CNV duplication load, hotspots and autism

Viewers here in the UK might remember the catchphrase of one Michael Barrymore on the show 'Strike It Lucky': "What is a hotspot not? A good spot". It is with a rather different kind of hotspot in mind, that I'm posting about today: genomic hotspots and autism with a specific focus on copy number variants.

An intriguing paper by Santhosh Girirajan and colleagues* (open-access) popped up on my Twitter radar recently discussing copy number variant (CNV) load in relation to autism spectrum disorders. Whilst only being an amateur enthusiast when it comes to all things genes and genomic, I can't offer an expert opinion on what CNVs are, just that fairly similar to single-nucleotide polymorphisms (SNPs), we're talking physical alterations to the genome and in particular gains/losses to segments of DNA (I think!)

A hotspot indeed... @ Wikipedia  

I'll start by saying that this is not the first time that CNVs have cropped up on this blog either with autism in mind (see here) or with other conditions such as ADHD (see here) and intellectual disability (ID) in mind (see here).

Indeed readers who looked at that ID link will see that we are talking about another paper from Girirajan following the previous suggestion that ID might be particularly prone to a high CNV load. Keep that in mind for now.

Thankfully the latest paper has been very nicely covered by a ScienceDaily entry (see here with a sigh of relief) so as to patch over my considerable non-expertise in this area. Without plagiarising the paper or SD entry, the general gist of the work was to initially look at CNV data from over 500 people with autism (n=274) or asymptomatic controls (n=242) derived from the CHARGE initiative (see here), to ascertain exactly what the CNV load was and how it might link into some of the signs and symptoms of autism. There was also a further testing group to confirm "the increased duplication load" based on a further cohort of autism and control cases but I'm not going to bore you with all the details.

If I'm reading this right, there were some interesting findings to take from this study:

• Children with autism "exhibited a significantly elevated copy number load, represented principally as an increase in duplicated base pairs found in large CNVs". Importantly, this copy number load seemed to include quite a bit of de novo, so not passed from parents to offspring.
• Duplication over deletion seemed to be the important variable for autism cases, which as the authors note "is associated with genomic variants with more modest functional impact". As per that previous CNV work with ID in mind, I think the authors seemed to be suggesting a sort of sliding scale of phenotypes based on CNV profiles: ID at the more severe end of the spectrum (with more deletions also), autism somewhere in the middle and dyslexia at the less severe end of the spectrum in terms of functioning. I could be wrong and I could be over-simplifying the whole thing so accept my apologies if so.
• Copy number load in autism cases also seemed to show some relationship with certain aspects of behaviour. Significant negative correlations for example, were observed between CNV load and VABS scores in core areas of communication and socialisation. That being said, the correlations were not exactly all that great (p=0.048 and p=0.022 respectively) and should be compared with other gold-standard schedules such as the ADOS that did not turn up anything significant. 
• The notion of genomic 'hotspots' is also raised as a consequence of the results, suggesting that parts of the autistic genome already under the spotlight might be more susceptible to such CNVs. Those words-of-the-hour DNA methylation get a mention alongside the folate story (see here). Personally and with my non-expertise caveat in full working order, I'm also wondering about those archived portions of viruses called HERVs - human endogenous retroviruses - (see this post and this post) which dot the genome and whether they might be contributory in any way, shape or form to any genomic instability in target areas.

Putting aside the complexity of the genome when it comes to autism and the suggestion that we might want to be rethinking how we view the condition** (I've a post coming up on this paper fairly soon), there are some interesting themes emerging from the Girirajan paper. That for example CNV load and the type of CNV (duplication or deletion) might roughly fit into phenotypic differences between inter-related conditions including autism and ID is definitely something worth pursuing in future work. That also such CNVs might tie into genomic hotspot areas is also an important point particularly when it comes to things like systems biology. Lest we also forget the potential importance of any genomic instability and how, with the DNA methylation point in mind, this *might* be attenuated via changes to the environment (remember SAMe)?

To close Chuck Berry and a song about Johnny B Goode and his guitar-playing skills.

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* Girirajan S. et al. Global increases in both common and rare copy number load associated with autism. Hum. Mol. Genet. March 2013.

** Moreno-De-Luca A. et al. Developmental brain dysfunction: revival and expansion of old concepts based on new genetic evidence. The Lancet Neurology. 2013; 12: 406-414.

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Girirajan S, Johnson RL, Tassone F, Balciuniene J, Katiyar N, Fox K, Baker C, Srikanth A, Yeoh KH, Khoo SJ, Nauth TB, Hansen R, Ritchie M, Hertz-Picciotto I, Eichler EE, Pessah IN, & Selleck SB (2013). Global increases in both common and rare copy number load associated with autism. Human molecular genetics PMID: 23535821

Gastrointestinal comorbidity for World Autism Awareness Day

Today (Tuesday 2 April 2013) is World Autism Awareness Day (WAAD).

I don't exactly know how one is supposed to communicate this message ('Happy world autism awareness day' just doesn't roll off the tongue). So I guess all I will say is to reiterate the subtext of this blog on what the spectrum - the very wide spectrum - means: "To some it means a need for life-long support. To others it is part of the varied tapestry of humanity. To all it means a need to foster a welcoming society with appropriate support and opportunities."

Onwards. Having discussed the latest paper from Drs Stephen Walker and Arthur Krigsman on bowel pathology in cases of autism potentially denoting a distinct condition from other inflammatory bowel diseases and stumbling upon the paper by Peeters and colleagues* on functional defecation disorder and autistic traits, I thought it appropriate to pop into the DeLorean and revisit a paper which never really received the recognition it deserved.

The subject matter for today is the paper by Karoly Horvath and colleagues** published in 1999 as we begin another trip down the autism research memory lane, same as I did when covering the the Mary Goodwin paper from 1971 on the gut-brain axis and autism (see here) and the John Money autism and autoimmunity paper also from 1971 (see here).

Hadrian's Wall @ Wikipedia  

Remember my name
The name Karoly Horvath will probably be familiar to quite a few people who've been on the autism research scene for a while. Another of Dr Horvath's papers*** created a bit of stir a while back based on some very preliminary findings on the use of the digestive hormone, secretin for cases of autism.

Following some initial reports of "transient, marginally significant improvements in autistic behaviors" in some cases as per studies like the one from Coniglio and colleagues****, a whole slew of subsequent trials have painted a rather less positive picture on the use of secretin for autism as per the review by Krishnaswami and colleagues***** (open-access) which quite emphatically stated that "secretin as a treatment approach for ASDs warrants no further study".

I'm not one to normally challenge paper conclusions - particularly systematic reviews - but will perhaps contrast that quote with the closing remarks made by the Cochrane Library review of Williams and colleagues******. They left the secretin research door slightly ajar for those who were potentially able to  identify "important subgroups of children with ASD who could benefit from secretin because of a proven link between the action of secretin and the known cause of their ASD, or the type of problems they are experiencing". I'm a great believer in subgroups when it comes to autism, or rather the autisms, and how a diagnosis of autism is seemingly protective of nothing when it comes to other conditions/states, so you can perhaps assume which quote was my preference.

Factoids
Anyhow, back to the Horvath 1999 paper. A few interesting factoids from their report:

• Thirty-six children all diagnosed with an autism spectrum disorder (ASD), mean age 5.7 years, formed the participant group. Children were all referred to the gastroenterology (GI) clinic where the authors worked following the presence of various GI symptoms ranging from abdominal pain to chronic diarrhoea and various other presentations.
• As well as quite a bit of review of participants' medical history, various clinical investigations were undertaken which included a "full upper gastrointestinal workup", analysis of digestive enzyme function in the small intestine and some histological examination.
• Results: quite a few important findings. Reflux esophagitis was present in nearly 70% of participants (25/36). Chronic inflammation of the gastric mucosa was determined in 15 children. Reduced disaccharidase activity was present in approximately 60% of children, and in particular low lactase levels. Following administration of secretin, participants with autism and diarrhoea comorbid showed signs of increased pancreatico-biliary fluid output potentially indicative of "upregulation of the secretin receptors" itself potentially related to "either a defect in secretin production or a problem of release from the intestinal S cells".
• "There was no evidence of either fungal or bacterial overgrowth in the duodenum" was another finding.

I know there is a lot to take in from those results so I'm going to try and put them into some kind of perspective with some of the other related literature in the peer-reviewed domain.

Lactose intolerance
I'll start with the disaccharidase activity side of things. The Horvath results were in some respects ahead of their time with their findings in this area. I've talked previously about the Rafail Kushak paper and their findings of the frequency "of lactase deficiency was 58% in autistic children ≤ 5 years old and 65% in older patients". Notice the similarity in the percentages between Horvath and Kushak. Indeed, this whole area of carbohydrate malabsorption present in cases of autism was very nicely continued by the Brent Williams paper looking at enzyme activity and autism. I know a few people have talked about how some of these findings might overlap with for example, the various reports on the use and effectiveness of a gluten- and casein-free (cereal grains and mammalian dairy free) diet in some cases of autism. Certainly, I wouldn't rule out a possible overlap to account for any results.

Reflux and GERD
Gastroesophageal reflux and reflux esophagitis - states pertaining to inflammation of the esophagus - were also commonly reported in the participant group and indeed also correlated with various behavioural manifestations noted in some cases (nighttime wakening, signs of irritability, abdominal discomfort) which are "typically reported by non-autistic children with esophagitis". A little reading around this topic suggests that many cases of such esophagitis are tied into things like GERD - gastroesophageal reflux disease - which is basically about stomach acid rising up instead of staying where it should be and causing damage. That being said, other explanations have also surfaced to potentially account for the damage done during GERD (see the paper by Souza and colleagues*******) highlighting a possible role for cytokines in this process. I'm also conscious of the findings of eosinophilic esophagitis being reported in individual cases of autism (see here). In terms of management options and without heading down any medical advice giving path, I was very interested to see a body of work appearing supporting the use of baclofen for cases of GERD********, a derivative of which - arbaclofen - has recently been touted as a potential intervention option for cases of autism. One has to wonder whether kum-ba-arbaclofen might be doing so much more than just affecting GABA receptors?

I'm going to stop there with the Horvath paper and its quite important observations. Once again it is a good example of how, just because we see a rising tide of new findings on autism or any other condition or state, we shouldn't neglect the older literature (published pre-social media) and the valuable insights that it has provided. Indeed, I am going to champion the paper by Horvath et al as an important one; particularly when it came to the assessment of carbohydrate digestive enzyme activity because it was truly ahead of its time and very possibly something that you might hear more about in the coming years of autism research.

Importantly for WAAD, the Horvath paper is a stark reminder that awareness of the autism spectrum should extend beyond just the triad (very soon to be dyad) of core symptoms and into the range of often very pronounced comorbidities which can also exist and affect quality of life. And just in case you need a more recent example of this, have a look at this paper from Francisca van Steensel and colleagues********* (open-access) and their findings on the over 50% rate of psychiatric comorbidity reported in their pediatric cohort. Their focus on 'anxiety disorders' does not need any more chatter from me.

To close, something musically, a little more contemporary. Bruno Mars and Locked Out Of Heaven.

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* Peeters B. et al. Autism spectrum disorders in children with functional defecation disorders. J Pediatr. March 2013.

** Horvath K. et al. Gastrointestinal abnormalities in children with autistic disorder. J Pediatr. 1999; 135: 559-563.

*** Horvath K. et al. Improved social and language skills after secretin administration in patients with autistic spectrum disorders. J Assoc Acad Minor Phys. 1998; 9: 9-15.

**** Coniglio SJ. et al. A randomized, double-blind, placebo-controlled trial of single-dose intravenous secretin as treatment for children with autism. J Pediatr. 2001; 138: 649-655.

***** Krishnaswami S. et al. A systematic review of secretin for children with autism spectrum disorders. Pediatrics. 2011; 127: e1322–e1325.

****** Williams K. et al. Intravenous secretin for autism spectrum disorders (ASD). Cochrane Database Syst Rev. 2012; 4: CD003495.

******* Souza RF. et al. Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury. Gastroenterology. 2009; 137: 1776-1784.

******** Cossentino MJ. et al. Randomised clinical trial: the effect of baclofen in patients with gastro-oesophageal reflux - a randomised prospective study. Aliment Pharmacol Ther. March 2012.

********* van Steensel FJA. et al. Psychiatric comorbidity in children with autism spectrum disorders: a comparison with children with ADHD. J Child Fam Stud. 2013; 22: 368–376.

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Horvath K, Papadimitriou JC, Rabsztyn A, Drachenberg C, & Tildon JT (1999). Gastrointestinal abnormalities in children with autistic disorder. The Journal of pediatrics, 135 (5), 559-63 PMID: 10547242

Antigen content exposure and autism: no link

I'm hopefully not setting myself up for a fall by discussing the study published by Frank DeStefano and colleagues* (open-access) suggesting no link between the 'too many too soon' argument of vaccination and risk of autism. As probably would be expected with such study results, there has been a flurry of interest on this paper (see here and here for example) and so once again I'm not going to add too much to the details which have already been reported.

The basics:

• Based on a final comparison of 256 children diagnosed with an autism spectrum disorder (ASD) with an asymptomatic control group of 752 children (all born between 1994 -1999), vaccination histories were examined and exposure to "total antibody-stimulating proteins and polysaccharides from vaccines was determined by summing the antigen content of each vaccine received". 
• For those like me, who are not too well-versed in the immunological principles of vaccination, the antibody-stimulating proteins and polysaccharides bit basically refers to the constituents of vaccines designed to invoke an immune response and the production of antibodies to recognise and fight the bacteria/virus being vaccinated against. Quite by coincidence, the BBC recently carried an interesting article about new vaccines potentially coming from some analysis on the UK synchrotron, the Diamond Light Source (see here - click on the interactive video) which quite neatly sums up the hows and whys of vaccination. 
• The study produced odds ratios (ORs) for ASD 'outcomes' during the first 2-years and found no evidence for any increased risk of autism based on antigen exposure. 
• Bearing in mind quite a few other potentially interfering variables were also collected (maternal exposures, child birth conditions, etc.), the results similarly suggested "no associations when exposures were evaluated as cumulative exposure from birth to 3 months, from birth to 7 months, or from birth to 2 years, or as maximum exposure on a single day during those 3 time period". In short, no statistical association between too many vaccines too soon and autism.

There's little more to say about the findings that hasn't already been said. I've talked before about immunisation uptake in siblings of children with autism (see here) and how the general topic of vaccination has been a real source of discussion/debate/argument in some quarters of the autism landscape; more often than not as a result of the disparity between personal experiences vs. the scientific literature.

Appreciating that quite a few people want to draw a line under the whole vaccination-autism affair in light of this and other data quite explicitly detailing no population-wide link between the two, I'm always open to further scientific inquiry on any aspect of autism. Take for example the work by Harumi Jyonouchi and colleagues on SPAD - specific polysaccharide antibody deficiency - in relation to cases of autism (see here) which may or may not be relevant and which is crying out for further independent replication. Or even the suggestion that post-vaccination paracetamol (acetaminophen) use might be tied into risk of autism as per the paper by Schultz and colleagues** (thanks Jen).

And then there are the various reports on cases being conceded on vaccination and 'autism-like symptoms' developing as per Hannah Polling. Indeed, with the n=1 very firmly in place, I note from the linked Time article "she received an unusually large number of vaccines in 2000 (when thimerosal was still in use). Because of a series of ear infections, Hannah had fallen behind in the vaccine schedule, so in a single day she was given five inoculations covering a total of nine diseases: measles, mumps, rubella, polio, varicella, diphtheria, pertussis, tetanus, and Haemophilus influenzae." According to the DeStefano results, the total antigen load was not an issue? So what might have been the issue/s? Did a mitochondrial problem show some involvement or not? (see the CDC FAQs on this topic).

I'm going to finish this post by highlighting just how important vaccination is (see here, again from the CDC), save any charges of irresponsible blogging being levelled against me. At the same time though, realising that no medicine is infallible and that continued vigilance and monitoring is required as per the article by Roberta Kwok*** and the recent flu vaccination - narcolepsy example.

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* DeStefano F. et al. Increasing Exposure to Antibody-Stimulating Proteins and Polysaccharides in Vaccines Is Not Associated with Risk of Autism. J Pediatrics. March 2013.

** Schultz ST. et al. Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey. Autism. 2008; 12: 293-307.

*** Kwok R. Vaccines: The real issues in vaccine safety. Nature. 2011; 473: 436-438.

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Frank DeStefano, Cristofer S. Price, & Eric S. Weintraub (2013). Increasing Exposure to Antibody-Stimulating Proteins and Polysaccharides in Vaccines Is Not Associated with Risk of Autism The Journal of Pediatrics

NICE on managing autism in children & young people: draft

A very quick post to direct readers to the draft version of the final strand of guidance from NICE (National Institute for Health & Care Excellence) on managing autism in children and young people here in Blighty. The guidance documents can be found here and include the rather sizeable draft version of the full guidance (here) alongside a more condensed summary version (here).

These are draft documents (at the time of this post) so there may yet be some movement in some of the wording. Consultation closes on May 10th 2013 and is only open to stakeholders.

I'm not offering any opinion on these at the moment (I'm employed by one of the stakeholder organisations) but please feel free to download, read and take in. And don't forget those other strands of guidance which have already been published by NICE: (a) pathways to diagnosis (here) and (b) diagnosis and management of adults with autism (here).

Inflammation, oxidative stress and autism: Saudi style

Saudi Arabia and autism research appearing on this blog? Regular readers know that this can mean only one thing: Laila Al-Ayadhi and special guests - in this case Afaf El-Ansary - and their fairly recent paper* (open-access) on plasma lipid mediators in autism.

Kingdom Tower @ Wikipedia  

You might already know that I'm a bit of a fan of the Saudi autism research group which also on occasion includes Gehan Mostafa. Their papers have an exquisite range of topics around autism, the most recent being that vitamin D and autoimmunity paper** which I recently blogged about (see here). This is a group on an autism research mission which rivals that of the all-powerful MIND Institute in terms of scope if not participant numbers.

This time around there was a familiar sound to the topic in question: inflammation and autism (yes that old hat), and some interesting observations based on some players in lipid mediation.

A few choice points to make bearing in mind the paper is open-access and goes off in quite a few directions:

• Impaired lipid metabolism was a focus, based on the measurement of three compounds in plasma which in a round-about kinda way tie into lipids, oxidative stress and inflammation: 8-isoprostane, cysteinyl leukotriene and prostaglandin E2.
• Actually another old favourite, arachidonic acid (AA), is the starting point for these compounds in a roundabout sort of way.
• As is usual with this research group, the participant numbers were not exactly all that impressive (autism: n=19, controls: n=20) but at least the autism group were well-defined and seemingly crossing over with some of their other research observations.
• Results: group analysis of all three compounds showed that they were elevated in the autism group compared with controls; indeed in all compounds,  the means and standard deviation (SDs) showing some clear statistical water between the groups, and some significant correlations between levels of the compounds (the leukotriene - PGE2 correlation reaching 0.926).
• As is also seemingly a pre-requisite for this research group, ROC analyses were also conducted and under certain circumstances showed 100% sensitivity but rather less in terms of specificity as predictive biomarkers for autism.

What more needs to be said? Well, further evidence that oxidative stress might be part and parcel of some cases of autism as per other research in this area***. Also, some support for further investigations into fatty acid metabolism in autism. And indeed inflammation... need I say much more about this?

Having said all that I'm not as sure that their suggestion about this suite of biomarkers informing the use of omega-3 fatty acids as a strategy to ameliorate inflammatory and oxidative stress in autism is necessarily reflected in the current evidence. Yes omega-6 fatty acids might play some role in autism as per (mouse) studies like that of Jones and colleagues**** but questions remain as to whether omega-3 supplementation really is cutting the mustard bearing in mind the heterogeneity and comorbidity present in autism.

Just before I go and hopefully not too far off-topic, did I mention the paper by McNamara and colleagues***** on fatty acid profiles in cases of schizophrenia?

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* El-Ansary A. & Al-Ayadhi L. Lipid mediators in plasma of autism spectrum disorders. Lipids Health Dis. 2012; 11: 160.

** Mostafa GA. & Al-Ayadhi LY. Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: Relation to autoimmunity. J Neuroinflammation. 2011; 9: 201.

*** Ming X. et al. Increased excretion of a lipid peroxidation biomarker in autism. Prostaglandins Leukot Essent Fatty Acids. 2005; 73: 379-384.

**** Jones KL. et al. Maternal diet rich in omega-6 polyunsaturated fatty acids during gestation and lactation produces autistic-like sociability deficits in adult offspring. Behav Brain Res. 2012; 238C :193-199.

***** McNamara RK. et al. Adult medication-free schizophrenic patients exhibit long-chain omega-3 Fatty Acid deficiency: implications for cardiovascular disease risk. Cardiovasc Psychiatry Neurol. 2013: 796462.

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El-Ansary A, & Al-Ayadhi L (2012). Lipid mediators in plasma of autism spectrum disorders. Lipids in health and disease, 11 (1) PMID: 23170784

The gut microbiome and chronic fatigue syndrome

I've hinted before on this blog and its sister blog about how one of the most unappealing of interventions - fecal bacteriotherapy - is starting to make some waves in managing various conditions. I know its not everyone's cup of tea but the concept of transplanting whole stools or specific types of enteric bacteria from one person to another is actually providing some well needed relief for quite a few people.

Insert here.... @ Wikipedia  

If it sounds like an undesirable treatment option, put yourself in the shoes of someone who for example is suffering as result of infection due to C. difficile and the potential consequences that this can entail after other treatment options have been exhausted and then wonder again. Better still, have a look at that probiotic yoghurt drink that is sitting in your fridge and ponder the question: where did the 'special' bacteria included in this drink originally come from? (hint: 'donor zero' is probably smiling at all of us).

Whilst fecal bacteriotherapy is moving into more mainstream medicine circles for conditions linked to things like C.diff, various other states and diseases are also starting to be discussed with the s--t transplant in mind. One person in particular is leading these discussions, Dr Thomas Borody, following his groundbreaking work on triple therapy for H.pylori infection (see here), and some discussions on 'emerging' applications* (no pun intended). Indeed Dr Borody is quite the leading light when it comes to fecal bacteriotherapy.

I was particularly interested to read the paper by Borody and colleagues** looking at the potential application of bacteriotherapy to cases of chronic fatigue syndrome (CFS). Regular readers might already know of my tendency to stray into the research domain of CFS (and ME) on this blog and beyond not least because quite a bit of the research there seems to overlap with what I talk about with autism in mind (e.g. immune function, mitochondrial issues, even HERVs..).

Anyhow, with many thanks to Sarah Finlayson, one of Dr Borody's co-authors, for sending me a copy of their paper, a few points are worth noting:

• This is a paper which kills two birds with one stone. On the one hand, there is quite a nice summary of CFS and the gut microbiome (hopefully this link still works for non-members). On the other hand, the paper describes the experiences of 60 patients with CFS attending Dr Borody's clinic some time in the mid-1990s and in receipt of transcolonoscopic (TC) and rectal infusions of "anaerobic bacterial culture". Distinct from the 'full works' of of a stool transplant or 'fecal microbiota transplantation (FMT)', bacteriotherapy involves the 'fusion of a mixture of 13 non-pathogenic enteric bacteria" which include those of the Bacteroidetes, Clostridia and E.coli families/phyla/species.
• Every participant received at least one TC infusion; most also received a second rectal infusion (n=52); a small number received two days of additional rectal infusion (n=3). Actually, as you'll see in a minute, there was a bit more to this than what is mentioned in the methods section of the paper.
• Results: it is slightly difficult to gauge what specific results were achieved from this trial given that participants were judged to be responders or non-responders at 4 weeks based on some fairly nebulous criteria. So for example, responders signified "a resolution of CFS symptoms (sleep deprivation, lethary/fatigue)" but without the paper actually saying how these outcomes were measured or what tools were used. I'd hazard a guess that it was a case of participant interview or questionnaire but I can't confirm this. 
• On the basis of this responder / non-responder coding, 35 (58%) were judged responders to bacteriotherapy. This figure improved when initial non-responders (n=15) were given a second TC infusion "followed by rectal infusion (n=4) or an oral course of cultured bacteria (n=6)"; up to 42 / 60 (70%) responders.
• Gastrointestinal (GI) symptoms were reported to be resolved in 37 of the 42 final responders.
• Follow-up of participants some 15-20 years later (12 of the original cohort) suggested that over half of them remained free of their CFS symptoms; although importantly, some relapsed (5/12) between 18-36 months post-bacteriotherapy.

I probably don't need to highlight the fact that this was very much an observational case-series study over anything like a clinical trial. My initial excitement at reading this paper was very slightly dampened by the way results were reported and those all-important missing details regarding how the authors measured change over the period of baseline vs. bacteriotherapy. Even the reported resolution of GI symptoms leaves me asking questions like: what GI symptoms, how were they measured and who did the measuring? There are gaps in this work, make no mistake of that. Bear however in mind issues such as when this study was initially carried out and how the diagnostic criteria of CFS might not necessarily have been as well-defined as they are today. Just sayin.

I can also imagine some people are reading this post and thinking what the .... ! How can a condition like CFS be sensitive to a bacterial transplant, and what about those methods used to introduce such a therapy... yeah right. Bear in mind however that our nether regions are actually quite good routes of drug administration bypassing for example, hostile environments like the stomach and onward the first-pass effect. Indeed the question should be: would you prefer this to the insertion of a naso-gastric tube as is the other option when delivering bacteria to where it is needed? Your choice...

Having said all that I am still interested in this line of inquiry. The authors for example, suggest a possible link between "the resolution of gastrointestinal and CFS symptoms" and how this "supports the theory of a possible gastrointestinal-associated etiology, potentially arising from alterations to the bowel flora". I kinda speculated about the many faces (Man-E-Faces?) of CFS in a previous post on HERVs and ME (see here) and how the spectrum of CFS/ME might be just that, a spectrum. It strikes me that one could very easily investigate this possible sub-types issue within a well-defined population.

There is obviously more to do in this area of endeavour. As per a recent article I played a small hand in writing, the gut microbiome is a relatively uncharted area of medicine in terms of its links to health and wellbeing and indeed our often varied response to the pharmaceutics we all take potentially as a result of our gut bacterial composition. There are obvious important questions to ask about safety (the gut virome anyone?) and efficacy of interventions like bacteriotherapy particularly when applied to conditions of unknown origin like CFS/ME. Indeed, the desperation of some sufferers makes them very vulnerable to all kinds of potential intervention options which might not necessarily be right for them.

But that's not to say there isn't already research movement (no pun intended) in the area of the gut microbiome and CFS/ME as per Sanjay Shukla study (detailed here) which should be reporting quite soon. That added to the Michael Maes suggestion of issues with gut permeability in cases of CFS/ME (sound familiar?) makes for quite a few hypotheses being open for testing with much greater focus on rigour in research methodology.

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* Borody TJ. & Khoruts A. Fecal microbiota transplantation and emerging applications. Nat Rev Gastroenterol Hepatol. 2011; 9: 88-96.

** Borody TJ. et al. The GI microbiome and its role in Chronic Fatigue Syndrome: A summary of bacteriotherapy. Journal of the Australasian College of Nutritional and Environmental Medicine. 2012; 31: 3-8.

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Thomas Borody, Anna Nowak, & Sarah Finlayson (2012). The GI microbiome and its role in Chronic Fatigue Syndrome: A summary of bacteriotherapy Journal of the Australasian College of Nutritional and Environmental Medicine, 31 (3)