Are gut problems in autism linked to anxiety and sensory issues?

I'd been waiting to get hold of the recent article by Dr Micah Mazurek and colleagues titled: Anxiety, sensory over-responsivity, and gastrointestinal problems in children with autism spectrum disorders* (abstract here) for quite a few days before posting about it.

This paper was always going to catch my eye given the focus on gastrointestinal (GI) problems comorbid to cases of autism. That and the authors connecting issues with anxiety and sensory issues to the presence of such functional GI problems in cases of autism, which really neatly falls within the remit of my interest in our second brain and how it might do some much more than just digest food. Don't get me wrong, I know all about the difference between correlation and causation - as in one does not necessarily mean the other - and tread carefully when discussing Dr Mazurek's findings.

Perhaps a few study details first:

• Quite a large sample of children aged between 2-17 years old (N=2973) diagnosed with an autism spectrum disorder were included for study derived from the Autism Treatment Network (ATN). This means that we can reliably assume that (a) participants were diagnosed with autism, and (b) diagnosis was confirmed by gold-standard instruments such as ADOS.
• Parent report data was collected on various features pertinent to the current study including a subset of items derived from the Short Sensory Profile (SSP), the Anxiety Problem T-score from the Child Behaviour Checklist (CBCL) and a GI Symptom Inventory Questionnaire to measure GI health related to five chronic functional GI symptoms. Cognitive functioning was also assessed.
• The results: about a quarter of the participants studied presented with at least one chronic GI problem - that is a GI problem "within the past 3 months, duration of 3 or more months"; most frequently constipation. Children with chronic GI issues (n=733) scored higher on the CBCL Anxiety Problem scale than those (n=2239) without. Children with a chronic GI problem also presented with greater sensory over-responsivity (SOS) than those without such issues. SOS included features such as tactile sensitivity, taste-smell sensitivity (see here), movement sensitivity and visual-auditory sensitivity (see here). 
• Finally, logistic regression analyses seemed to indicate that both anxiety and SOS "significantly contribute to the prediction of chronic constipation, chronic abdominal pain, chronic bloating and chronic nausea".

To my mind, these findings make for some very persuasive reading. One could argue about whether parent report is the most accurate way of collecting such data. I would however highlight two studies in the autism research field which suggest that parent reporting might not be totally off the mark as per developmental history recall (here) and that very important study by Phillip Gorrindo and colleagues** on parent reporting of GI issues in autism.

What more to say that has not already been said. The possibility that functional GI issues might be over-represented in cases of autism is to my mind a point which requires little more research in light of research like this and this and this. Obviously not everyone with autism presents with such bowel problems and not everyone with such bowel problems presents with autism. Science still needs to determine whether there might be a specific autism phenotype where bowel issues are a primary somatic symptom as per the findings on lactose intolerance from Tim Buie and colleagues. But for those who, for whatever reason, would once argue that comorbid bowel features are merely a fluke finding to autism, some autism... show me your evidence.

Such bowel issues if present are more than likely going to affect people with autism at least to the same extent as they do to those with not-autism particular when in the paediatric population. I think back to the Autism Now series aired April 2011 and vaguely recall some description of a child with autism also with bowel problems and the way their behaviour seemed to manifest such issues. It certainly is not outside the realms of possibility that a person with autism with a comorbid bowel issue like constipation for example, might well have some accompanying stress and anxiety over going to the toilet for a number two with the expectation of the discomfort that this might well bring. In terms of more chronic generalised anxiety, well the research literature suggests that functional bowel problems and anxiety might already share the same bed as per studies like this one from Waters and colleagues***.

An important implication from the Mazurek findings is that if there is a connection between functional GI issues, anxiety and sensory issues, one would expect that attempts to resolve the GI issues may very well impact on the other symptom areas too and vice-versa. The authors talk about the use of cognitive behavioural therapy (CBT) as one potential avenue of intervention for these overlapping issues. Personally I'm not a great fan of CBT as being particularly useful to "treat" bowel problems in autism either directly or periperhally; to coin a phrase from a good friend of mine, bowel problems are probably not present as a result of some unconscious desire to obsessively collect bus tickets or anything like that. Rather better looking at a more physical - somatic causation is likely to yield more productive, long-term positive effects.

I've talked previously about how those trillion or so bacteria which make up our gut microbiota might very well have the ability to influence our behaviour - or at least in animal models. A friend of mine (thanks Dr Mark Wetherell) also put another interesting recent article my way by Dinan & Cryan**** which talks about the stress response potentially being affected by aspects of the gut microbiota. If we assume that the functional bowel issues noted in cases of autism might very well be partially present as a result of some bacterial issues - such as those here and here, it's not too difficult to suggest some tentative connection.

I hope I'm not getting too speculative when I also bring to your attention studies like this one from Messaoudi and colleagues***** and the use of probiotic formulations to reduce stress and anxiety responses in both animals and human volunteers. OK, no mention is specifically made about functional bowel problems in the Messaoudi paper, although similar probiotic formulations have been suggested to also affect bowel issues like constipation****** (full-text).

I do also wonder about the more traditional pharmacotherapies used to treat constipation and diarrhoea or indeed more serious underlying issues such as inflammatory bowel diseases and whether there could be potential positive effects from those also in cases of autism. This paper makes mention of the "symptomatic improvement in their behavior and general well-being after bowel clearance before colonoscopy" noted in cases of autism. I've often wondered whether interventions like the gluten- and casein-free diet which seem also to impact on bowel issues in cases of autism might be another case in point.

More research needed on the gut-brain axis in autism perhaps?

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* Mazurek M. et al. Anxiety, sensory over-responsivity, and gastrointestinal problems in children with autism spectrum disorders. Journal of Abnormal Child Psychology. August 2012.

** Gorrindo P. et al. Gastrointestinal dysfunction in autism: parental report, clinical evaluation, and associated factors. Autism Research. 2012; 5: 101-108.

*** Waters AM. et al. Functional gastrointestinal symptoms in children with anxiety disorders. Journal of Abnormal Child Psychology. July 2012.

**** Dinan TG. & Cryan JF. Regulation of the stress response by the gut microbiota: Implications for psychoneuroendocrinology. Psychoneuroendocrinology. 2012; 37: 1369-1378.

***** Messaoudi M. et al. Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. British Journal of Nutrition. 2011; 105: 755-764.

****** Guerra PV. et al. Pediatric functional constipation treatment with Bifidobacterium-containing yogurt: a crossover, double-blind, controlled trial. World Journal of Gastroenterology. 2011; 17: 3916-3921.

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Mazurek MO, Vasa RA, Kalb LG, Kanne SM, Rosenberg D, Keefer A, Murray DS, Freedman B, & Lowery LA (2012). Anxiety, Sensory Over-Responsivity, and Gastrointestinal Problems in Children with Autism Spectrum Disorders. Journal of abnormal child psychology PMID: 22850932

Propionic acid and autism

Another post, another organic acid (!) but please don't click away just yet as I attempt once again not to blind you with science. The topic of the day today is propionic acid (PPA) otherwise known as propanoic acid and the very tentative suggestions of some link to autism. 

Search on-line for propionic acid and you're quite likely to get lots of industrial chemical information about it including a materials safety data sheet (MSDS) (here) implying that this stuff is toxic, combustible and corrosive. So why on earth am I talking about it with regards to autism?

Well, like many things in modern life, the chemical industry isn't the only source of 'chemicals' as per our wonderful chemical factory that is the human body and the surprising effects of some of the bacteria which inhabit us. Not for the first time, I might add, has bacteria and biochemistry come together on this blog (see here) and probably not the last time either.

PPA is an organic acid - a short chain fatty acid - which as well as being used as a food additive / preservative and used in the process of polymer production apparently, is also what might be considered a natural product as a result of its endogenous production. Short chain fatty acid you say? Y'mean like the ones discussed not so long ago in relation to autism by Wang and colleagues? Yes, the very same.

Continuing with autism in mind, I am taken back to this news report from 2007 where Dr Derrick MacFabe discussed this piece of research* (followed up by this study** too) suggesting that you are what you eat in terms of foodstuffs and bacteria combining to produce PPA and what effect it had on the rat brain following "intraventricular infusions" (to you and me injecting the stuff directly into rat brains). Dr MacFabe has very definitely taken the lead when it comes to looking at PPA and autism. 

Indeed I was interested to see the effects of PPA administration on rat brains including activated microglia and decreased glutathione alongside the more overt effects on rat behaviour. Understanding that rats (like mice and fish) are not humans, indications of issues with glutathione have been quite strongly shown to be related to cases of autism and indeed the brain has become a recent focus for this area of research. As for microglia, I would once again refer you to this post by Paul Patterson on the suggested dietary habits of microglia in autism with the promise of a post on this research area soon.

Other research groups have also entertained a possible role for PPA in autism. The paper by El-Ansary and colleagues*** replicated the results from the MacFabe group and indeed added a few new aspects also making mention of lactate dehydrogenase and elevations in IL-6 among other things; both factors having been reported in connection to autism (here and here respectively). I think we can, with some degree of confidence, assume from this collected work, that propionic acid injections are probably not good news for rats.

We move onwards then to another piece of research by El-Ansary and colleague**** (full-text) looking at the possibility that supplementation with omega-3 fatty acids might afford some protection against the effects of PPA administration to rats. They reported that omega-3 supplementation did indeed alter some of the parameters associated with PPA administration including some interesting data on caspase-3, an executioner molecule involved in apoptosis previously reported in cases of autism (see here for more information). It seems rats fed a diet rich in omega-3 fatty acids might have some protection against various effects of PPA administration. I assume this ties into this paper by Thomas and colleagues***** (including Dr MacFabe).

So to summarise. An overlap between direct PPA administration and some key biochemical changes noted in cases of autism. Fine. A potential protective effect via use of omega-3 fatty supplementation from PPA administration. OK (fatty acids have some history in cases of autism as per this older post). PPA found to be elevated in cases of autism (based on the analysis of stools). Right.

Reading all that might convince some people of a role for PPA in autism but I'm going to play devil's advocate for a second and suggest why we need more research in this area. First, as mentioned rats aren't human beings. Rats might make good models for human being - as do some mice - but rats are not human beings. Second, administration of PPA was either intracerebroventricularly or at "neurotoxic doses" over 3 days (250mg/kg body weight). Either of these two factors whilst good for studying rats in a lab over a relatively short space of time is probably not going to be representative of chronic PPA exposure in people with autism. Unless of course that is, that something causes a huge acute surge in PPA that is. Finally(!) aside from the Wang findings on fecal PPA levels, the research in this area is still a little bit scant in terms of PPA levels in other biofluids. I haven't for example, seen anything as of yet looking at whether rates of the metabolic disorder propionic acidaemia is any more prevalent in cases of autism than not autism or likewise whether propionic acidaemia is accompanied by an increase in cases of autism accepting the seriousness and poor prognosis of this rare metabolic conditions. A few possible routes to further study perhaps.

That being said, I am still intrigued about propionic acid and the research done so far with regards to autism whether animal model-based or direct measurement. The whole connection back to short chain fatty acids, digestion and gut bacteria is an interesting and very under-researched area with autism in mind -  indeed with lots of other behavioural / cognitive / psychiatric conditions in mind. Could it hurt to put a little more research efforts into this area?

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* MacFabe DF. et al. Neurobiological effects of intraventricular propionic acid in rats: possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders. Behavioral Brain Research. 2007; 176: 149-169.

** MacFabe DF. et al. Effects of the enteric bacterial metabolic product propionic acid on object-directed behavior, social behavior, cognition, and neuroinflammation in adolescent rats: Relevance to autism spectrum disorder. Behavioral Brain Research. 2011; 217: 47-54.

*** El-Ansary AK. et al. Etiology of autistic features: the persisting neurotoxic effects of propionic acid. Journal of Neuroinflammation. April 2012.
DOI: 10.1186/1742-2094-9-74

**** El-Ansary AK. et al. On the protective effect of omega-3 against propionic acid-induced neurotoxicity in rat pups. Lipids in Health & Disease. 2011; 10: 142.

***** Thomas RH. et al. The enteric bacterial metabolite propionic acid alters brain and plasma phospholipid molecular species: further development of a rodent model of autism spectrum disorders. Journal of Neuroinflammation. 2012; 9: 153.

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No single SNP associated with autism?

A quote to begin this relatively short post:

"Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level."

One of the conclusions reached in this article by Richard Anney and colleagues* (full-text). SNPs (single nucleotide polymorphism(s) are the tiny rearrangements in our genetic code which have all but replaced the older research fashion of one gene - one condition from times gone by. The theory being that these small mutations might offer some assistance with regards to for example, identifying an individuals risk or response to a condition or pharmacotherapy for disease as has been noted in conditions like breast cancer.

SNPs in relation to autism have been discussed previously on this blog as per posts like this one and this one.  The net result so far suggest that such genetic glitches are present in at least some cases of autism, but - and it is rather a large but - SNPs are a rather complicated area of genetic research. As per the Anney paper, consistent individual SNPs across all cases of autism are not yet apparent.

I don't want to make to much of a meal of the Anney results with regards to the modest individual effects noted by the authors. Suffice to say that based on quite a large dataset numbering in the couple of thousands of participants "no genome-wide significant association with specific common variants" was reported.

Where next I hear you ask? Well, it was unlikely that one single SNP would be apparent across the whole of the autism spectrum similar to the findings based on the long and as yet unsuccessful search for the 'autism gene'. Everyone carries their own mutations and in the most part these don't seem to unduly affect day-to-day health and wellbeing bearing in mind important interfering variables like comorbidity - as in, is the SNP/s related to autism or related to other things like learning disability or epilepsy or other more somatic things? The fact that autism is a constellation of symptoms also makes the interpretation of any findings even more problematic.

More likely that more than one SNP is going to be involved in specific 'types' of autism and there is some degree of interaction between them. A fantastic case for looking more at endophenotypes based on symptoms presentation (including regression as per the latest study from Barger and colleagues**) or even based on possible responsiveness to specific interventions. That and/or the possibility that epigenetics and the methylation / acetylation / phosphorylation of DNA, or histones, is likely to be a more fruitful area of research combining both genes and environment as per the recent suggestion by Emily Simonoff***.

To finish, London has bid farewell to the 2012 Olympic flame and so I leave you with a song from the best of British, Paul McCartney / Wings and 'Live and Let Die'. One small note to the closing ceremony organisers: if you are going to play a Kate Bush song to denote something 'British' outside of just a reference to a hill, make sure its Wuthering Heights. Looking forward to the Rio party.

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* Anney R. et al. Individual common variants exert weak effects on risk for Autism Spectrum Disorders. Human Molecular Genetics. July 2012.

** Barger BD. et al. Prevalence and onset of regression within autism spectrum disorders: a meta-analytic review. JADD. Ausgust 2012.

** Simonoff E. Autism spectrum disorder: prevalence and cause may be bound together. British Journal of Psychiatry. 2012; 201: 88-89.

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Anney R, Klei L, Pinto D, Almeida J, Bacchelli E, Baird G, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Casey J, Conroy J, Correia C, Corsello C, Crawford EL, de Jonge M, Delorme R, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Gilbert J, Gillberg C, Glessner JT, Green A, Green J, Guter SJ, Heron EA, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Jacob S, Kenny GP, Kim C, Kolevzon A, Kustanovich V, Lajonchere CM, Lamb JA, Law-Smith M, Leboyer M, Le Couteur A, Leventhal BL, Liu XQ, Lombard F, Lord C, Lotspeich L, Lund SC, Magalhaes TR, Mantoulan C, McDougle CJ, Melhem NM, Merikangas A, Minshew NJ, Mirza GK, Munson J, Noakes C, Nygren G, Papanikolaou K, Pagnamenta AT, Parrini B, Paton T, Pickles A, Posey DJ, Poustka F, Ragoussis J, Regan R, Roberts W, Roeder K, Roge B, Rutter ML, Schlitt S, Shah N, Sheffield VC, Soorya L, Sousa I, Stoppioni V, Sykes N, Tancredi R, Thompson AP, Thomson S, Tryfon A, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Vorstman J, Wallace S, Wing K, Wittemeyer K, Wood S, Zurawiecki D, Zwaigenbaum L, Bailey AJ, Battaglia A, Cantor RM, Coon H, Cuccaro ML, Dawson G, Ennis S, Freitag CM, Geschwind DH, Haines JL, Klauck SM, McMahon WM, Maestrini E, Miller J, Monaco AP, Nelson SF, Nurnberger JI Jr, Oliveira G, Parr JR, Pericak-Vance MA, Piven J, Schellenberg GD, Scherer SW, Vicente AM, Wassink TH, Wijsman EM, Betancur C, Buxbaum JD, Cook EH, Gallagher L, Gill M, Hallmayer J, Paterson AD, Sutcliffe JS, Szatmari P, Vieland VJ, Hakonarson H, & Devlin B (2012). Individual common variants exert weak effects on the risk for autism spectrum disorderspi. Human molecular genetics PMID: 22843504

Folate and autism: more questions than answers

Athenian sunset @ Paul Whiteley

I don't know if you could tell but my previous few blog posts were a sort of stand-in whilst I took a few days off. Not exactly repeats of favourite soap operas or anything like that, but more like watching some pre-recorded non-league football (soccer) compared to the Premiership live. Suffice to say that I'm back now and ready to press on with some 'proper' posts.

Whilst away I've been thinking quite a bit about the paper from Rebecca Schmidt and colleagues* on maternal folic acid intake and offspring risk of autism spectrum conditions discussed in this post. Don't get me wrong I'm not disputing their findings of anything like that; recognising that is, the retrospective 'tell me what you did' methodology used and how studies of association are just that: studies of association.

The media attention following the Schmidt paper however painted an interesting picture of folic acid supplementation and autism. As perhaps expected, some outlets have taken up the 'preventative' side of folic acid supplements with headline such as this one: 'Consuming folic acid during early pregnancy cuts risk of an autistic child'. Maybe it's just me, but I don't believe that headlines like this paint as accurate a picture of the folic acid-autism link as perhaps the research literature suggests, as in this post I try and explain why.

There is no denying the important functions that folic acid supports not just to the developing foetus during early pregnancy but also in adult health, as for example seen in the growing literature on folic acid reducing the risk of stroke.

With autism in mind, the literature on folic acid is however a little more muddled in terms of the early days/months/years effects of supplementation and indeed the cycle of compounds in which folic acid finds itself in:

• Eugene Rogers** published a speculative paper (in a speculative journal!) a few years back, asking whether supplementation with folic acid during pregnancy has influenced natural selection and further autism prevalence. The theory goes that children who carry previously discussed SNPs in genes like everyone's favourite Scrabble classic gene, MTHFR, which might influence the effectiveness of folate, are surviving in greater numbers as a result of mum's increased folate intake. After birth, kids with mutations in the MTHFR gene still need lots more folate but aren't getting enough; hence important processes like methylation aren't able to be carried out optimally and behavioural consequences are apparent (see here). Before you roll your eyes and click away, there is some evidence (albeit limited) to back up this hypothesis. So, SNPs in MTHFR in autism: check; elevations in homocysteine in kids with autism: check; suggestions of hypomethylation in cases of autism (and mums with children with autism): check. Some evidence at least, although as always I could be cherry-picking the data.
• Beard and colleagues*** in a similar stance, also asked the question (in the same journal) as to whether excess folic acid supplementation might be a risk factor for autism. I'm slightly less convinced by their associations and presented data, but the question of whether "too much folic acid may result in nervous tissue damage associated with autism" is an interesting one particularly in light of research like this from Junaid and colleagues**** and over 1000 genes suspected to be 'dysregulated' by high folic acid supplementation.
• The older literature on folic acid and autism also carries some interesting papers. So, this paper by Gillberg and colleagues***** reports results from a very small study on the supplementation of folic acid to boys diagnosed with autism and "the fragile X syndrome". Reviewing the evidence for a larger effect from folic acid supplementation for Fragile X syndrome, it has to be said however that it is not all that impressive (here).
• I've talked before about an important piece of research which looked at folate receptor autoantibodies in cases of autism. In this scenario, folic acid is not necessarily the main issues but rather the fact that the folate receptors may not be functioning optimally, and so for example, are influencing the delivery of 5-MTHFR to cells. The suggestion from this (and another******) paper was that supplementation with folinic acid may be a better option. I shall at this point reiterate that medical advice is neither given nor intended in this or any post on this blog.

I hope I've made a preliminary case for some greater inspection of folic acid and its relations in cases of autism in light of how the recent Schmidt findings have been disseminated in some quarters. Recognising that vitamins and minerals are readily available to everyone combined with the possibility of a suggestion that increased folic acid intake during pregnancy might 'offset' the risk of offspring autism, to my mind makes for a strong requirement for some balanced advice on this matter.

The picture accompanying this post is a holiday snap from some family vacation time in Greece. Warm, very warm summer days and nights, cicada making their music and cycling seemingly becoming very popular in Greece (with the usual safety caveats suspended in quite a few cases). So to finish some Greek pop music from Mr Michalis Hatzigiannis. Ελλάδα γεια σου.

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* Schmidt RJ. et al. Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study. American Journal of Clinical Nutrition. May 2012.
DOI: 10.3945/​ajcn.110.004416

** Rogers EJ. Has enhanced folate status during pregnancy altered natural selection and possibly Autism prevalence? A closer look at a possible link. Medical Hypotheses. 2008; 71: 406-410.

*** Beard CM. et al. Is excess folic acid supplementation a risk factor for autism? Medical Hypotheses. 2011; 77: 15-17.

**** Junaid MA. et al. Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochemical & Biophysical Research Communuications. 2011; 412: 688-692.

***** Gillberg C. et al. Folic acid as an adjunct in the treatment of children with the autism fragile-X syndrome (AFRAX). Developmental Medicine & Child Neurology. 1986; 28: 624-627.

****** James SJ. et al. Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in children with autism. American Journal of Clinical Nutrition. 2009; 89: 425-430.

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Schmidt RJ, Tancredi DJ, Ozonoff S, Hansen RL, Hartiala J, Allayee H, Schmidt LC, Tassone F, & Hertz-Picciotto I (2012). Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study. The American Journal of Clinical Nutrition, 96 (1), 80-9 PMID: 22648721

Autism: getting some interference from interferon?

Autism research has on more than one occasion looked at the possibility that there is an immune component to at least some cases of autism. Indeed I hope I am not being too scientifically reckless when I say that immune involvement seems to be becoming quite a central finding to a proportion of people on the autism spectrum as per the results from researchers like Harumi Jyonouchi and Paul Ashwood. The big questions remain however: what are the central immune issues, who exactly on the spectrum are immune findings most pertinent to, and what comes first: autism or immune involvement? (I don't have the answers to these questions by the way, although have recently looked to Paul Patterson for some interesting directions).


Putting such 'chicken or egg' philosophical issues to one side, I offer another review-type entry with the immune system in mind with this post on autism and the interferons. A description first. If you've ever heard mention of the interferons, most likely it will have been referencing the cytokine interferon-gamma or IFN-gamma or IFN-γ (if you prefer the Greek character). Quite a good and comprehensive overview of IFN-γ is this one by Schroder and colleagues* (full-text). 


Bear however in mind that IFN-γ is but one member of family of proteins associated with lots of processes related to the immune system including macrophages (the 'big eaters' of the immune system) following the detected presence of a pathogen (bacteria, parasite, virus). The interferons also play quite an important anti-viral role as per their name.


Allowing for the fact that our immune systems' are probably always to some degree 'activated' given our continually interacting with our environment and all the bugs 'n stuff in it, one can perhaps see that the presence of significant elevations in levels of the interferons might be an important marker as to current the state of the immune system. Importantly, whether it is fighting infection or at least thinks its fighting an infection and how long the fight goes on for. 


So what's the story of interferon and autism? Quite a bit actually:

• Vijendra Singh** was one of the first to report on the presence of elevations in plasma levels of IFN-γ (and another cytokine, IL-12, a stimulator of IFN-γ) among participants with autism compared to asymptomatic controls. Similar increases in levels of IFN-γ in cases of autism were also noted by Croonenberghs and colleagues*** who reported on a few other relevant details also such as "a trend toward a significantly increased production of IL-6" despite no significant group differences between autism and controls. IL-6 you say? Similar findings of elevated levels of IFN-γ in autism have been replicated a few more times bearing in mind the different tissues analysed (here, here and here). 
• Gene Stubbs**** reported results for a small (very small!) participant group with autism based on levels of IFN-alpha (IFN-α) suggesting elevations compared to an even smaller control group. I was intrigued by this preliminary finding given that alpha interferon, normally used as pharmacotherapy for certain types of cancer (here), as well as being involved in immune function also (a) has the propensity to induce neuropsychiatric symptoms (here) and (b) exhibits some opioid activity as per its analgesic effect and affinity for certain types of opioid receptor (here). All that being said, I can't seem to find any other paper in the research literature which has looked at IFN-α in cases of autism. Perhaps it just isn't interesting enough (don't even ask about the other interferons).

There are a few other small details to add to the work in progress that is the interferons and autism.


As you will probably have noted, examination of the interferons has, in the majority of studies, been done alongside other biological parameters of the immune system, specifically other cytokines such as the various interleukins (those compounds prefaced by IL). What this perhaps implies is that the various findings on the interferons is part and parcel of a wider set of immune-related functions and parameters. The trick is determining which ones might be core to autism, and which ones are just after-effects.


Inflammation also features quite a bit in this story as it seems to have done based on other autism research. As with many cytokines and the blurring which comes with regards to (a) inflammation being universally a bad thing - it's not, (b) the black or white issue of being pro- or anti-inflammatory - it's not so simple, the relationship between interferons and inflammation is just as complicated. So for example, there is evidence that as well as being pro-inflammatory, interferons might also limit the inflammatory response as per this article by Sauer and colleagues***** (full-text). Just think Anakin Skywalker and his 'mixed' relationship with the Force as a kind of template.


Finally, I stumbled across this interesting paper by Barker and colleagues****** just to throw into the mix, and their suggestion that IFN-γ may be able to influence vitamin D levels. I'm interested in this paper on so many levels: the IFN-γ levels noted in cases of autism, vitamin D potentially being related to autism (and a few other things), etc. Accepting that Barker looked at a specific condition associated with 'inflammatory stress' and the old adage about correlation not being the same as causation, one has to wonder whether this may also impact on the interferon findings noted in autism. Indeed whether chronic activation of interferons and other immue parameters towards inflammation, may have much more far-reaching consequences than just immune involvement in autism. Gut permeability perhaps?


To close, preaching is what Papas do best so why should we stop? (and we do it oh so well).


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* Schroder K. et al. Interferon-γ: an overview of signals, mechanisms and functions. Journal of Leukocyte Biology. 2004; 75: 163-189.


** Singh VK. Plasma increase of interleukin-12 and interferon-gamma. Pathological significance in autism. Journal of Neuroimmunology. 1996; 66: 143-145.


*** Croonenberghs J. et al. Activation of the inflammatory response system in autism. Neuropsychobiology. 2002; 45: 1-6.


**** Stubbs G. Interferonemia and autism. JADD. 1995; 25: 71-73.


***** Sauer I. et al. Interferons limit inflammatory responses by induction of tristetraprolin. Blood. 2006; 107: 4790-4797.

****** Barker T. et al. Circulating interferon-γ correlates with 1,25(OH)D and the 1,25(OH)D-to-25(OH)D ratio. Cytokine. June 2012.

The mixed up world of brain-derived neurotrophic factor and autism

I have to say that I am becoming quite settled with my new found interest in blogging after some 16 months of running this blog. Indeed as hopeful as I am that my posts are accurate, balanced and of some interest to at least someone, the whole process of writing a blog entry is also quite good for me and my learning curve on the multitude of research that has been, and continues to be done on autism and things related. Makes you wonder whether blogging would ever count as CPD?

A case in point is this entry on the various research examining a role / connection between brain-derived neurotrophic factor (BDNF) and autism. I've heard mention of BDNF down the years but never considered myself to be fully capable of saying what the stuff is and what has been found in relation to autism. I'm trying to remedy that situation with this post, so let's see how I do.

BDNF is probably best described as a protein, a member of the neurotrophin family, and a growth factor for neurons and synapses. Quite a good overview of the neurotrophins can be found here* by Allen & Dawbarn (full-text). The link between BDNF and neuronal health is perhaps why the molecule has found quite a bit of interest in autism research circles and in particular, its proposed link to the serotonergic system - serotonin having quite a long history in relation to autism.

It is worth point out that BDNF levels and function are known to be influenced by several factors. So, age and gender seem to be able to affect levels of BDNF (here) as does specific pathology such as depression and schizophrenia (here) depending on where you look and what medium you look in. The neuronal 'plasticity' relationship to BDNF (among quite a few other actions I might add) seems to have been taken up by quite a few authors; particularly adult plasticity, contributory perhaps to the more lifelong view of brain plasticity which predominates these days over older theories of 'after childhood, set in stone'.

With autism in mind, there is a body of evidence on BDNF which suggests a few things albeit not exactly consistently:

• I am a little bit unsure whether BDNF is meant to be 'generally' high or low in cases of autism. Accepting the factors which can influence BDNF listed above, there seems to be some conflicting evidence on findings related to blood/plasma. So for example, this paper by Al-Ayadhi** (full-text), an author mentioned in previous posts, reported lower levels of serum BDNF in their cohort of children with autism. This contrasts with this paper by Connolly and colleagues*** who reported elevations in BDNF. Just to complicate matters further Lisa Croen and colleagues**** (full-text) reported no significant differences in blood concentrations of BDNF in either mums mid-pregnancy nor their young offspring subsequently diagnosed with autism compared with asymptomatic and learning disability control participants. I might be comparing apples and oranges at different times of year, but suffice to say that results are not yet clean-cut.
• When it comes to genes and BDNF in cases of autism, the waters aren't really any less muddy. This paper by Correia and colleagues***** reported elevations in plasma BDNF in their autism cohort but the source of the increase did not seem to stem from issues with the BDNF gene. Without being an expert on all things genetic, I think this finding might also tie into the results published by Garcia and colleagues****** who suggested that BDNF elevations might not be "transcriptionally driven" (see here for a summary of mRNA). There are other studies looking at other features of BDNF seemingly reporting contrasting findings such as decreased BDNF and anti-apoptotic function (here) and SNPs in the BDNF gene in autism (here and here). The message continues: it's complicated.

One could perhaps suggest that the various results relating to BDNF in autism mirror quite a few other areas of research insofar as not being able to make consistently reproducible statements of fact about autism. Having said that there are perhaps lessons to be learned from compounds such as BDNF in terms of fluctuating levels throughout the lifetime, differences depending on the tissue or biological medium being analysed and some degree of individual responsiveness behind the various findings so far. The fact that BNDF levels might also show involvement in other conditions, such as depression for example, is also worth bearing in mind.

Finally, and without trying to tie every single finding in autism back to gut bacteria or other of my areas of interest, there may yet be something in this relationship accounting for at least some of the BDNF findings in autism. I note for example this paper by Bercik and colleagues******* (similar work commented on here) which suggested that in mice at least, disruption of the gut microflora by antibiotic use seemed to increase brain levels of BDNF.

An example of a real gut-brain interface in action?

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* Allen SJ, Dawbarn D. Clinical relevance of the neurotrophins and their receptors. Clinical Science. 2006; 110: 175.191.

** Al-Ayadhi LY. Relationship between Sonic hedgehog protein, brain-derived neurotrophic factor and oxidative stress in autism spectrum disorders. Neurochemical Research. 2012; 37: 394-400.

*** Connolly AM. et al. Brain-derived neurotrophic factor and autoantibodies to neural antigens in sera of children with autistic spectrum disorders, Landau-Kleffner syndrome, and epilepsy. Biological Psychiatry. 2006; 59: 354-363.

**** Croen LA. et al. Brain-derived neurotrophic factor and autism: maternal and infant peripheral blood levels in the Early Markers for Autism (EMA) Study. Autism Research. 2008; 1: 130-137.

***** Correia CT. et al. Increased BDNF levels and NTRK2 gene association suggest a disruption of BDNF/TrkB signaling in autism. Genes, Brain & Behavior. 2010; 9: 841-848.

****** Garcia KL. et al. Altered balance of proteolytic isoforms of pro-brain-derived neurotrophic factor in autism. Journal of Neuropathology & Experimental Neurology. 2012; 71: 289-297.

******* Bercik P. et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology. 2011; 141: 599-609.