders and schizophrenia. Neuro Endocrinology Letters. 2010;31:117-121.
** Narasimhachari N. & Himwich H. GC-MS identification of bufotenin in urine samples from patients with schizophrenia and infantile autism. Life Sciences. 1973; 12: 475-478.
*** Takeda N. et al. Bufotenine reconsidered as a diagnostic indicator of psychiatric disorders. Neuroreport. 1995;6:2378-2380.
**** Piggott LR. Overview of selected basic research in autism. JADD. 1979; 9:199-218.
**** Shanahan MR. et al. Peptide diagnostic markers for human disorders. Ortho-Clinical Diagnostics Inc. European Patent: EP0969015A2
Friday, 1 July 2011
Brain and gut in autism: a historical perspective
History was always something of interest to me at school, particularly British history throughout the Industrial Revolution. I don't know why, but listening to the life and times of people like Richard Arkwright and inventions like the Spinning Jenny, stirred something in me, combined also with having a very enthusiastic teacher. It is with history in mind that I offer this entry.
Whilst the primary aim of this blog is to look at the various contemporary research produced on autism, I also intend to go back thorugh the archives occasionally and look at some of the older research done, just to see if there is anything we can learn. In this post, I want to cover this paper* by Goodwin and colleagues first published in 1971; one of the first papers I've found that talks about the gut-brain connection in relation to autism. The paper was published in the Journal of Autism and Childhood Schizophrenia which has evolved to become the Journal of Autism and Developmental Disorders. Indeed, it was one of the very first papers to be published in the journal.
Nowadays there is quite a lot of discussion about the gut-brain axis in relation to autism and lots of other things. Neurotransmitters such as serotonin (5-HT to us Brits) are for example, found in both gut and brain. There is, therefore some good reason to suspect that what effects the brain may also affect the gut and vice-versa.
The Goodwin paper basically followed up a previous piece of research published by the same authors (Goodwin & Goodwin, 1969) where autism was found coincidental to coeliac disease. The aim of the follow-up research was to compare and contrast various parameters pertinent to the gut-brain relationship in children with autism (n=15) (and their siblings, n=14) compared to asymptomatic children (n=25) and adults (n=300) and adults with schizophrenia (n=200) and non-specific 'mental disorders' (n=6).
There are a few really interesting details to arise from this paper including:
Bearing in mind that this was research conducted almost a decade before autism came into the mainstream psyche (as represented by Wing and Gould's seminal 1979 paper), I find myself most interested in the reported findings. Not only were functional bowel problems being reported and discussed as co-morbidities to autism, the early food intolerance signs follow a similar path to those initially reported by Kanner in 1943. The somatic co-morbidities are also of interest, and in particular, the case study on coeliac disease and autistic symptoms which mirrors that of the most recent findings by Genuis.
I highlighted the gliadin and placebo drink because one of the main problems with the research looking at gluten- (and casein-) free diets for autism is the lack of double-blind, placebo-controlled trials. Whilst some research has been done on looking at developing GFCF and placebo test foods for such a trial, Goodwin and colleagues offer an extremely easy alternative: put your gluten (and casein) into a drink! It just goes to show that not seeing the wood for the trees is not an exclusively 'autistic' trait.
The last point highlighted is perhaps something we need to work on: providing meticulous medical care for people with autism and in particular the GI problems that a proportion present with. I don't want to do any finger-pointing but certainly there is some indication that some people with autism are not receiving the care they should be in this and other areas, despite all the relevant guidance and documentation being available.
To finish, a song released in 1971 from someone who has already been mentioned in previous posts.
* Goodwin MS. et al. (1971) Malabsorption and cerebral dysfunction: a multivariate and comparative study of autistic children. Journal of Autism and Childhood Schizophrenia. 1: 48-62.
Whilst the primary aim of this blog is to look at the various contemporary research produced on autism, I also intend to go back thorugh the archives occasionally and look at some of the older research done, just to see if there is anything we can learn. In this post, I want to cover this paper* by Goodwin and colleagues first published in 1971; one of the first papers I've found that talks about the gut-brain connection in relation to autism. The paper was published in the Journal of Autism and Childhood Schizophrenia which has evolved to become the Journal of Autism and Developmental Disorders. Indeed, it was one of the very first papers to be published in the journal.
Nowadays there is quite a lot of discussion about the gut-brain axis in relation to autism and lots of other things. Neurotransmitters such as serotonin (5-HT to us Brits) are for example, found in both gut and brain. There is, therefore some good reason to suspect that what effects the brain may also affect the gut and vice-versa.
The Goodwin paper basically followed up a previous piece of research published by the same authors (Goodwin & Goodwin, 1969) where autism was found coincidental to coeliac disease. The aim of the follow-up research was to compare and contrast various parameters pertinent to the gut-brain relationship in children with autism (n=15) (and their siblings, n=14) compared to asymptomatic children (n=25) and adults (n=300) and adults with schizophrenia (n=200) and non-specific 'mental disorders' (n=6).
There are a few really interesting details to arise from this paper including:
- They make mention of the work of the late Curt Dohan and his research on schizophrenia and cereal grains.
- Several participants diagnosed with autism had siblings also diagnosed with autism.
- Several somatic co-morbidities were noted in the autism group including anaemia (crescent cell which I think is better known as sickle-cell anaemia these days), eczema, asthma and hyperthyroidism.
- There were quite a few cases of persistent co-morbid functional bowel problems noted in the autism group (6/15), as well as individual cases of coeliac disease and episodes of gastroenteritis.
- Signs of early food intolerance (colic, milk intolerance, diarrhoea) were 'reported for all autistic subjects'.
- A case of autism and co-morbid coeliac disease is described: 'A normal diet, ordered in error, produced a brief relapse with exacerbation of autistic symptoms' (corrected by reinstitution of a gluten-free diet).
- The authors note a novel way of introducing gliadin (gluten) and placebo to participants via a drink.
- Gliadin introduction decreased cortisol levels and affected circadian rhythms.
- The authors state that their results suggest childhood autism may be caused by a 'fundamental neurological dysfunction' but correlated with 'malabsorption and sensitivity to food'.
- Finally, the authors suggest that there is as much a need for further investigations, as there is 'a need for meticulous medical care, correction of sensory and gastrointestinal defects, and sustained observation of the autistic child in an environment conducive to learning and growth'.
Bearing in mind that this was research conducted almost a decade before autism came into the mainstream psyche (as represented by Wing and Gould's seminal 1979 paper), I find myself most interested in the reported findings. Not only were functional bowel problems being reported and discussed as co-morbidities to autism, the early food intolerance signs follow a similar path to those initially reported by Kanner in 1943. The somatic co-morbidities are also of interest, and in particular, the case study on coeliac disease and autistic symptoms which mirrors that of the most recent findings by Genuis.
I highlighted the gliadin and placebo drink because one of the main problems with the research looking at gluten- (and casein-) free diets for autism is the lack of double-blind, placebo-controlled trials. Whilst some research has been done on looking at developing GFCF and placebo test foods for such a trial, Goodwin and colleagues offer an extremely easy alternative: put your gluten (and casein) into a drink! It just goes to show that not seeing the wood for the trees is not an exclusively 'autistic' trait.
The last point highlighted is perhaps something we need to work on: providing meticulous medical care for people with autism and in particular the GI problems that a proportion present with. I don't want to do any finger-pointing but certainly there is some indication that some people with autism are not receiving the care they should be in this and other areas, despite all the relevant guidance and documentation being available.
To finish, a song released in 1971 from someone who has already been mentioned in previous posts.
* Goodwin MS. et al. (1971) Malabsorption and cerebral dysfunction: a multivariate and comparative study of autistic children. Journal of Autism and Childhood Schizophrenia. 1: 48-62.
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