More scientific flesh on the bones of non-coeliac gluten/wheat sensitivity

I was really, really pleased to read the paper by Melanie Uhde and colleagues [1] (open-access) I don't mind telling you. Covering a topic close to my blogging and research heart - sensitivity to wheat or gluten but not coeliac disease - the authors provide some much needed scientific clarification when it comes to how gluten or wheat might impact on some of those "who reported symptoms in response to wheat intake and in whom coeliac disease and wheat allergy were ruled out." Some media interest in the paper can also be seen here.

With an authorship list including some of the great and good on this issue (see here for example) researchers included 80 participants presenting with non-coeliac wheat sensitivity (NCWS) according to "criteria recently proposed by an expert group" [2]. These NCWS participants reported "experiencing intestinal and/or extraintestinal symptoms after ingestion of gluten-containing foods, including wheat, rye or barley. The reported symptoms in all subjects improved or disappeared when those foods were withdrawn for a period of 6 months, and recurred when they were re-introduced for a period of up to 1 month." All 80 provided serum samples for analysis that were compared with similar samples from 40 participants with "biopsy-proven active coeliac disease" and 40 samples from asymptomatic controls on a non-restrictive diet.

The sort of information sought from those serum samples included quite a bit. Not only were "established markers" of coeliac disease (CD) assayed for - including IgA antibody to TG2 - but various immunological markers towards gluten were also included for study. Based also on the idea that "intestinal cell damage and systemic immune response to microbial components" might be an important feature of NCWS, researchers also markers associated with "compromised intestinal epithelial barrier integrity."

Results: well, as per the media interest in this paper: "The findings suggest that these individuals [with NCWS] have a weakened intestinal barrier, which leads to a body-wide inflammatory immune response."

A few further details are worthwhile discussing. First, the genetics of coeliac disease (those DQ2 and/or DQ8 heterodimers) were present in about a quarter of those with NCWS "a rate not substantially different than in the general population." Second, most of those with NCWS did not show the characteristic mucosal signs of CD as per the Marsh gradings (0 or 1) throughout the cohort. This was in direct contrast to the CD participants who all "expressed HLA DQ2 and/or DQ8 and presented with Marsh 3 grade intestinal histological findings." The conclusion: CD and NCWS participants are not one and the same (just in case you needed telling).

Next: "Serum levels of both LBP [lipopolysaccharide (LPS)-binding protein (LBP)] and sCD14 were significantly elevated in individuals with NCWS in comparison with patients with coeliac disease and healthy individuals." This implies that there is 'systemic immune activation' on-going in those participants with NCWS not seen to the same extent in the other groups. These findings were also complemented by results indicative of that compromised intestinal epithelial barrier integrity previously discussed. The final picture emerging being one where NCWS participants seem to be in a state of 'immune activation' "linked to increased translocation of microbial and dietary components from the gut into circulation, in part due to intestinal cell damage and weakening of the intestinal barrier." I might add that some smaller scale analysis of serum samples from those NCWS participants "both before and after 6 months of a self-monitored diet free of wheat, rye and barley" suggested "a significant decline in the markers of immune activation and gut epithelial cell damage, in conjunction with the improvement of symptoms."

And rest.

For those as interested in this area of research as I am, I'm sure that you can understand my happiness in seeing the Uhde results and what it might mean for many, many people who've been perhaps been 'fobbed off' down the years with regards to their gluten ills. I can't help but see a possible connection between these findings and others reported with autism in mind for example (see here and see here). The added suggestion that 'intestinal cell damage' might be a feature of NCWS also possibly ties in with all that talk about 'leaky gut' and some autism (see here) but I don't doubt it may go well beyond just [some] autism [3]. Not looking so tree-hugging now eh?

Of course there is more to do in this area: "Further research is needed to investigate the mechanism responsible for the intestinal damage and breach of the epithelial barrier, assess the potential use of the identified immune markers for the diagnosis of affected individuals and/or monitoring the response to specific treatment strategies, and examine potential therapies to counter epithelial cell damage and systemic immune activation in affected individuals." I might also add in a role for those trillions of wee beasties that call our gut home (the gut microbiota) as potentially also being a target for further scientific research too (see here for example).

I await further studies...


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[1] Uhde M. et al. Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease. Gut. 2016. July 25.

[2] Catassi C. et al. Diagnosis of Non-Celiac Gluten Sensitivity (NCGS): The Salerno Experts’ Criteria. Nutrients. 2015;7(6):4966-4977.

[3] Whiteley P. Nutritional management of (some) autism: a case for gluten- and casein-free diets? Proc Nutr Soc. 2015 Aug;74(3):202-7.

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Uhde, M., Ajamian, M., Caio, G., De Giorgio, R., Indart, A., Green, P., Verna, E., Volta, U., & Alaedini, A. (2016). Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease Gut DOI: 10.1136/gutjnl-2016-311964

Pregnancy multivitamins 'are a waste of money' (except when they're not)

Science headlines eh? Who would trust them and their sometimes inflated press releases?

I start today with a science headline taken from the BBC website reading: "Pregnancy multivitamins 'are a waste of money'" based on the findings of a review article [1] published in the journal Drug and Therapeutics Bulletin.

In it we are told that complex multi-vitamin and mineral supplements are 'unlikely to be needed and are an unnecessary expense' during the nine months that made us. Further that certain vitamins are not indicated for supplementation during pregnancy including that contributory to excess vitamin A. All pregnant women have to do, we are told is "to have a healthy, varied diet including fresh fruit and vegetables" and avoid the old phrase 'eating for two'. What could be simpler?

The irony behind such findings and those BBC and other media headlines is that although one needs to be careful about one's vitamin and mineral intake (treat them as what they are, medicines) there is a long tradition of vitamin supplementation being indicated when it comes to that special time called pregnancy. Indeed, and I quote from the BBC article: "pregnant women should make sure they take folic acid and vitamin D, as well as eating a well-balanced diet, as per NHS guidelines, they add."

So let me get this straight: don't take a multi-vitamin supplement but makes sure that you take a (multi) supplement containing folic acid and vitamin D? You can perhaps see how confusing such headlines are and how grandiose ideas that every woman pre-conceptual and during pregnancy is feasting down on 5-a-day (or even 8-a-day if you actually believe it will make you happier!) are not necessarily based in reality. We would all love to think that important health messages about maternal fruit and vegetable consumption during pregnancy for example, are being heard loud and clear but the reality is that they aren't for everyone. The reality is that people are using vitamin and mineral supplements to supplement their dietary needs for whatever reasons and headlines further confusing the population about such supplementation being a 'waste of money' is only likely to put more people off using them without perhaps giving greater thought about the ways and means to help people alter their diet accordingly. The net result: more pregnant women potentially becoming deficient in certain core nutrients during pregnancy and more potential effects/risks for her and her offspring.

I do have a bee in my bonnet about this issue because time after time the research evidence points to how important pregnancy nutrition is for a variety of maternal and offspring outcomes [2]. Outside of folic acid and vitamin D, various other nutrients are also pretty important during pregnancy (i.e. iodine - 'good for baby, good for the economy') and the unfortunate reality is that most people can't or don't get enough of them from their diet alone. The late David Barker was a pioneer in the area of foetal programming including that related to pregnancy nutrition; one can only wonder what he would make of the suggestion that universally, supplementary multivitamin use during pregnancy is a 'waste of money'?

And finally, you want more people to eat fruit and vegetables? Don't focus too much on just price and positioning at the supermarket, focus on home economics (or just cookery!) classes at school [3] for starters and make fruit and vegetables interesting...

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[1] Vitamin supplementation in pregnancy. Drug & Therapeutics Bulletin. 2016. July 11.

[2] Harding JE. The nutritional basis of the fetal origins of adult disease. Int J Epidemiol. 2001 Feb;30(1):15-23.

[3] McMorrow L. et al. Perceived barriers towards healthy eating and their association with fruit and vegetable consumption. J Public Health (Oxf). 2016 May 24.

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Drug and Therapeutics Bulletin (2016). Vitamin supplementation in pregnancy Drug and Therapeutics Bulletin DOI: 10.1136/dtb.2016.7.0414

Autism in adults in the UK continued

The paper by Traolach Brugha and colleagues [1] makes for some blogging fodder today and the suggestion that: "The combined prevalence of autism in adults of all ages in England was 11/1000."

Just before going through the Brugha paper it is perhaps appropriate to put it into some context based on other work from this group previously covered on this blog (see here) and the findings again by Brugha and colleagues [2] (a further report on their findings that time around can be seen here).

On that last occasion published in 2011, the estimated prevalence of adult autism in the UK - living in the community - was reported on, arriving at a figure of 9.8/1000. That finding was based on data from the 2007 Adult Psychiatric Morbidity Survey (APMS) and whilst important, was not without it's methodological weaknesses including the fact that: "Sampling excluded institutional residents and adults with intellectual disability severe enough to prevent them from participating in the assessment." I'll come back to the 'weakness' issues shortly also with one of the screening instruments in mind...

Anyhow, the Adult Psychiatric Morbidity Survey (2007) once again formed the basis for the recent paper by Brugha added to "a population case-register survey of 290 adults with intellectual disability". Those additional 290 adults have already been discussed in another publication from this group (see here) and were collectively termed the IDCR cohort (Intellectual Disability Case Register study). I have to admit that at first I thought it was the 2014 reincarnation of the APMS that formed the bulk of the data for this latest paper - data from the publication of which is due out soon - but this was not the case as we are told that: "The sample from the first general population study was extended with the inclusion of representative samples of adults with intellectual disability omitted from the earlier survey" i.e. those additional 290 adults included as part of the IDCR study. The value added bit to the latest Brugha paper was the inclusion of adults both living in both private households or in communal care both "sampled from learning disability case registers."

The 2-stage screening affair held with the 2007 APMS cohort where the the Autism-Spectrum Quotient (AQ) - the AQ20 - was the starting point, followed by the ADOS (Autism Diagnostic Observation Schedule) (module 4) as and when required. ADOS module 1 was actually the preferred assessment scheme for those IDCR study participants (module 1 "is designed for individuals who do not consistently use phrase speech") and the AQ initial screen did not seem to figure.

The results: well, I've already indicated that the estimated prevalence was around 1.1% of the adult population, up from the previous 0.9% estimate. This was based on "14 men and 4 women with autism in the APMS subsample, and 49 men and 40 women with autism in the IDCR subsample." It should be noted that of the original 290 participants interviewed from the IDCR cohort, only 276 were eventually assessed for autism as a consequence of some presenting with quite profound difficulties not conducive to a "confident assessment".

The authors report that estimated autism prevalence was higher in those with moderate to profound learning (intellectual) disability and that there was a 'gradient' of autism prevalence by learning disability status. A quote by the authors relays this finding perfectly: "almost two in five adults with moderate to profound intellectual disability had autism." Indeed, the link between autism and learning disability is something that has also been discussed in recent posts (see here) on this blog. Authors also observed that: "Male gender was a strong predictor of autism only in those with no or mild intellectual disability" so highlighting how the gender ratio for autism in those with moderate or profound intellectual disability was nowhere near the traditional 4:1 ratio commonly touted.

Although important data filling a very important gap in terms of the estimated adult prevalence of autism here in Blighty, I would like to return to the potential 'weakness' aspect of the last and latest Brugha papers. For those who follow this blog you'll probably know that I have a few issues with one of the primary screening instruments put forward with 'autistic traits' in mind: the Autism Spectrum Quotient (AQ). It's nothing personal when it comes to my growing unease with the instrument but in these days of the 'are you autistic?' pop psychology survey (see here) I'm not convinced that (a) it is all that reliable as an accurate screening measure [3] for autism and (b) that it is specifically 'tuned into autism' at the expense of other possible diagnoses (see here). The fact that the AQ20 was the first stage screener for those potentially requiring subsequent ADOS-ing at least in the APMS 2007 cohort does bring into question exactly how accurate the Brugha findings are in terms of the final estimated prevalence of adult autism among those where learning disability does not feature. Indeed, even the authors in a further relevant publication have even questioned their 2-stage methodology used [4]: "The AQ-20 was only a weak predictor of ADOS-4 cases." Hmm.

To reiterate, I don't want to come down to hard on the Brugha findings because they are some of the best data we currently have when it comes to estimates of numbers of cases of adult autism in the UK. The fact that the data - systematically collected on this and the previous testing occasion - seemed to be pointing towards a significant role for learning disability when it comes to autism alongside an increase in cases when this factor is taken into consideration also plays into all those debates about whether autism is truly on the rise (see here) and what further planning and resources are going to be needed in future years. It is however only with time and continued monitoring that we will see what trends become apparent with regards to autism prevalence in adults here in the UK and what more we will see when APMS 2014 finally begins to report...

To close, having watched the fantastic film Ant-Man with my brood recently, we're never going to look at Thomas the Tank Engine in quite the same light...

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[1] Brugha TS. et al. Epidemiology of autism in adults across age groups and ability levels. Br J Psychiatry. 2016 Jul 7.

[2] Brugha TS. et al. Epidemiology of autism spectrum disorders in adults in the community in England. Arch Gen Psychiatry. 2011 May;68(5):459-65.

[3] Ashwood KL. et al. Predicting the diagnosis of autism in adults using the Autism-Spectrum Quotient (AQ) questionnaire. Psychol Med. 2016 Jun 29:1-10.

[4] Brugha TS. et al. Validating two survey methods for identifying cases of autism spectrum disorder among adults in the community. Psychol Med. 2012 Mar;42(3):647-56.

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Brugha TS, Spiers N, Bankart J, Cooper SA, McManus S, Scott FJ, Smith J, & Tyrer F (2016). Epidemiology of autism in adults across age groups and ability levels. The British journal of psychiatry : the journal of mental science PMID: 27388569

Blood glutamate levels in autism meta-analysed

"The meta-analysis provided evidence for higher blood glutamate levels in ASD [autism spectrum disorder]."

That was the research bottom-line reported by Zhen Zheng and colleagues [1] (open-access available here) who surveyed the current peer-reviewed science literature in this area and found something to see based on: "Twelve studies involving 880 participants and 446 incident cases."

Drawing on the idea that glutamate is a rather important amino acid that plays a role in various biological processes including that related to the manufacture of GABA (see here), Zheng et al observed higher circulating blood levels of the stuff; a sort-of proxy for what might also be going on with regards to brain levels of glutamate. That "excess glutamate has been shown to be a potent neurotoxin that leads to neuronal cell death and plays a role in the pathophysiology of some neuropsychiatric disorders" is an important point to make as to the potential implications from the Zheng meta-analysis.

Zheng et al do mention how important glutamate is for the purposes of GABA production and in particular, how issues with glutamate decarboxylase (GAD) - a key enzyme that converts glutamate into GABA - described in some cases of autism [2] might account for the elevated levels of glutamate yet the generally lower levels of GABA seen in autism (see here). I'd be inclined to agree that this is perhaps one of the more important implications for glutamate in autism; particularly when added to the whole 'glutamate linked to epilepsy' bit knowing how close a relationship autism and epilepsy seem to share (see here).

Where next with this research area I hear you ask? Well, I'd like to know a little more not just about glutamate but also another linked amino acid called glutamine. It has already been talked about in the autism research literature a while back (see here) but a lot more follow-up work is required on these two important compounds and what their differing ratio might mean. I'd also like to see more work done on the idea that "the mood stabilizer valproic acid, which exerts neuroprotective effects against glutamate-induced excitotoxicity, is effective in ASD [autism spectrum disorder] with seizures." Yes, I know that valproic acid a.k.a valproate is a bit of a double-edged sword when it comes to autism and other offspring developmental issues under certain circumstances (see here) but much like another research story in autism (see here) timing of exposure seems to be a key issue and one wonders whether other unrelated compounds might also exert a similar neuroprotective effect.

As to the idea that "blood glutamate levels may serve as a potential biomarker in the diagnosis of ASD" made by Zheng and colleagues, we'll wait and see...

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[1] Zheng Z. et al. Blood Glutamate Levels in Autism Spectrum Disorder: A Systematic Review and Meta-Analysis. PLoS One. 2016 Jul 8;11(7):e0158688.

[2] Yip J. et al. Decreased GAD65 mRNA levels in select subpopulations of neurons in the cerebellar dentate nuclei in autism: an in situ hybridization study. Autism Res. 2009 Feb;2(1):50-9.

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Zheng Z, Zhu T, Qu Y, & Mu D (2016). Blood Glutamate Levels in Autism Spectrum Disorder: A Systematic Review and Meta-Analysis. PloS one, 11 (7) PMID: 27390857

Probiotics degrading gluten peptides - part 2

I going to assume that readers have some background knowledge about probiotics, gut bacteria, bacterial dysbiosis and coeliac disease before reading this post. I'd love to be able to give detailed descriptions of each here but fear that this would turn a short post into a much longer one...

So... in a previous post titled: 'Probiotics degrading gluten peptides?' I covered the potentially important suggestion that certain types of bacteria might have the ability to breakdown (degrade) immunogenic gluten peptides. This may be particularly relevant to conditions like coeliac disease where specific peptides derived from gluten are involved in a cascade of biological processes that can and do affect a sizeable proportion of the population.

In this part 2 post I'm turning my attention to the findings reported by Alberto Caminero and colleagues [1] who observed that: "Small intestinal bacteria exhibit distinct gluten metabolic patterns in vivo, increasing or reducing gluten peptide immunogenicity." Further that: "This microbe-gluten-host interaction may modulate autoimmune risk in genetically susceptible persons and may underlie the reported association of dysbiosis and CeD [coeliac disease]."

How did they arrive at such conclusions? Well, it all started with some bacterial seeding, where "bacteria isolated from the small intestine of CeD patients or healthy controls" was implanted into a germ-free mouse/mice. Said mice were given gluten (gluten gavage) and various measures of gliadin content and the extent of breakdown of gluten proteins were measured. The specific peptides "produced by bacteria used in mouse colonization" were subjected to analysis via one of the gold-standards of analytical chemistry: LC-MS/MS. Said peptides were then evaluated for their immunogenic potential "using peripheral blood mononuclear cells from celiac patients after receiving a 3-day gluten challenge."

Results: well I've already mentioned that different types of intestinal bacteria seemed to have different patterns of gluten protein degradation. This is rather important because not 10-15 years ago most people in the know would have suggested that gluten protein degradation is solely under the control of the body's biological systems designed for this purpose. Now it appears, there may be bacterial helping hands also at work. So: "Lactobacillus spp. from the duodenum of non-CeD controls degraded gluten peptides produced by human and Psa [Pseudomonas aeruginosa] proteases, reducing their immunogenicity." But for every 'good guy' there must be a 'bad guy' and in this case Psa assumes that role: "Psa-modified gluten peptides activated gluten-specific T-cells from CeD patients."

One still has to be a little cautious about this and other related work as things stand but such results are promising. Not only because more and more the gut microbiome is being implicated in conditions like coeliac disease (see here for example) but also because there may be something that can be done about it [2] and science has the technology to identify other potential gluten-digesting bacteria [3] too. Indeed, alongside a suite of other potential intervention options (see here for example) the management of conditions like coeliac disease by avoidance of dietary gluten may eventually not be the only option. Whether this may also extend to the slightly more grey areas of gluten sensitivity (see here) remains to be seen as does the idea that certain bacteria might also 'work' on accompanying issues such as those linked to gut barrier integrity [4]...

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[1] Caminero A. et al. Duodenal bacteria from patients with celiac disease and healthy subjects distinctly affect gluten breakdown and immunogenicity. Gastroenterology. 2016 Jun 30. pii: S0016-5085(16)34713-8.

[2] Duar RM. et al. Identification and characterization of intestinal lactobacilli strains capable of degrading immunotoxic peptides present in gluten. J Appl Microbiol. 2015 Feb;118(2):515-27.

[3] Berger M. et al. Rapid isolation of gluten-digesting bacteria from human stool and saliva by using gliadin-containing plates. Exp Biol Med (Maywood). 2015 Jul;240(7):917-24.

[4] Orlando A. et al. Lactobacillus GG restoration of the gliadin induced epithelial barrier disruption: the role of cellular polyamines. BMC Microbiol. 2014 Jan 31;14:19.

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Caminero, A., Galipeau, H., McCarville, J., Johnston, C., Bernier, S., Russell, A., Jury, J., Herran, A., Casqueiro, J., Tye-Din, J., Surette, M., Magarvey, N., Schuppan, D., & Verdu, E. (2016). Duodenal bacteria from patients with celiac disease and healthy subjects distinctly affect gluten breakdown and immunogenicity Gastroenterology DOI: 10.1053/j.gastro.2016.06.041

Risk of cancer in mums of children with autism

I very carefully approach the findings reported by Jennifer Fairthorne and colleagues [1] today detailing "the occurrence of hospital admissions and treatment/services for cancer in mothers of children with ASD [autism spectrum disorder] with or without ID [intellectual disability] compared with other mothers." Appreciating that families touched by autism probably have enough on their plate without additional talk about the 'big C', I do however think that this kind of research is important if not only as part of the process of 'caring for the carers'.

Based on the analysis of various "Western Australian administrative health databases" (something gaining research ascendancy), researchers sought to estimate the odds, sorry hazard ratios, of hospitalisation and/or use of services in relation to cancer when it came to mums of children with autism (with and without learning disability) "compared with other mothers." They concluded that there may be something more to see when it comes to elevated use of cancer services among mothers of children with autism. Mothers of children with autism but not with accompanying learning disability in particular seemed to be a group in need of quite a bit more scientific investigation.

Minus any sweeping generalisations nor scaremongering, this is important work. I've kinda touched upon the idea that risk of cancer might be something to look at in first degree relatives of those with autism (see here) before. As per reports such as the one by Erin Ingudomnukul and colleagues [2] the risk is not wildly increased similar to the risk of cancer among people with autism themselves (see here), but certainly enough to start asking more research questions about possible mechanisms and the potential applicability of preferential screening services. Indeed, on the topic of possible mechanisms it might be useful to note the growing interest in the idea that autism genes are not necessarily just genes for autism (see here) and that just outside of structural genetics, there is another branch of science ripe for further dual inquiry [3]...

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[1] Fairthorne JC. et al. Mothers of Children with Autism have Different Rates of Cancer According to the Presence of Intellectual Disability in Their Child. Journal of Autism and Developmental Disorders. 2016. July 6.

[2] Ingudomnukul E. et al. Elevated rates of testosterone-related disorders in women with autism spectrum conditions. Horm Behav. 2007 May;51(5):597-604.

[3] Latham KE. et al. The epigenetic lorax: gene-environment interactions in human health. Epigenomics. 2012 Aug;4(4):383-402.

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Fairthorne, J., de Klerk, N., Leonard, H., & Whitehouse, A. (2016). Mothers of Children with Autism have Different Rates of Cancer According to the Presence of Intellectual Disability in Their Child Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-016-2847-9

On probiotics and irritable bowel syndrome (IBS)

Granted, I am taking a slight departure from the material typically discussed on this blog by introducing the paper by Yan Zhang and colleagues [1] who reported the findings of a meta-analysis examining "the efficacy of different probiotic types, doses and treatment durations in IBS [irritable bowel syndrome] patients diagnosed by Rome III criteria via a meta-analysis of randomized controlled trials (RCTs)." The results however - "Probiotics are an effective pharmacological therapy in IBS patients" - were important enough for me to think about discussing, particularly in the context that IBS might not be stand-alone condition (see here) and some recent research in progress [2] (see here for my take) that could illustrate some wider relevance.

The Zhang paper is open-access so doesn't need any grand rewriting from me in terms of methods or findings but a few things stick out. First is the fact that quite a few different probiotic preparations have been experimentally examined with IBS in mind. From the 21 studies looked at by Zhang et al, we have some recurring themes including different types of Lactobacillus acidophilus and Lactobacillus rhamnosus for example being included in the preparations. The inclusion of a preparation called VSL#3 also caught me eye in light of some discussions about a potential 'antibiotic brain' recently on this blog (see here) and what might reverse this in mice. Of additional note was the use of an old friend: Saccharomyces boulardii that continues to impress [3].

Second, and related to the first point, are the authors conclusions that: "Single probiotics, a low dose, and a short treatment duration were more effective with respect to overall symptom response and QoL [quality of life]." The authors provide some rather interesting forest plots illustrating how the analysed data helped them reach this conclusion; albeit bearing in mind that "the effects of individual probiotic species" were not analysed in the current meta-analysis. In other words, some preparations seem to work pretty well but we don't know enough about which ones used under which circumstances.

Finally, I noted that the whilst the use of a placebo was an important eligibility criteria for inclusion in their meta-analysis - "the studies were randomized controlled trials (RCTs) that compared probiotics with placebo" - the authors did not shy away from the fact that: "An appreciable placebo effect was detected in some studies, which may have minimized the effects of probiotics." Placebo effects and IBS is something again, that has been discussed before on this blog (see here) bearing in mind I'm not saying that IBS is 'all in the mind' or anything like that.

Set within the context of other recent meta-analyses concluding that: "There were alterations of gut microbiota in IBS patients and it implied that alterations of gut microbiota might be involved in the pathogenesis of IBS" [4] one shouldn't necessarily be surprised that there may have been effects from the use of probiotics in cases of IBS. Assuming that an oral probiotic is able to survive the stomach environment and actually colonise [parts of] the gastrointestinal (GI) tract (if only for a defined amount of time) the cost-effectiveness of this intervention coupled with the low rates of side-effects makes for impressive reading in terms of the treatment of at least some cases of IBS.

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[1] Zhang Y. et al. Effects of probiotic type, dose and treatment duration on irritable bowel syndrome diagnosed by Rome III criteria: a meta-analysis. BMC Gastroenterology. 2016; 16: 62.

[2] Santocchi E. et al. Gut to brain interaction in Autism Spectrum Disorders: a randomized controlled trial on the role of probiotics on clinical, biochemical and neurophysiological parameters. BMC Psychiatry. 2016 Jun 4;16:183.

[3] Szajewska H. & Kołodziej M. Systematic review with meta-analysis: Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea. Aliment Pharmacol Ther. 2015 Oct;42(7):793-801.

[4] Zhuang X. et al. Alterations of gut microbiota in patients with irritable bowel syndrome: A systematic review and meta-analysis. J Gastroenterol Hepatol. 2016 Jun 14.

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Zhang Y, Li L, Guo C, Mu D, Feng B, Zuo X, & Li Y (2016). Effects of probiotic type, dose and treatment duration on irritable bowel syndrome diagnosed by Rome III criteria: a meta-analysis. BMC gastroenterology, 16 (1) PMID: 27296254

Surgery for "chronic idiopathic constipation" and autism

I can't profess to be an expert on the techniques called sigmoidectomy and appendicostomy so won't even try and pretend that I am. From what I gather from Dr Google, the latter is a surgical technique generally performed to "help deliver enemas more easily" to relieve constipation, whilst the former involves the surgical removal of some or all of the sigmoid colon. Both are only generally indicated when traditional methods of treating constipation for example, fail.

The reason I'm briefly talking about sigmoidectomy and appendicostomy today revolves around the paper by Luis De La Torre and colleagues [1] who following a review of 8 cases of "chronic idiopathic constipation complicated by megarectosigmoid and fecal incontinence" reported that half of their small cohort "have autism" whilst all "had severe social problems." They reported that after their surgery "all patients were having daily bowel movements without fecal accidents."

For regular readers I probably don't have to stress the substantial weight of peer-reviewed scientific evidence suggesting that functional bowel issues are over-represented when it comes to a diagnosis of autism. For any newcomers straying onto this blog (a dangerous thing indeed!) I might direct you to one of my more recent entries on this important comorbidity (see here) and how despite some headline fails (see here) preferential screening for bowel issues should really follow an autism diagnosis. Add it to the list of screening potentially indicated...

The observations made by De La Torre et al represent the extreme of tackling functional constipation as and when it appears and how such a bowel issue can not only wreck quality of life but also potentially put someone in a life-threatening situation (yes, it has sadly happened and with autism mentioned). Nobody likes the idea of surgically removing parts of the gastrointestinal (GI) tract nor 'creating a pathway from belly button to the large intestine' in any patient, less so when that patient may have autism and potentially other comorbidity leaving open significant debate on issues such as informed consent. But, given the current lack of knowledge about the hows and whys of constipation when it occurs alongside autism, I think we are going to see more and more extreme cases such as this in both the clinical and research domains.

The onus therefore is on putting any prejudice aside when the words 'bowel' and 'autism' are strung together in the same sentence (see here) and making some real scientific strides into the mechanisms potentially involved in such over-representation. People diagnosed with autism and suffering some often quite terrible bowel issues deserve so much more than just further health inequality...

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[1] De La Torre L. et al. Primary sigmoidectomy and appendicostomy for chronic idiopathic constipation. Pediatr Surg Int. 2016 Jul 2.

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De La Torre L, Cogley K, Calisto J, Nace G, & Correa C (2016). Primary sigmoidectomy and appendicostomy for chronic idiopathic constipation. Pediatric surgery international PMID: 27372298

Sensory processing issues are present throughout the autism spectrum

I want to make an initial point about the paper by Corentin Gonthier and colleagues [1] and their research findings titled: 'Sensory Processing in Low-Functioning Adults with Autism Spectrum Disorder: Distinct Sensory Profiles and Their Relationships with Behavioral Dysfunction', I'm not a great fan of the use of the term 'functioning' when it comes to autism.

Yes, I know what message it's trying to convey in terms of 'severity' of autism and/or accompanying learning (intellectual) disability and/or the level of day-to-day adaptive skills a person possesses with the aim of providing some indication of how 'able' or 'disabled' they are. My issue, and indeed I'm not the only one with a bee in their bonnet about this, are that the terms 'low functioning' and 'high functioning' rarely provide an accurate portrayal of the cumulative aspects of a person. One example of this can be seen in the quite depressing statistics when it comes to employment and autism, and how even those 'high-functioning' people on the spectrum, sometimes with above average intellect, are much less likely to be employed than their peers. High-functioning does not always mean 'can-function' in real life (even those with seemingly impressive skills) and importantly, tends to take little account of how comorbid issues such as anxiety can be so utterly disabling for a person.

I digress. The Gonthier study set about asking an important question about an important group: do the various sensory processing issues quite commonly reported in those on the more able side of the autism spectrum also extend to those peoples with more profound difficulties? Based on data "collected for a representative sample of inpatients in autism care centers (N = 148) and a non-clinical control group" researchers concluded that yes, sensory dysfunction is "highly prevalent in low-functioning adults with ASD [autism spectrum disorder]" but no, there is no 'one-size-fits-all' profile for this population. Indeed, that lack of a universal profile in the cohort studied pretty much mirrors what has been noted in  the 'more able' autism phenotype.

One other detail mentioned in the Gonthier findings also caught my eye in that sensory dysfunction "predicts specific patterns of behavioral disorders" at least in this cohort. This is an intriguing suggestion that potentially amongst the myriad of issues falling under the heading of 'challenging behaviours' for example, there may be a role for sensory processing issues too. It does kinda make sense that sensory issues could invoke some of those so-called challenging behaviours allied to other research looking, for example, at how pain might manifest among some of those on the autism spectrum (see here). It also makes for an even stronger case that screening for the presence of ophthalmic issues as one potential source/complication of those sensory issues should be more widely indicated irrespective of where someone lies on the autism spectrum (see here) (and whatever description you use of their place on the spectrum).

But a lot more research is required on the topic of sensory processing issues, and indeed, covering the entire autism spectrum in line with other writings [2] ...

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[1] Gonthier C. et al. Sensory Processing in Low-Functioning Adults with Autism Spectrum Disorder: Distinct Sensory Profiles and Their Relationships with Behavioral Dysfunction. J Autism Dev Disord. 2016 Jun 30.

[2] Tager-Flusberg H. et al. Conducting research with minimally verbal participants with autism spectrum disorder. Autism. 2016 Jun 26. pii: 1362361316654605.

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Gonthier C, Longuépée L, & Bouvard M (2016). Sensory Processing in Low-Functioning Adults with Autism Spectrum Disorder: Distinct Sensory Profiles and Their Relationships with Behavioral Dysfunction. Journal of autism and developmental disorders PMID: 27364513

Autism 'disclosure cards' and negative judgements?

I have to say that I initially felt slightly uncomfortable reading the study results published by Jillian Austin and colleagues [1] providing "preliminary validation for the use of autism disclosure cards in buffering negative judgment." Uncomfortable because, despite the fact that it is human nature for people to stop, stare and perhaps question something when it seems 'out of the ordinary', the idea that when children with autism specifically 'misbehave' in a public place their parents need to somehow justify their child's behaviour to a staring crowd of strangers seems a trifle unfair.

As is the experience of most parents, whether their child is diagnosed or not with autism or anything else, children are not always 'little angels' every time they are out and about ("no, it is not appropriate to start a public conversation about farting when one 'catches a whiff' of something in the shopping centre"). Most parents can usually get away with a nervous smile to any interested on-lookers (or nosey parkers) and that really should be the end of it. Of course, for some children under some circumstances, behaviour can sometimes go beyond just tantrums and onward can raise a few eyebrows but...

Austin et al started with the premise that parents of children with autism are "increasingly using disclosure cards to reduce negative perceptions" when out and about with their children to make "an invisible diagnosis apparent". They devised an experiment using "vignettes of a parent-child interaction in which the child was misbehaving and investigated the efficacy on 160 parents' perceptions." Disclosure cards were provided to some of the parent participants all of whom had at least one child aged between 6-12 years. Various factors covering "Maternal Skill Deficit and Negative Reaction" and "Sympathy for Mother" were analysed as a function of receipt of disclosure cards or not.

"Those who received the disclosure card reported significantly lower Maternal Skill Deficit and Negative Reaction to the Dyad and no difference in Sympathy for the Mother." In other words, making an 'invisible' diagnosis more visible seemed to have an effect in terms of views around 'it must the parent's fault that their child is behaving that way' (negative judgement) but did little when it came to empathising with the mother's position in that situation.

Austin and colleagues discuss how the 'invisibility' of autism and frames of reference - "people will evaluate and compare individuals to some perceived norm or standard" - in this case, so-called typically developing children, may be driving forces underlying those negative judgements from others about children on the spectrum and their parents. I can't quibble with this line of thought or what impact it might have on children and their parents (and other significant others). But it strikes me that in these days of increased numbers of children being diagnosed with autism (see here) - indeed the numbers just keep on growing - and accompanying high-profile campaigns to raise awareness about autism, movement towards the idea that every parent has to 'identify' their child as being on the autism spectrum as and when they, pardon my French, 'fart the wrong way' seems to place too much emphasis on the child and parent and not enough on their fellow citizens and their own understanding and reactions.

OK, I get that people have busy lives and that outside of media depictions (see here), most people wouldn't typically ask 'could it be autism?' when a child has a 'meltdown' in a public spot. I also get that under some circumstances, making particular groups of people aware of a person's autism might be a good thing as per contact with law enforcement agencies for example. The question however of whether strangers really need to be given quite sensitive information about a person and 'their diagnosis' just because they (the stranger) 'can't deal with a particular situation' strikes me as being more than a little one-sided...

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[1] Austin JE. et al. Influencing Perception About Children with Autism and their Parents Using Disclosure Cards. J Autism Dev Disord. 2016 May 30.

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Austin JE, Zinke VL, & Davies WH (2016). Influencing Perception About Children with Autism and their Parents Using Disclosure Cards. Journal of autism and developmental disorders PMID: 27241346

1 in 3 people with CFS might benefit from methylphenidate?

I'm cautious about the findings reported by Daniel Blockmans & Philippe Persoons [1] talking about how long-term use of the stimulant medication methylphenidate (MPH) might be something to consider for at least some people diagnosed with chronic fatigue syndrome (CFS). Cautious because the sole use of a questionnaire looking "for possible improvement of concentration difficulties and fatigue" following the use of MPH on this research occasion is not exactly a top tier scientific method...

Nonetheless, I have chosen to blog about this paper and the suggestion that MPH might be indicated for 'some' CFS because this is not the first time that this particular class of medicine has been mentioned for this purpose [2] and under slightly more controlled circumstances. That patient views of the way that their symptoms are being treated/managed might also be important to clinical outcomes should also not be forgotten. I might add that even on this blog I've mentioned how, as part of a sort of polypill, MPH also continues to garner some interest in CFS research circles (see here).

In the latest publication, Blockmans & Persoons describe responses from some 150 patients diagnosed with CFS (somehow!) on their experience of MPH. Perhaps most importantly, they reported that most of their patient group - about two-thirds - "had stopped the intake of methylphenidate" post prescription. Make of that what you will with regards to medicines compliance and the issue of side-effects ("Side effects (agitation, palpitations, and dry mouth) were reported significantly more in patients who had stopped methylphenidate than in those who still took it") but just over a third continued to use it either on a daily basis or 'occasionally'.

For those who continued to take MPH, there are some interesting experiences reported. So: "48% reported an at least 50% improvement of fatigue, and 62% reported an at least 50% improvement of concentration difficulties. This continued intake of methylphenidate resulted in more working hours in these patients." Appreciating that data such as '48% of those taking it reported at least a 50% improvement in fatigue symptoms' actually means very little in objective terms, I do find these data interesting. That the authors also mention that concentration difficulties also seemingly eased ties into (a) the expected 'nootropic' effects of MPH and (b) the idea that CFS (and ME, myalgic encephalomyelitis) can also manifest in other non-fatigue ways as per the suggestion of 'brain fog' being voiced by several patients [3].

There is more to do in this area including additional placebo-controlled trials and further focus on those potential 'best-responders' to MPH in these days of heterogeneous pluralisation of diagnostic labels. That the actions of something like MPH might go a little further than that listed on the package insert is also something to consider (see here); relevant also to other CFS research findings [4]. All this bearing in mind that no medicine is without side-effects [5] to at least some who take it.

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[1] Blockmans D. & Persoons P. Long-term methylphenidate intake in chronic fatigue syndrome. Acta Clin Belg. 2016 Jun 27:1-8.

[2] Blockmans D. et al. Does methylphenidate reduce the symptoms of chronic fatigue syndrome? Am J Med. 2006 Feb;119(2):167.e23-30.

[3] Jason LA. et al. Classification of myalgic encephalomyelitis/chronic fatigue syndrome by types of fatigue. Behav Med. 2010 Jan-Mar;36(1):24-31.

[4] Fukuda S. et al. A potential biomarker for fatigue: Oxidative stress and anti-oxidative activity. Biol Psychol. 2016 May 17;118:88-93.

[5] Snell LB. & Bakshi D. Neurological adverse effects of methylphenidate may be misdiagnosed as meningoencephalitis. BMJ Case Reports. 2015:

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Blockmans D, & Persoons P (2016). Long-term methylphenidate intake in chronic fatigue syndrome. Acta clinica Belgica, 1-8 PMID: 27351244

Reconsidering the Autism-Spectrum Quotient (AQ) for autism screening?

A quote to begin: "The AQ's [Autism Spectrum Quotient] utility for screening referrals was limited in this sample. Recommendations supporting the AQ's role in the assessment of adult ASD [autism spectrum disorder], e.g. UK NICE guidelines, may need to be reconsidered."

Taken from the paper published by Ashwood and colleagues [1], the findings from this team don't make for great reading if you happen to be a fan of the AQ as a potential screening instrument for adult autism. Indeed, mention of the specific NICE guidance where the AQ is mentioned - "consider using the Autism-Spectrum Quotient – 10 items (AQ-10)" - might make for quite a few uncomfortable discussions in times to come.

Based on the analysis of "476 adults, seen consecutively at a national ASD diagnostic referral service for suspected ASD" here in Blighty, self- and informant-report AQ scores (a supposed measure of autistic traits) were examined (both AQ10 and AQ50) in relation to who would eventually go on to receive a diagnosis of autism using some of the gold-standard assessment measures (ADOS and ADI).

The results: about three-quarters of those referred did eventually end up with a expert clinician diagnosis of autism. But... "Self-report AQ scores did not significantly predict receipt of a diagnosis" (at least not when it came to the two variants of AQ and ADOS cut-off scores) and nearly two-thirds of those who scored below the AQ cut-off "did in fact have ASD." Also important was the suggestion that "generalized anxiety disorder may 'mimic' ASD and inflate AQ scores, leading to false positives."

Although requiring independent replication, the implications of the Ashwood findings are potentially far-reaching to several aspects of autism research, practice and indeed, politics. There are a few points to make about the Ashwood paper in relation to the fact that around 1 in 5 AQ50 questionnaires for example, had to be corrected in some way as a result of between 1-4 missing items ("corrected score=raw score x (50 / (50 – missing items)"). That also schizophrenia as a discrete diagnosis was excluded from the analysis of of comorbid conditions potentially affecting AQ scores is something else that perhaps needs be looked at in view of other reports in the peer-reviewed arena [2] on this topic. Indeed, as I've indicated in other posts on this topic, the question of what exactly the AQ is measuring is still something requiring an answer (see here) minus any sweeping generalisations.

The observation that generalised anxiety disorder (GAD) when present might be something that 'inflates' scores on the AQ (particularly the AQ10 self-report) is also important to re-iterate. Bearing in mind that autism and anxiety are not unstrange diagnostic bedfellows (see here), one could argue that treating or managing anxiety should then potentially also have an impact on the presentation of autism. This follows suggestions about what might happen when other important psychiatric comorbidity 'over-represented' in autism are similarly managed (see here).

Perhaps a little more political is the additional idea that self-diagnosis - something gaining prominence in some parts - where AQ is used as the self-diagnosis tool, might not be a particularly great strategy. I know this opinion might conflict with other viewpoints but as I've said before, the process of formal diagnostic assessment for autism is there for a very good reason. Pop quizzes headed under titles like 'are you autistic?' often do a real disservice to what autism can (and does) mean to an awful lot of people and could also lead to other important conditions (such as schizophrenia and/or personality disorders) being missed or overlooked [3].

If there is a research-based take-away point from the Ashwood findings it is that reliance on AQ alone as an autism screening measure is probably not such a good idea. This point will also be further discussed when it comes to a blog about the findings from Brugha and colleagues [4] scheduled to appear shortly...

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[1] Ashwood KL. et al. Predicting the diagnosis of autism in adults using the Autism-Spectrum Quotient (AQ) questionnaire. Psychol Med. 2016 Jun 29:1-10.

[2] Lugnegård T. et al. Asperger syndrome and schizophrenia: Overlap of self-reported autistic traits using the Autism-spectrum Quotient (AQ). Nord J Psychiatry. 2015 May;69(4):268-74.

[3] Lugnegård T. et al. Personality disorders and autism spectrum disorders: what are the connections? Compr Psychiatry. 2012 May;53(4):333-40.

[4] Brugha TS. et al. Epidemiology of autism in adults across age groups and ability levels. Br J Psychiatry. 2016 Jul 7. pii: bjp.bp.115.174649.

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Ashwood KL, Gillan N, Horder J, Hayward H, Woodhouse E, McEwen FS, Findon J, Eklund H, Spain D, Wilson CE, Cadman T, Young S, Stoencheva V, Murphy CM, Robertson D, Charman T, Bolton P, Glaser K, Asherson P, Simonoff E, & Murphy DG (2016). Predicting the diagnosis of autism in adults using the Autism-Spectrum Quotient (AQ) questionnaire. Psychological medicine, 1-10 PMID: 27353452

Increased microbial translocation in ME/CFS

"The cause of ME/CFS [myalgic encephalomyelitis/chronic fatigue syndrome] is unknown, but gut dysbiosis could be contributing to some of the symptoms and their severity. Developing therapeutic interventions aimed at reducing local inflammation, restoring gastrointestinal tract immunity and integrity and modifying the intestinal microbiome may ameliorate ME/CFS symptoms in a number of affected patients."

Those were the important conclusions reported by Ludovic Giloteaux and colleagues [1] (open-access) who "profiled gut microbial diversity by sequencing 16S ribosomal ribonucleic acid (rRNA) genes from stool as well as inflammatory markers from serum for cases (n = 48) and controls (n = 39)." Authors recount how all 'cases' (participants) fitted the "Fukuda diagnostic criteria" for CFS/ME but "most, perhaps all, also fit the description of SEID [Systemic Exertion Intolerance Disease]." We're also told that a majority of participants with ME/CFS "self-reported gastrointestinal disturbances such as constipation, diarrhea, or intestinal discomfort" something perhaps not unfamiliar to the peer-reviewed research domain (see here).

Looking at inflammatory markers as well as the composition and diversity of those trillions of wee beasties that call us home (the gut microbiome), Giloteaux et al reported some important differences between their groups that might even be considered 'diagnostic' at some point in the future (emphasis on 'some point'). "[The] gastrointestinal tract of ME/CFS  patients is a pro-inflammatory environment" is another of their observations; indeed, based on the idea that: "Abnormal immune activation can be caused by translocation of microbes from an inflamed gut" and reporting elevations in some of the blood markers potentially pertinent to this process. Said microbial translocation (MT) was evidenced by: "(i) significantly raised levels of plasma LPS [lipopolysaccharide] and (ii) significantly higher levels of sCD14 [soluble CD14] and LBP [LPS-binding protein], as indicators of direct LPS stimulation." Interestingly however: "Levels of hsCRP [high-sensitivity C-reactive protein] were higher in the ME/CFS population in comparison to healthy controls... but the difference was not statistically significant."

Examination of stool samples from study participants also found some potentially important differences between the groups as "less diversity as well as increases in specific species often reported to be pro-inflammatory species and reduction in species frequently described as anti-inflammatory" were found in the ME/CFS group. Of particular note were "lower levels of the genus Faecalibacterium, a member of the Ruminococcaceae in the ME/CFS population" and that "Proteobacteria were more abundant in ME/CFS patients than in controls." Minus any sweeping generalisations, such combined findings have been reported in cases of inflammatory bowel disease (IBD) among other things. Utilising a machine-learning approach (something we've seen before on this blog) authors were also "mostly successfully classified into healthy and ME/CFS groups" on the basis of the inflammatory and microbiome data with a little more investigation required.

This is of course not the first time that the gut microbiome has been 'implicated' in cases of ME/CFS (see here). The application of the 'yuck factor 10' that is the faecal microbiota transplantation as one effort to alter the gut microbiome in cases of ME/CFS has also been mentioned too (see here). These latest results add to the interest and indeed, the idea that the gut might be a central organ of either cause or effect when it comes to at least some cases of ME/CFS (see here and see here). But I might also add there is more to do in this area. Giloteaux et al talk a lot about gut barrier integrity as being implicated but didn't directly measure permeability or by how much...

Finally, I do think due credit should be given to some of the research pioneers upon which the Giloteaux findings are based. I'm thinking specifically of Michael Maes of NIOF fame (see here) who has been quite consistently talking about "increased translocation of LPS from gram negative bacteria with subsequent gut-derived inflammation" in cases of CFS/ME and importantly, what could be potentially done about it [2]. It appears that replicative science might indeed be on his, and his research teams', side. And he just keeps going (see picture).

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[1] Giloteaux L. et al. Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome. 2016; 4: 30.

[2] Maes M. & Leunis JC. Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria. Neuro Endocrinol Lett. 2008 Dec;29(6):902-10.

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Giloteaux L, Goodrich JK, Walters WA, Levine SM, Ley RE, & Hanson MR (2016). Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome, 4 (1) PMID: 27338587