SHANK3, gut issues and (mouse) autism continued

"We conclude that apart from its well-known role in the CNS [central nervous system], SHANK3 plays a specific role in the GI [gastrointestinal] tract that may contribute to the ASD [autism spectrum disorder] phenotype by extracerebral mechanisms."

So said the findings reported by Ann Katrin Sauer and colleagues [1], and yet more evidence that issues with SHANK3 mentioned in relation to 'some' autism, may well (partly) explain much more than just behaviour (see here and see here).

The Sauer study was yet another mouse study. They specifically focused on the "Shank3αβ KO" mouse, where KO means knock-out, referring to the engineering of this mouse strain to mimic issues with the functioning and availability of SHANK3, "a known scaffolding protein of the postsynaptic density (PSD) of glutamatergic excitatory synapses." Said knock-out mice have been "reported to display ASD-like behavior with abnormal ultrasonic vocalization, repetitive self-grooming, and reduced interest in novel mice." I say this being careful to reiterate that we're talking about a mouse not human beings (see here).

On the basis of the observation that SHANK3 is expressed in the gut as well as brain and that GI issues are no stranger to autism (see here), researchers set about looking at how SHANK3 issues might also manifest as gut issues, and what this *could* mean for some autism. They observed some interesting things:

• "analysis of the GI tract of Shank3αβ KO mice revealed significantly altered gut morphology" which included, among other things, increased levels of ZONULIN1 ("a modulator of tight junctions and alterations"). Zonulin is something that I'm particularly interested in on this blog (see here and see here) on the basis of its *connection* to intestinal barrier function and the misnomer that is 'leaky gut' (see here).
• "The Microbiome of Shank3 KO Mice Is Altered." Bearing in mind the increasing importance of the gut microbiome to autism (see here), researchers reported some interesting difference between "Shank3αβ KO mice" and controls with regards to several different bacterial species. 
• Researchers describe how those gut morphology and gut bacterial differences seemed to be linked to alterations in the "expression of inflammatory markers" too as they talked about "signs of increased immune activation in the periphery and the brain." A familiar cytokine is mentioned - IL-6 - and quite a few avenues for further investigation.

The net result of all this work is to say that, yes, the SHANK3 mouse model *potentially* mimicking some of the behavioural signs and symptoms of autism does also appear to show some significant gut-related issues. No, this does not directly translate into issues for 'all human autism', but it does add further credence to the idea that the gut-brain axis is likely important to at least 'some autism'. Where also SHANK3 issues are identified as coinciding with 'human autism', one might also entertain the idea that gut issues should be screened and treated/managed. And there might be lots of ways to manage them (see here for one example)...

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[1] Sauer AK. et al. Altered Intestinal Morphology and Microbiota Composition in the Autism Spectrum Disorders Associated SHANK3 Mouse Model. Int. J. Mol. Sci. 2019; 20: 2134.

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Constipation and autism is not an uncommon combination

For those who know (or think they know) anything about autism, the title of this post - "Constipation and autism is not an uncommon combination" - is unlikely to be new or novel. Indeed, I've talked again and again and again about how functional gastrointestinal (GI) symptoms are very well over-represented when it comes to a diagnosis of autism (see here for example).

Enter then two further recent articles - one from Bradley Ferguson and colleagues [1] and one from María José Penzol and colleagues [2] - which further add to the evidence base in this area. Both papers are open-access, so please peruse at your leisure. The long-and-short of them can be quickly summarised:

• The Ferguson paper set out to examine the "relationships among GI [gastrointestinal] problems, problem behaviors, and internalizing symptoms in a sample of 340 children and adolescents with ASD [autism spectrum disorder]." Caregivers/parents reported on their child's GI issues. Bottom line: "The majority of the sample experienced constipation (65%)." Various other functional GI issues were also reported.
• The Penzol paper "reviewed the medical records of all patients admitted to the Comprehensive Medical Program for ASD (AMITEA) at Gregorio Marañón University General Hospital from January 2012 to December 2015." They analysed records for nearly 850 patients diagnosed with ASD. Their data were collected and transcribed by physicians including the "presence of fGID [functional gastrointestinal disorders] (gastrointestinal reflux, aerophagia, functional diarrhea, functional constipation, functional abdominal pain, cyclic vomiting)." Bottom line: "At least one fGID was present in 30.5% of patients, constipation being the most prevalent (47.4% of fGID patients)." They also observed that GI issues *seemed* to be related to the presence of intellectual (learning) disability, sleep issues and behavioural problems. These are not novel associations (see here and see here).

Of course there are strengths and weaknesses to those studies. No-one would dispute the fact that these are not perfect data. But, set within the context of a mountain of peer-reviewed science suggesting that something like constipation is over-represented when it comes to a diagnosis of autism, the collected results add a further layer of evidence. They also ask the question 'why', why oh why have we not got a greater handle on how to successfully treat/manage such symptoms?

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[1] Ferguson BJ. et al. The Relationship Among Gastrointestinal Symptoms, Problem Behaviors, and Internalizing Symptoms in Children and Adolescents With Autism Spectrum Disorder. Front Psychiatry. 2019 Apr 9;10:194.

[2] Penzol MJ. et al. Functional Gastrointestinal Disease in Autism Spectrum Disorder: A Retrospective Descriptive Study in a Clinical Sample. Front Psychiatry. 2019 Apr 10;10:179.

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A test "that distinguishes ASD fast response constipation from ASD persistent right-sided constipation"?

The quote heading this post - "A test that distinguishes ASD [autism spectrum disorder] fast response constipation from ASD persistent right-sided constipation" - comes from the findings reported by Stephen Walker and colleagues [1]. The Walker results continue a theme from this research group (see here) whereby some important data is being generated on how to treat some fairly prevalent bowel issues that seem to accompany quite a few diagnoses of autism (see here).

Much like other research from this authorship group, the research material examined was biopsy tissue - "ascending colon biopsy tissues" - provided by 35 children diagnosed with an autism spectrum disorder "and chronic constipation on a background of enterocolitis." I know some people don't like the word 'enterocolitis' in the context of autism (see here) but prejudices aside, there is nothing in the current research literature to suggest that a diagnosis of autism is somehow protective against the development of inflammatory bowel disease and/or its symptoms. Nothing.

Anyhow, 20 of those 35 children were categorised as 'slow responders' on the basis of showing "recurrent right-sided fecal loading requiring regular colon cleanouts during treatment for enterocolitis" and 15 were defined as 'fast responders' as a function of experiencing "a sustained state of GI [gastrointestinal] symptomatic remission while on maintenance anti-inflammatory therapy." In effect the group was divided up into those whose bowel symptoms got better (n=15) and those whose bowel symptoms did not (even after multiple attempts) (n=20). Researchers analysed those biopsy samples with the expression of genes in mind as per other research occasions [2].

Results: "Significant differences were found between the two clusters with fast responder-predominant cluster showing an upregulation of transcripts involved in the activation of immune and inflammatory response and the slow responder-predominant cluster showing significant over-representation of pathways impacting colonic motility (e.g. genes involved in tryptophan and serotonin degradation and mitochondrial dysfunction)." Apologies for the long quote taken from the Walker paper, but they said it better than I ever could. The translation: gene expression data was different between the fast and slow responder groups.

Obviously more research is needed in this area with larger participant groups and perhaps using samples from other non-autism groups who present (or don't) with various types of bowel issues, whether sensitive to treatment or not. The cluster of genes that were used in the authors' modelling did all right when it came to talk of possible 'biomakers' - "The sensitivity (sensitivity = 0.88), specificity (specificity = 0.89), and kappa (kappa = 0.77) statistics all reflect a good strength of agreement between prediction and actual assignments" - but still need more work before any big claims are made.

There are a couple of other things to mention from the Walker results. So, results suggested that: "predominantly chronic constipation in fast responders is not only related to the inflammatory status of the right colon but is likely a direct consequence of this colonic inflammation." Inflammation perhaps equalling constipation? Interesting. And it not only offers lots more avenues for further study but also some important treatment options.

Next, the amino acid tryptophan was singled out as being potentially "especially significant." I've always been interested in the aromatic amino acids in relation to some autism (see here). Tryptophan is a particularly important aromatic amino acid because it's eventually metabolised into a whole slew of important compounds from serotonin (5-HT) to melatonin and beyond, with some interesting connections to autism (see here). Walker and colleagues mention how: "In the slow responder cluster of patients, there was a significant upregulation of transcripts in each of the metabolic degradation pathways for tryptophan, serotonin, and melatonin, suggesting that TRP [tryptophan] insufficiency (and therefore 5-HT insufficiency) may be an important factor in the sustained hypomotility seen in this patient cohort." There's some much more study that one could do in this area. Particularly when 'gut hypomotility' is a potential issue for quite a few people on the autism spectrum (see here).

There are other things to consider from the Walker paper - "A third relevant theme apparent from the slow response gene expression profile involves a number of pathways that converge in the mitochondria and impact mitochondrial function" - but I'll leave that for now (see here). Suffice to say that there is enough evidence emerging in the peer-reviewed domain to say that (a) pathological bowel problems are more than present alongside a diagnosis of autism, (b) said bowel issues also overlap with functional GI symptoms such as constipation in particular, (c) there are physiological reasons for such bowel issues outside of any psychobabble explanations, and (d) lots more research is required in this area without fear or favour pertinent to improving quality of life...

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[1] Walker SJ. et al. A molecular biomarker for prediction of clinical outcome in children with ASD, constipation, and intestinal inflammation. Sci Rep. 2019 Apr 12;9(1):5987.

[2] Walker SJ. et al. A Putative Blood-Based Biomarker for Autism Spectrum Disorder-Associated Ileocolitis. Sci Rep. 2016 Oct 21;6:35820.

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A poo(p) transplant for [some] autism? 2 years on with caveats...

The results published by Dae-Wook Kang and colleagues [1] provide some important follow-up work to a study already discussed on this blog (see here) which suggested that: "MTT is safe and well-tolerated in children with ASD ages 7–16 years" and also "led to significant improvements in both GI- and ASD [autism spectrum disorder] -related symptoms" [2]. MTT by the way, refers to Microbiota Transfer Therapy, or in other words a poo(p) transplant. A press release accompanying the recent Kang paper is also available (see here).

The original Kang study included quite a bit more than just a poo(p) transplant as per their use of a 4-stage protocol: "(1) oral vancomycin, (2) MoviPrep, (3) SHGM [Standardized Human Gut Microbiota], and (4) Prilosec" with 18 participants diagnosed with an autism spectrum disorder (ASD). The results on that last occasion were promising insofar as (a) adverse effects being small and fairly limited and (b) some improvements noted in relation to behaviour and gastrointestinal (GI) symptoms. That all being said, one needs to remember that the previous study was an open trial and results were therefore preliminary.

On this latest research occasion, Kang et al followed up their 18 participants "two years after treatment was completed." The follow-up involved "the same GI and behavior tests that we employed previously" which involved the use of various parent- and professional-report questionnaires on behaviour, questionnaire analysis of GI issues and analysis of poo(p) samples: "16 out of 18 original ASD participants provided an additional fecal sample two years after the open-label trial."

Researchers reported that "most improvements in GI symptoms were maintained, and autism-related symptoms improved even more after the end of treatment." They observed something of a possible *relationship* between bowel and behavioural signs and symptoms whereby "GI relief provided by MTT may ameliorate behavioral severity in children with ASD, or vice versa, or that both may be similarly impacted by another factor" which is interesting (see here). They also noted that the bacterial composition of stools analysed at follow-up showed evidence of sustained change "including significant increases in bacterial diversity and relative abundances of Bifidobacteria and Prevotella." In short, things were still looking pretty good after 2 years.

"Despite steady and continuous improvement in behaviors over two years, we must underscore that the original clinical trial and current follow-up study are open-label trials without a control for placebo effect." The authors are frank about the limitations of their studies, and how behavioural and GI symptoms in particular can potentially be influenced by all-manner of different variables. Indeed, they noted that "12 of 18 participants made some changes to their medication, diet, or nutritional supplements" which allied to the waxing and waning of symptoms typically associated with autism (see here), means that one has to be careful about making too many sweeping statements about cause-and-effect.

But in the context that for these 18 participants, a poo(p) transplant was seemingly not associated with too many adverse side-effects and that their behavioural and GI data typically followed a course of improvement, one cannot easily discount the Kang results. The call for further research "with a placebo-control arm" made by the authors should echo throughout the autism research landscape. And with it, further focus on how gut bacterial make-up and the all-important metabolites that specific bacterial species produce seem to be something quite important to at least some autism (see here)...

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[1] Kang D-W. et al. Long-term benefit of Microbiota Transfer Therapy on autism symptoms and gut microbiota. Scientific Reports. 2019; 9: 5821.

[2] Kang D-W. et al. Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome. 2017; 5: 10.

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The gastrointestinal (GI) effects of a gluten- and casein-free diet in autism (continued)

It took a few attempts for me to get this blog post discussing the the paper by Carlo Alessandria and colleagues [1] right. The reasons? Well, predominantly it was because I'm no expert when it comes to the gastrointestinal (GI) tract and autism and, in particular, some of the intricacies of the clinical findings in that context. Don't get me wrong, I am a very keen observer of the peer-reviewed science literature on the bowel and autism (see here and see here  and see here for examples) but I'm no gastroenterologist.

What I did take away from the Alessandria findings is that science is continually looking at the possibility of a link between the various GI issues identified in cases of autism and the still-important peer-reviewed literature on how use of a gluten- and/or casein-free diet (GCFD) seems to have a positive impact for some people on the autism spectrum (see here). Indeed, that there may be lots more to see when it comes to a gut-diet-behaviour interface in relation to (some) autism...

So, slowly does it. First, the aim of the Alessandria study: "evaluating the distribution of human leukocyte antigen (HLA)-DQ2/DQ8 typing among patients with ASD [autism spectrum disorder] with GI symptoms, together with its correlation with duodenal histology and response to GCFD."

HLA-DQ2/DQ8 'typing' are words more commonly found in relation to the prototypical 'dietary gluten can affect health' condition that is coeliac disease. They describe some of the genetics of coeliac disease (CD), and are key components involved in risk for the condition and perhaps other diagnoses of a similar autoimmune ilk. From the 150 or so participants - "with ASD with GI symptoms referred to our outpatient clinic" - who were screened for HLA-DQ2/DQ8, around half were positive (72/151). But researchers did not just stop there. Alongside they also screened for "CD-specific antibodies" (see here and see here for the flavour of what this includes) and concluded that "134 (89%) were negative." To summarise, around half of participants with autism and bowel symptoms possessed the genetics of coeliac disease. But, only around 10% showed a pattern of antibodies related to CD indicative of an immune response to gluten as well as other issues (see here).

And there was more: "Patients were prescribed a 6-month GCFD, and then clinically reassessed." This is where another 'assessment' also becomes relevant to the Alessandria findings. As part of their clinically indicated procedures, participants also underwent endoscopy. This allowed researchers to both look at the inner workings of some of the GI tract and also potentially take biopsy samples. At baseline, before any diet was put in place, they observed that: "56 (37%) showed duodenal microscopic inflammation." 'Duodenal' refers to the duodenum, a part of the GI tract fairly close to the exit of the stomach. Inflammation means just that. And something interesting seemed to connect such bowel findings and dietary response: "Response to diet was related to the presence of histological duodenal alterations at baseline (odds ratio 11.323, 95% confidence interval 1.386-92.549 for Marsh 2 pattern)." In other words, and accepting that correlation is not the same as causation, issues identified in the duodenum - "duodenal histology" - seem to be a possible predictor of response to a gluten- and casein-free diet in relation autistic people.

There is a need for lots more study in this area. Alessandria and colleagues reported their observations on the basis of patients presenting at their clinic with medical needs. This was not a clinical trial in the respect of being randomised (e.g. receiving a diet or not or some other medication to treat such identified bowel issues) or being blinded (researchers and patients not knowing who got what intervention). Knowing a little bit about the use of a GCFD in the context of autism (see here) I'm also acutely aware that 6 months following such a diet is a long time. Even with the best will in the world, some people will not be able to follow such a restrictive diet day-in, day-out. There are issues.

But the Alessandria results are important and promising. They provide a template for further study and an addition to the wealth of biologically-based information on who, on the autism spectrum, might be a 'best candidate' for dietary intervention which excludes gluten and/or casein. I know some people might start up with the 'it's too invasive' arguments in relation to the use of endoscopic and indeed, colonoscopic inquiry when it comes to autism. My counter-argument is that if physicians were presented with a child or adult who did not have autism yet had the same bowel problems as this and other cohorts, would they not be afforded the best healthcare available to them including such inquiry? And why then should a diagnosis of autism but exclusionary to accessing such healthcare? Oh, and it's worth mentioning that at least one of the authors on the Alessandria paper has talked about how technology might eventually make such invasive techniques that little less invasive [2]. Indeed, they've also talked about what else aside from a gluten- and casein-free diet might be clinically indicated for some people on the autism spectrum [3] too with GI issues in mind...

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[1] Alessandria C. et al. HLA-DQ Genotyping, Duodenal Histology, and Response to Exclusion Diet in Autistic Children With Gastrointestinal Symptoms. J Pediatr Gastroenterol Nutr. 2019 Feb 7.

[2] Balzola F. et al. Panenteric IBD-like disease in a patient with regressive autism shown for the first time by the wireless capsule enteroscopy: another piece in the jigsaw of this gut-brain syndrome? Am J Gastroenterol. 2005 Apr;100(4):979-81.

[3] Campion D. et al. The role of microbiota in autism spectrum disorders. Minerva Gastroenterol Dietol. 2018 Dec;64(4):333-350.

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"a probiotic (Bifidobacterium infantis) in combination with a bovine colostrum product (BCP)" for autism?

The study findings reported by Megan Sanctuary and colleagues [1] caught my eye recently, and their aim to "assess tolerability of a probiotic (Bifidobacterium infantis) in combination with a bovine colostrum product (BCP) as a source of prebiotic oligosaccharides and to evaluate GI [gastrointestinal], microbiome and immune factors in children with ASD [autism spectrum disorder] and GI co-morbidities."

I appreciate that such a study is probably not going to be everyone's cup of tea given, for example, the rather *interesting* history of colostrum and autism (including the words 'transfer factor' [2]). The Sanctuary study however, should be taken on its own merit regarding "concurrent supplementation with both the probiotic B. infantis and bovine colostrum product (BCP) as a source of immune factors and prebiotic glycans could alter the microbiota to a more beneficial composition in order to improve gut health in children with ASD and GI symptoms." The rationale behind such work is that (a) what goes on the in the deepest, darkest recesses of the GI tract in a microbial sense could impact on the functional gut symptoms, and (b) said functional gut symptoms seem to be 'over-represented' in relation to autism (see here) and *could* in some cases, be linked to behavioural presentation (see here). Ergo, try and impact on functional gut symptoms and one *might* be able to impact on behaviour...

Sanctuary et al report preliminary findings designed to "assess tolerability" and "to evaluate GI, microbiome and immune factors in children with ASD and GI co-morbidities." This work represented a first step towards a bigger research trial to ascertain whether such a supplemental combination *might* be useful for some people on the autism spectrum in a 'clinically relevant' sense. Despite being a pilot study, researchers did conduct what is considered a gold-standard study insofar as it being a "double-blind, crossover, randomized clinical trial (RCT)." The study protocol was also research registered (see here), so quite a few methodological boxes were ticked.

Given that this study was carried out at the MIND Institute, an institution that has quite a lot of experience in all-manner of different autism research areas (see here and see here), researchers were pretty precise when it came to diagnosing autism/ASD and ascertaining the presence or not of GI symptoms in their small cohort (N=11). The authors also provide quite a bit of information about the supplements used including "the bovine colostrum product (Imucon)" and details of its safety: "The product was tested and found to be negative for Escherichia coli, Salmonella, Listeria, coagulase positive Staphylococcus and antibiotic residue." Insofar as dosages, we are told that: "The colostrum powder dose administered in this study was 0.15 g/lb body weight per day" and "The probiotic dose administered in this study was 20 billion CFU [colony forming units] per day." A couple of supplemental combinations were examined during the study including BCP on its own and BCP+probiotic.

Results: there were quite a few different types of results reported on for 8 of the original 11 participants. Importantly: "Bovine colostrum product appears to be well-tolerated in these children [diagnosed with autism] as its own treatment as well as when combined with the probiotic B. infantis." 'Well-tolerated' means that there were "no participants needing to withdraw due to adverse events" despite a small number of reports of things like gassiness. A couple of kids were also reported to find the taste of the products not too great.

Also: "Some participants on both treatments saw a reduction in the frequency of certain GI symptoms, as well as reduced occurrence of particular aberrant behaviors." Being really careful here because of the small participant number included for study for example, researchers reported that "87.5% (7/8) of participants exhibited some improvement in GI symptoms while on the BCP only arm and 100% (8/8) of participants exhibited some improvement in GI symptoms while on the combination treatment arm." The sorts of GI effects mentioned included reductions in "pain with stooling, frequency of diarrhea, and consistency." Researchers also reported that appetite seemed to be improved for some kids too, particularly the consumption of fruit and meat.

A few other changes were noted in the study, but on the basis of the small participant size and the aims of the study I'm gonna leave them for now. As the authors mention: "the lack of a clear control group receiving a placebo" means that this was a "cross-over study where each participant was his own control" and therefore one needs to be cautious for now. What is needed next is a larger trial and more focus on the behavioural presentation side of autism...

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[1] Sanctuary MR. et al. (2019) Pilot study of probiotic/colostrum supplementation on gut function in children with autism and gastrointestinal symptoms. PLoS ONE 14(1): e0210064.

[2] Fudenberg HH. Dialysable lymphocyte extract (DLyE) in infantile onset autism: a pilot study. Biotherapy. 1996;9(1-3):143-7.

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Gut symptoms are important for 'psychiatric outcomes' in autism

"Individuals with autism spectrum disorder (ASD) are at heightened risk of psychiatric comorbidities across the lifespan, including elevated rates of internalizing, externalizing, and self-injurious behaviors." And: "Gastrointestinal (GI) conditions are of particular interest, as they are prevalent among those with ASD, may share genetic or neurobiological etiologies with the core features of ASD, and are linked with psychiatric difficulties in the general population."

Putting the issue of 'psychiatric comorbidities' and 'gastrointestinal (GI) conditions' together are the results of the findings reported by Emily Neuhaus and colleagues [1] who concluded that: "the presence and quantity of GI symptoms should be considered when evaluating psychiatric and behavioral concerns among children with ASD." Importantly too, they talk about how 'alleviating' accompanying bowel issues in the context of autism *might* also have some important influences on some of those psychiatric issues.

The starting point for Neuhaus and colleagues was a recognition that autism does not exist in some sort of diagnostic vacuum. This means that various 'comorbid' conditions/labels seem to be over-represented when it comes to autism, covering the behavioural/psychiatric (see here) and also the somatic (see here). The authors specifically zoomed in on GI symptoms because they've mentioned over and over and over again as being part-and-parcel of quite a few instances of autism (see here). Marrying the psychiatric and gastrointestinal together, they had two aims: "First, we sought to document the prevalence and variety of GI concerns within a large, well-characterized sample of children and adolescents with ASD. Second, we sought to understand relationships between ASD symptoms and GI concerns over and above the effects of psychosocial factors."

So, authors "draw on data from nearly 2,800 children and adolescents with ASD within the Simons Simplex Collection" pertinent to their aims and objectives. The Simons Simplex Collection (SSC) is no stranger to autism research for various reasons (see here and see here). Importantly too, the SSC is not stranger to specifically looking at GI issues in relation to autism (see here). They reported that: "Consistent with previous literature, families in the SSC frequently reported that their child with ASD had significant GI symptoms" to the tune of over one third of their sample experiencing at least one GI symptom.

Looking at their types of psychiatric symptoms - "internalizing, externalizing, and self-injurious behaviors" - they observed "evidence of unique variance associated with GI symptoms across all three measures of psychiatric symptoms we examined." This didn't mean that GI symptoms were 'the' [singular] cause of those psychiatric/behavioural issues; merely that the presence of such physical symptoms should be considered as one possible factor alongside things like "ASD symptoms, verbal IQ, adaptive behavior, family income." Given that something like self-injurious behaviour (SIB) can be pretty hard-hitting in terms of effects on the person and the people around them (see here), the idea that GI issues might be 'in the mix' alongside "more ASD symptoms, lower adaptive behavior, lower income" should not be ignored. To quote again: "levels of GI symptoms accounted for unique variance in psychiatric outcomes over and above these other factors, linking increased GI problems with increased psychiatric symptoms in children with ASD."

There is a further scheme of work to be followed in this important area.

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[1] Neuhaus E. et al. Gastrointestinal and Psychiatric Symptoms Among Children and Adolescents With Autism Spectrum Disorder. Front. Psychiatry. 2018. Oct 22.

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"a Brief Parent-Report Screen for Common Gastrointestinal Disorders in Autism"

I wanted to bring the findings reported by Kara Margolis and colleagues [1] to your attention today. Their observations pertinent to the "development of a brief, parent-report screen that relies minimally upon the child’s ability to report or localize pain for identifying children with ASD [autism spectrum disorder] at risk for one of three common gastrointestinal disorders (functional constipation, functional diarrhea, and gastroesophageal reflux disease)" represent something that 'fills a gap' in autism research and practice. Their authorship group including some of the great and the good looking gastrointestinal (GI) issues being over-represented in autism (see here and see here) was also an attraction to blogging about these results.

So, GI or gut problems are no stranger to autism. I don't think anyone (anymore) would seriously question such a finding given the multitude of times it has been recorded in the peer-reviewed science domain and beyond. Indeed, it's now even becoming more readily accepted that outside of functional bowel issues such as constipation and diarrhoea being over-represented in autism (see here), so other more pathological bowel states are also present for some too (see here and see here). And be in no doubt that such issues can be truly life-altering in their effects (see here and see here)...

It should also be acknowledged that when it came to starting the conversation about bowel issues and autism, it was parents and caregivers that led the way with their very astute observations of their nearest and dearest. Yes, there have always been 'professionals' who've shown an interest (and concern) in such observations, but parents and caregivers were there first. And despite many parents not (initially) being 'gastrointestinal experts', their observations, in the most part, were/are typically considered pretty accurate ones (see here).

So, Margolis et al talk about how the development of a screening instrument is the next logical step to ensure that parent reports of their children with autism potentially presenting with bowel issues are accurately recorded, onward to eventually leading to more specialised screening, evaluation and hopefully, appropriate intervention. Over 130 parents of children diagnosed with autism registered with the Autism Treatment Network (ATN) initiative agreed to take part in the study. Initially, parents were given a 35-item questionnaire looking at 3 particular functional bowel issues: "functional constipation, functional diarrhea, and gastroesophageal reflux disease" and asked to respond on behalf of their children. Gastroenterologists were also asked to evaluate the children; said professional were blinded to the parental responses to the questionnaire. When looking at these combined data sources, researchers were able to whittle down the 35-item questionnaire to 17 questions that seemed most important to the lay identification of potential bowel issues. Some further nifty statistics led authors to conclude that: "this 17-item screen identified children having one or more of these disorders with a sensitivity of 84%, specificity of 43%, and a positive predictive value of 67%." Ergo, the authors have 'the makings of' a potentially important parent/caregiver-based questionnaire to assess for the possible presence of bowel issues in autism. The makings of...

Obviously more work is required in this area. This instrument is labelled a 'screen' for such bowel issues so there is still the requirement for professional involvement when it comes to diagnosis and intervention. But one should never forget the very important perspective that parents/caregivers can have with regards to the presence of bowel issues in their children...

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[1] Margolis KG. et al. Development of a Brief Parent-Report Screen for Common Gastrointestinal Disorders in Autism Spectrum Disorder. J Autism Dev Disord. 2018. Oct 22.

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"Bowel perforation in chronic idiopathic megarectum and megacolon" and autism: 15 years on...

There was something all-too familiar about the case report detailed by Chukwuebuka Anyaegbuna and colleagues [1]. The description of a young man in his mid-twenties "with autism spectrum disorder" and a "history of chronic constipation" (going back years with "multiple previous admissions") eventually being admitted to intensive care on the basis of a potentially life-threatening bowel state is, unfortunately, nothing new to science and clinical practice (see here).

Bowel issues - both functional and more pathological - are over-represented when it comes to a diagnosis of autism (see here and see here for examples). The specific diagnosis of 'megarectum' detailed in the Anyaegbuna paper in relation to autism had also been noted some 15 years previously [2] in the peer-reviewed science literature. Indeed, the paper by Nadeem Afazal and colleagues [2] looking at over 100 children with autism "who were referred for gastroenterological assessment" showed that constipation was not an infrequent finding for this group. They also reported that many autistic children in their cohort "had moderate/severe loading or acquired megarectum." Their observation that "consumption of milk [was found] to be the strongest predictor of constipation in the autistic group" also chimed with me, as an interested researcher of diet as being a potentially important variable for 'some autism' [3]. And indeed, such an observation also seemingly intersects with other more recent dietary-bowel findings too (see here)...

The Anyaegbuna findings represent the continued failure of autism research and practice to take seriously the issue of bowel problems associated with autism. Stretching back over a period of about twenty years or so, I've noted the various comments from various (typically ill-informed) people protesting that various gastrointestinal (GI) investigations are 'not medically indicated' when it comes to some cases of autism. Some even made jokes about it. It's probably not unreasonable for me to say that set within this atmosphere, there has been a general reluctance to look at such issues for fear of castigation or shaming. There have been some brave research souls (see here and see here) who've kept on looking at bowel issues and autism, but not half as many as there should be. And it is those suffering with such bowel problems who have been let down: please do make sure that you take a good look at the X-rays accompanying the Anyaegbuna report to see what I mean.

Having said all that, I would like to think that things are slowly changing. It's no longer taboo to talk about bowel issues being over-represented in relation to autism. Indeed, we've had study after study all pointing in the same direction: bowel issues are seemingly related to autism, covering both childhood and adulthood. And such bowel issues might have some important effects on behaviour (see here). What we are sadly lacking at the current time however, is a concerted research effort asking 'why'? and 'what can we do to prevent (yes, prevent) such bowel issues occurring rather than just treating them when they occur?'

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[1] Anyaegbuna C. et al. Bowel perforation in chronic idiopathic megarectum and megacolon. BMJ Case Rep. 2018 Aug 20;2018. pii: bcr-2018-225406.

[2] Afzal N. et al. Constipation with acquired megarectum in children with autism. Pediatrics. 2003 Oct;112(4):939-42.

[3] Whiteley P. et al. 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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Shocker alert: gut problems in autism impact on sleep (again)

"Increased odds of sleep problems were most frequently associated with gastrointestinal distress (GID) and non-verbal IQ (NVIQ), followed by male sex and age."

That was one of the findings reported by Ann Johansson and colleagues [1] who set out to examine "the relationship between sleep problems and characteristics of children with ASD [autism spectrum disorder] in a large, nationwide sample." Mention of the words 'Simons Simplex Collection' in the Johansson article provides a clue as to the source population examined in this study and some of the hows-and-whys of the research. From what I also understand, this paper is part of a doctoral thesis by Johansson looking at some of the possible genetics of sleep with autism in mind (see here). Indeed, if one scrolls to page 70 of the thesis, one finds the study in question...

The Simons Simplex Collection Sleep Interview (SSCSI) was the instrument of choice for assessing sleep issues. This is a short parent-report questionnaire that includes both a composite score for total sleep issues and subscale scores for things like 'sleep duration issues'. Alongside, GID was classified "if they were reported (yes/no) to have bloating/excess gas, celiac disease, constipation, diarrhea, ulcers, gastroesophageal reflux disease, inflammatory bowel disease (Crohn’s disease, ulcerative colitis), irritable bowel syndrome, abdominal pain, unusual stools, vomiting, and/or other GID." Throw in scores on the ADOS "used to measure ASD severity" and crunch the data...

I've inserted the word 'again' into the title of this post because this is not the first time that functional gastrointestinal issues 'over-represented' in autism have been connected to sleep issues (see here). This time around, researchers mention that over 40% of their cohort (2000+ children) "were categorized as having mild or moderate/severe sleep problems" according to their SSCSI composite score. 'Difficulty falling asleep' seemed to be one of the more frequently reported issues. GID - gastrointestinal distress - was the strongest factor linked to sleep issues (odds ratio = 2.79), again based on the SSCSI composite score for sleep issues. There were other combinations of symptoms potentially linking to sleep noted by the authors but I'm minded to put them to one side for now.

Caveats? Well, one big caveat sticks out: the reliance on parent-reported responses to a questionnaire about sleep without any reference to objective measures of sleep. I've gone on and on (and on) about the use of actigraphy when it comes to sleep research relating to various diagnostic labels (see here and see here for examples) and well, keep coming to the same conclusion about a strong requirement for such objective measures on sleep-wake cycles. I appreciate that there may be some 'consumer resistance' to wearing a wristband for example, to measure activity and rest cycles (see here), but surely someone, somewhere can engineer something when kids don't want to wear such gadgets? Insofar as the classification of GID also relying on parental report, I'm a little kinder to this because the evidence is pretty good for suggesting that parents might be tuned into what is typical and what is not typical from a functional bowel habits perspective in their offspring (see here)...

No mind, the results do accord with other independent data on how gut issues present in autism can seemingly have some far-reaching effects. As to 'how', well, I would always start with the obvious explanation: pain and discomfort caused by bowel issues affecting sleep, and then work back from there. Indeed, as if I need to say it again, bowel issues (both functional and more pathological) are truly 'over-represented' when it comes to a diagnosis of autism (see here) and science and clinical practice really need to do a lot more to tackle such issues as and when they are reported/detected...

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[1] Johansson AEE. et al. Characteristics of sleep in children with autism spectrum disorders from the Simons Simplex Collection. Research in Autism Spectrum Disorders. 2018; 53: 18-30.

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Constipation in kids with autism: financial as well as health implications

I've always be a little perplexed about the response to gastrointestinal (GI) issues appearing alongside autism. Time after time after time, the peer-reviewed science domain serves up evidence that both functional and more pathological bowel issues are over-represented in autism (see here and see here for examples) and cause considerable suffering. Yet some parts of the lay and research community seemingly 'gloss over' such findings. It's almost as if the acceptance that 'some' autism seems to be 'bowel-related' would shatter some people's view of autism. Perhaps it's also because there would have to be some [partial] acceptance of other related uncomfortable findings too (see here)...

The findings reported by Brandon Sparks and colleagues [1] continue the theme that functional bowel issues such as constipation are part and parcel of some autism. And not only do they have often severe health implications for the person concerned, but there may also be wider economic implications too. So, researchers concluded that: "ED [emergency department] visits by children with ASD [autism spectrum disorder] were more likely to be constipation-related compared with visits by children with other chronic conditions or children with no chronic conditions." Further: "Hospital charges were higher in children with ASD than in those without chronic conditions."

Based on data derived from the Nationwide Emergency Department Sample (NEDS), a US initiative that records diagnostic trends in ER (also known as Accident & Emergency here in Blighty) visits, authors looked for those with and without a diagnosis of autism (ASD). They observed that constipation was an important variable in those ER visits when it came to autism and continued to be important when ER visits turned into hospital admissions. They conclude by saying that there may be a need for "developing more effective outpatient therapies for constipation in children with ASD."

Constipation might not sound like a condition that requires an ER visit. But if and when it does, I guess you could probably say that it's something quite serious. Just as reports in relation to those with a learning disability have highlighted how constipation is (a) over-represented, and (b) has actually been cited as a cause of death (see here), so perhaps you can see why there should be a lot more urgency in this area of the autism research and practice landscape.

I added in the 'financial as well as health implications' bit to the title of this post to stress how, even if someone chooses to ignore the pain and physiological effects that constipation can cause, such symptoms are also placing quite a burden on resources and finances. I personally don't much like the idea of talking too much about 'how much autism costs' but if that's the only way to make people listen and actually do something about bowel issues in relation to autism, then I'm quite willing to continue to talk money and strains (no pun intended) on resources...

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[1] Sparks B. et al. Constipation in Children with Autism Spectrum Disorder Associated with Increased Emergency Department Visits and Inpatient Admissions. The Journal of Pediatrics. 2018. June 1.

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"children with ASD who experience GI symptoms have an imbalance in their immune response"

The findings reported by Destanie Rose and colleagues [1] piqued my interest recently for a variety of reasons. Not only was there an emphasis on gastrointestinal (GI) issues in relation to autism (see here) but mention of the words 'microbiota composition' and 'impaired gut barrier function' make an important reference to something of a new triad in relation to [some] autism (see here).

First things first, as well as being another welcome research publication from the MIND Institute, the name Destanie Rose has appeared before on this blog with reference to maternal immune activation (MIA) and 'Old World monkeys' (see here). This work illustrated how infection during pregnancy can, under certain circumstances and at critical times, have a bearing on offspring development and behaviour; keeping in mind, that is, the possibility of logical fallacies (see here) when it comes to extrapolating from animal studies.

This latest time around, and including other notable names on the authorship list including Alessio Fasano (zonulin man) and Paul Ashwood (gut and immune system man), the focus shifted to immune function in the context of real life autism with the aim to "determine whether there are biological signatures in terms of immune dysfunction and microbiota composition in children with ASD with GI symptoms."

Four groups of children diagnosed with an autism spectrum disorder (ASD) participated in the study, including those with and without a diagnosis of ASD and with and without "current or previous GI symptoms." Both blood and stool samples were donated by study participants and subject to various analyses pertinent to assessing 'cytokine production' (cytokines are chemical signallers of the immune system) and ahem, the 'microbial composition' of poo(p) samples.

Results: those in the ASD + GI symptoms group showed "increased levels of mucosa-relevant cytokines including IL-5, IL-15 and IL-17" under "Toll-Like receptor (TLR)-4 stimulation" compared with those diagnosed with autism but with no bowel symptoms. TLR-4 is a protein that, as one of its duties, "plays a fundamental role in pathogen recognition and activation of innate immunity." Artificial stimulation of TLR-4 kinda mimics what would happen in real life as and when the body comes across a pathogen such as bacteria and needs to activate those immune defences.

Alongside other findings suggestive of "differences in microbiome composition between ASD and TD [typically developing] children with GI symptoms", authors also observed some interesting findings pertinent to impaired gut barrier function too. So: "The ASDGI also showed an over-representation of the gene encoding zonulin, a molecule regulating gut permeability, compared to the other groups." The gene in question is something called HP or Haptoglobin, and specifically HP2 which refers to a "common polymorphism consisting of two structural alleles: HP1 and HP2" [2]. As per the Vanuytsel paper [2], the HP2 allele is described as a risk allele for things like inflammatory bowel disease (IBD).

Bearing in mind that symptoms such as functional bowel issues (such as constipation and diarrhoea) are not necessarily the same as pathological bowel conditions such as the IBDs, I was interested in one of the figures included in the Vanuytsel paper on how HP2 links into gut permeability issues. In particular how "it is not unlikely that carriers of the zonulin gene (i.e., individuals with genotype HP21 or HP22) could possibly have an increased risk to develop IBD, because of the permeating effect of zonulin on the intestinal barrier." Zonulin has been something else of interest to this blog in the context of autism and so-called 'leaky gut' (see here) hence the interest in "a propensity to impaired gut barrier function which may contribute to their [gastrointestinal] symptoms and clinical outcome."

From what I gather, there was an over-representation of the HP2 allele (HP22 genotype) and under-representation of the HP1 allele in the ASDGI group examined in the Rose study, but things were not [statistically] completely cut-and-dried. This however, has to be set in the context of a seemingly increased risk of IBD as and when autism is diagnosed (see here).

What are the take-away messages from the Rose findings? Well bowel symptoms - functional bowel symptoms - occurring alongside autism probably have quite a complicated series of genetic and biological processes going on behind them. Both the mucosal immune system and the wider immune system are probably going to show 'some kind of relationship' to such chronic symptoms and, unsurprisingly, those trillions of wee beasties known as the gut microbiota are also probably involved/affected. The "propensity to impaired gut barrier function" associated with autism + bowel issues is also mentioned by Rose, and offers further testable hypotheses regarding the possibility of a gut-brain axis in relation to [some] autism (see here) and indeed, what measures might ease the pressures of such bowel issues. Also, whether bowel symptoms *might* show a connection to certain presented behaviour (see here) is another important area of further investigation...

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[1] Rose DR. et al. Differential immune responses and microbiota profiles in children with autism spectrum disorders and co-morbid gastrointestinal symptoms. Brain, Behavior, and Immunity. 2018. March 20.

[2] Vanuytsel T. et al. The role of Haptoglobin and its related protein, Zonulin, in inflammatory bowel disease. Tissue Barriers. 2013;1(5):e27321.

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Physical conditions accompanying intellectual disabilities

By linking to some media discussing the inquest findings for Richard Handley (see here) I don't want to trivialise his death or use it as some kind of 'I told you so' example. Here was a man who died as a result of "gross failures" in his care as someone with Down's syndrome who also had a history of bowel issues. His death, linked to chronic constipation and "as a result of choking on his own vomit having inhaled gastric contents following complications with surgery", represents failures on many different levels. Not least is a seeming lack of appreciation of how bowel issues can very much be part of the clinical profile of many conditions / labels / diagnoses considered within the spectrum of intellectual or learning disabilities. Said issues require both regular monitoring and appropriate and timely intervention.

It is perhaps notable then that the paper by Deborah Kinnear and colleagues [1] is published these days, highlighting how various physical conditions are over-represented alongside diagnoses characterised by intellectual (learning) disability. The authors reported that: "The five most prevalent were visual impairment, obesity, epilepsy, constipation and ataxic/gait disorders."

Based on the examination of data for "people with intellectual disabilities living within the geographical area of Greater Glasgow Health Board, Scotland" between 2002 and 2004, researchers reviewed case records and "completed a comprehensive semi-structured health interview and targeted physical examination and followed a phlebotomy protocol, with the person with intellectual disabilities and their carer." This was time consuming affair - the "complete assessment process took about 4 hours per participant" - covering over 1000 people.

Alongside the reporting of those 'top five most prevalent conditions', researchers also observed several other important details. Namely that nearly all of their cohort had a least one co-existing health condition. The average number of comorbid conditions was 11. Yes, that's 11. And some people had over 25 comorbid physical conditions. When also taking into account the presence or not of Down's syndrome, not much changed in relation to the detected physical comorbidity. Similarly, when age and sex/gender were examined, the authors concluded that there only minor differences noted in terms of comorbidity profiles for example.

Relevant to the case of Richard Handley are some discussions in the Kinnear paper about constipation and learning disability. So: "Constipation was the fourth most prevalent physical health condition." Further, they note in another study [2]: "Eight people with chronic constipation had serious side effects (rectal prolapse, diverticula of colon, intestinal obstruction, megacolon and haemorrhoids) and four eventually died of intestinal obstruction... Thus, as well as being painful, constipation may remain undetected for a long time and can cause death due to missed clinical symptoms." Constipation can cause death. It shouldn't in this day and age, but it still does...

In relation to the implications of their findings, the authors make some additional comments. So: "Medical education is also focused on assessment and management of single conditions, yet management of multimorbidity is far more complex." This is important. It implies that outside of the view of one [primary] diagnosis being present per patient, clinicians and others need to have a more plural view, particularly when it comes to something like learning disability. The focus also on 'physical' comorbidities is also important insofar as how various developmental / behavioural / psychiatric conditions can very much manifest other non-developmental / behavioural / psychiatric conditions. This kinda mirrors what has been discussed with autism in mind (see here and see here for examples) and, alongside, the barriers that need to be overcome when it comes to appropriate diagnoses being made in such contexts (see here).

Set within other data indicating that premature mortality is very much over-represented when it comes to learning disability (see here), and that much of that early mortality is due to the presence of physical health conditions, the Kinnear findings should serve as a wake-up call to many sectors of the professional and other communities. Screening, diagnosing and implementing timely and appropriate intervention(s) are key recommendations; with a specific focus on the person as a whole rather than just being the sum of individual somethings like the diagnosis of learning disability. Bear in mind also that guidance on the management of something like constipation in the context of learning disability does exist in the peer-reviewed domain [3].

And finally, just in case you think that today's discussions aren't directly relevant to autism, constipation has also been mentioned in the death of another young person (see here)...

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[1] Kinnear D. et al. Prevalence of physical conditions and multimorbidity in a cohort of adults with intellectual disabilities with and without Down syndrome: cross-sectional study. BMJ Open. 2018; 8: e018292.

[2] Evenhuis HM. Medical aspects of ageing in a population with intellectual disability: III. Mobility, internal conditions and cancer. J Intellect Disabil Res. 1997 Feb;41 ( Pt 1):8-18.

[3] Robertson J. et al. Constipation management in people with intellectual disability: A systematic review. J Appl Res Intellect Disabil. 2017 Nov 23.

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Bowel issues over-represented in autism (and perhaps linked to some behaviours)

"Make it so Mr WORF"

Once again(!) more evidence emerges from the peer-reviewed science domain highlighting how functional gastrointestinal (GI) issues such as constipation and diarrhoea are very much over-represented when it comes to a diagnosis of autism (see here). The study providing the data this time was by Zhu and colleagues [1] and was carried out in China; thus illustrating how such bowel issues cross countries and ethnicity when it comes to autism.

There's little novelty in their findings that all-manner of functional bowel condition were more frequently present in their cohort of over 320 children diagnosed with an autism spectrum disorder (ASD) compared with some 200 not-autism controls. The authors' observation that almost 50% of their sample of children diagnosed with autism presented with at least one bowel issue is not as surprising in research-terms as it perhaps once might have been.

What is perhaps interesting is the growing focus on how such bowel issues may *correlate* with behaviour noted in children with autism, as per the results of other independent findings (see here). To quote from Zhu et al: "Compared with ASD children without GID [gastrointestinal disorders] (n=166), the ASD children with GID (n=162) got higher scores in the "Body and Object Use" of ABC [Autism Behavior Checklist] scale... and had more emotional problems. Moreover, the score of behavior problems questionnaire was higher in the ASD children with GID." This is not necessarily new news to many people (particularly to parents and caregivers) but should be a topic that is given more research and clinical consideration among professionals.

More needs to be done in this area, not least on:

• improving the ways of detecting and reporting on functional bowel issues in the context of autism (see here),
• ensuring that questions about bowel function are asked during autism assessments and exams,
• moving away from over-simple 'psychological' assumptions/explanations to potentially account for bowel issues in relation to autism (see here) without appropriate gastroenterological referral (also including ridding ourselves of the old-saying 'it's part of their autism'),
• ensuring that appropriate gastroenterological resources are available and timely referral is present (particularly for paediatric resources),
• following guidance that is out there in the peer-reviewed domain on screening and treating bowel issues in the context of autism (see here),
• not being afraid to look for signs of more serious bowel pathology as and when functional bowel symptoms are present (see here) and,
• embracing the idea that gut and brain might not be completely separate and independent in the context of autism and beyond (see here). 

'Nuff said I think.

But just before you go, some other study results [2] for you to mull over with regards to the question: what is the 'normal range' of bowel movements? Answer: anything from 3 a day to 3 a week apparently.

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[1] Zhu J. et al. Association between behavioral problems and gastrointestinal disorders among children with autism spectrum disorder. Zhonghua Er Ke Za Zhi. 2017 Dec 2;55(12):905-910.

[2] Mitsuhashi S. et al. Characterizing Normal Bowel Frequency and Consistency in a Representative Sample of Adults in the United States (NHANES). Am J Gastroenterol. 2018 Jan;113(1):115-123.

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"Minor physical anomalies" and autism: hypermobility very much included

'Minor physical anomalies' (MPAs) are defined as "subtle, abnormal morphological features, such as deviations in morphology of the head, eyes, ears, mouth, hands, and feet." I appreciate that such a term is probably not going to everyone's cup of tea, but given the embryological links between organs such as the brain and skin, it's assumed that "MPAs may mirror altered brain development."

That was the starting point for the study results published by Lynnea Myers and colleagues [1] looking for the presence of MPAs in a cohort of over 110 twins, around half of whom had received a concordant or discordant neurodevelopmental disorder diagnosis such as "intellectual disability (ID), communication disorders, autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), specific learning disorders, and motor disorders." Alongside various behavioural and diagnostic assessments, researchers also used a special MPA checklist "containing a total of 179 anomalies for males (24 body regions) and 171 for females (23 body regions)" with their cohort. This checklist also included various other 'issues' that are "commonly assessed for in physical exams."

Various results were produced bearing in mind the quite complicated participant mix included for study (i.e. presence or not of a neurodevelopmental disorder, concordance among twins, zygosity, specific neurodevelopmental diagnosis, etc). Autism was the only neurodevelopmental diagnosis that was "significantly associated with the extent of MPAs." If twins were concordant for autism or autism spectrum disorder (ASD), researchers observed that they "had descriptively the highest median (Md) number of MPAs." Where twins were discordant - one had autism, the other not - researchers still observed MPAs, albeit to a slightly lesser degree (number). Further: "The most common MPAs in participants with ASD included overweight (39%), hypermobility (36%), pes planus (29%), straight eyebrows (29%), vision impairment (25%; 29% of these with corrective lenses), arachnodactyly/long toes (25%), long eyelashes (21%), and microtia (21%)."

Putting to one side the important findings that almost 40% of those with ASD were described as overweight (see here) or that vision issues were present in a quarter (see here), I was drawn to the suggestion that quite a percentage of those with autism (36%) were described as having hypermobility. Hypermobility, where joints are more flexible than usual, in the context of autism is something of an interest of mine (see here and see here). Not least because it is an area of the autism research landscape crying out for a lot more investigation, both as part of a wider 'psychiatric picture' (see here) and also in the 'ESSENCE' context that autism rarely exists in some sort of diagnostic vacuum (see here).

Minus any sweeping generalisations, there are a few potentially important implications either linked to or arising from hypermobility in the context of autism. Poor balance and/or coordination is one possible outcome from hypermobility that would perhaps tie into what has been discussed in the autism research literature for years and years now [2] (even Kanner mentioned it). The observation that functional gastrointestinal (GI) issues such as constipation and diarrhoea also seem to be over-represented in relation to hypermobility [3] also potentially accords with findings pertinent to quite a lot of autism (see here) (bearing in mind that I'm not saying that all bowel issues noted in autism are necessarily hypermobility-connected). If however one was to stretch things further, one might be looking at something like joint hypermobility in the context of connective tissue disorder and what that could mean for something like intestinal permeability issues associated with 'some' autism (see here). I know this is speculative, but at least it provides a research plan of action to include in future investigations in this area.

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[1] Myers L. et al. Minor physical anomalies in neurodevelopmental disorders: a twin study. Child and Adolescent Psychiatry and Mental Health. 2017; 11: 57.

[2] Cassidy S. et al. Dyspraxia and autistic traits in adults with and without autism spectrum conditions. Mol Autism. 2016 Nov 25;7:48.

[3] Fikree A. et al. Functional gastrointestinal disorders are associated with the joint hypermobility syndrome in secondary care: a case-control study. Neurogastroenterol Motil. 2015 Apr;27(4):569-79.

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The art of the gut microbiome: 'Excretory Wipings' across 45+ years

Excretory Wipings May 18-October 21, 1970 is a piece of art composed by the artist Billy Apple (more accurately known as Billy Apple®). Due to possible copyright issues et al I don't want to show the actual piece on this blog but will describe to you what it comprises: a conceptual art work including toilet paper with erm, traces of a bowel movement provided during that particular period of 1970.

It's probably not everyone's cup of tea when it comes to art, but believe it or not, it might potentially be a rather important research starting point if say you wanted to characterise the gut microbiome past and present. Indeed, that is exactly what the paper by Thilini Jayasinghe and colleagues [1] describes, as they compared the bacterial colonies present in the 1970 sample(s) with a more up-to-date set of samples provided by the same artist in 2016.

Some media interest in the Jayasinghe results can be seen here. In short, three archived samples sourced from the 1970 art piece were compared with three more recent samples sourced exactly 46 years later (2016). Researchers performed 16SrRNA sequencing to "study bacterial phylogeny and taxonomy" [2] and try and find out whether there were similarities/differences in the types of bacteria present and indeed, whether overall bacterial diversity had reduced/stayed the same/increased between the testing periods.

Following this N=1 study, a few details emerged. So: "We observed that 45% of the microbial species were retained over the 45 year interval." Such a finding has to bear in mind that the artist "was suffering from diverticular disease in 2016" and that such a condition may well impact on the type of gut bacteria that is present and/or predominating. Indeed, the authors talk quite a bit about how "the 2016 microbiomes contained significantly higher level of genus Prevotella... which may be related to the observed diverticular disease by having a negative impact on gut immune system." Interestingly too, the word 'butyrate' appears in the Jayasinghe text, as in lower levels of butyrate-producing bacteria being present in the more recent sample. Butyrate is currently going through a period of bacterial 'sainthood' [3] at the moment...

Next: "The diversity of the microbial species from samples taken when Apple was 80 years of age was lower than that from samples when he was 35." Bacterial diversity is something of real interest these days, as more and more people start talking about gut bacterial diversity (and the loss of it) as potentially being related to all-manner of life-enhancing and life-not-so-enhancing correlations. The recent results are framed by the authors in the context of being "consistent with the idea of a drift towards a core microbiome" where ageing seems to play a role in diversity.

Of course, one shouldn't forget that this was a N=1 study and that gut bacterial populations are subject to all-manner of influences pushing and pulling on what bacteria may or may not be present in a longitudinal sense. These latest results say very little outside of what happened to the bacterial profile of Billy Apple® between the testing occasions.

But I'm still intrigued by such findings and the idea that there may be other resources to 'tap into' when it comes to looking either long-term at gut bacterial profiles or indeed, comparing gut bacterial patterns as a function of time and various ages. Y'know, comparing bacterial profiles of various ages in years gone by with similarly aged participants in more modern times, and trying to determine what various factors linked to modern life might have done (or not) to gut bacterial profiles. I don't doubt that some results might be rather interesting and discussion-provoking...

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[1] Jayasinghe TN. et al. Long-term stability in the gut microbiome over 46 years in the life of Billy Apple®. Human Microbiome Journal. 2017; 5-6: 7-10.

[2] Janda JM. & Abbott SL. 16S rRNA Gene Sequencing for Bacterial Identification in the Diagnostic Laboratory: Pluses, Perils, and Pitfalls . Journal of Clinical Microbiology. 2007;45(9):2761-2764.

[3] Canani RB. et al. Potential beneficial effects of butyrate in intestinal and extraintestinal diseases. World Journal of Gastroenterology : WJG. 2011;17(12):1519-1528.

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