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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"the first nationwide population-based study to investigate the risk of CFS in patients with IBD"

The quote titling this post - "the first nationwide population-based study to investigate the risk of CFS [chronic fatigue syndrome] in patients with IBD [inflammatory bowel disease]" - comes from the research published by Shin-Yi Tsai and colleagues [1].

Inflammatory bowel disease (IBD) covers quite a bit of diagnostic ground, but typically refers to ulcerative colitis (UC) or Crohn's disease (CD). There are many similarities between the conditions, but also some important differences too (see here). Both conditions manifest in the bowel (inflammation) and have pathological effects; both also typically show functional bowel symptoms too.

Utilising that fabulous (but sadly now defunct) research resource that was the National Health Insurance Research Database (NHIRD) in Taiwan, researchers set out to "evaluate the subsequent risk of CFS in patients with IBD" on the basis of "possible common pathophysiology between IBD and CFS" among other things. One of those 'pathophysiological' mechanisms quite prominently featuring in the Tsai article is "a similarity to the impaired intestinal mucosa of IBD." Interesting (see here).

So, from a starting population of a million people (or medical insurance records of a million people), authors whittled the figures down to the thousands in two groups: an IBD group (n=2163) and a non-IBD group (n=8652). All were "newly diagnosed" with IBD apparently; and none had a previous diagnosis of CFS "before the index date." Then: "Both groups were followed from the index date until the diagnosis of CFS, withdrawal from the NHI program, or December 31, 2011" with said CFS diagnosis following the Fukuda/CDC criteria.

Results: before heading into the CFS frequency figures according to group, there was another important observation made, potentially pertinent to a gut-brain connection: "The prevalence of depression, anxiety, [and] sleep disorder... was higher in the IBD group than in the non-IBD group." Indeed, the increased frequency of sleep disorder in the IBD group *might* have some important 'connection' with another diagnosis where sleep and 'gut issues' has been mentioned (see here and see here). And I might as well also mention depression and anxiety in that context too (see here).

Continuing: "After adjustment for age, and comorbidities, the risk of CFS was higher in the IBD group than in the non-IBD group (adjusted HR, 2.25; confidence interval [CI], 1.70–2.99)." There was also a possible sex-linked relationship too: "we identified male sex, advanced age, absence of comorbidities, and CD as the predictors of increased CFS risk." There's a pretty little diagram to accompany the Tsai findings (see here) outlining what *could* be going on with regards to IBD and CFS. Terms like 'bacterial translocation' and 'immunoinflammatory pathways' are used, in line with some other research in this area [2]. There's no mention of any psychobabble 'biopsychosocial' or the like in the Tsai paper which is always a good thing.

What else is there to say? Well authors go on to mention about the possibility of "intrinsic defects in IBD patients that precipitates CFS" which could have some quite profound implications for at least some cases of CFS. They added that future work might want to have a look at what certain immunotherapies indicated for some IBDs * might* mean for CFS and it's potential *treatment* too. We'll have to wait and see.

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[1] Tsai S-Y. et al. Increased risk of chronic fatigue syndrome in patients with inflammatory bowel disease: a population-based retrospective cohort study. Journal of Translational Medicine. 2019; 17:55.

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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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Vitamin D impacts on intestinal inflammation in 'active' ulcerative colitis: an autism research agenda item?

The results reported by Mayur Garg and colleagues [1] are slightly outside of the typical remit of this blog primarily focused on autism research, but give me a minute or two and I'll hopefully bring them back into the [research] fold.

Garg et al published findings looking at what effect (if any) a quite large dose of vitamin D delivered over 8 weeks might have in relation to a small group of participants "with active UC [ulcerative colitis],... with inactive UC and... non-IBD [inflammatory bowel disease] controls." They concluded that said intervention - "40,000 [international] units cholecalciferol weekly for 8 weeks" - (a) was associated with an increase in functional levels of vitamin D as would be envisaged, (b) *correlated* with a reduction in one measure of inflammation commonly used to grade the activity of UC (faecal calprotectin) and (c) did not seem to significantly impact on various measures examined in inactive and/or non-IBD participants. They concluded that: "Vitamin D supplementation was associated with reduced intestinal inflammation in patients with active UC" with the requirement for much more investigation in this area.

What's the possible autism link? Well, minus too many sweeping generalisations, there may be quite a few. First are the observations that IBDs such as UC may well be 'over-represented' when it comes to the label of autism (see here and see here). I know such findings might have the ability to furrow brows when it comes to autism research history (see here for example) but there is a clinical need for greater screening (and treatment) efforts when it comes to such IBDs in the context of autism. I'd also mention that faecal calprotectin in a 'low-grade intestinal inflammation' sense, has been discussed before on this blog (see here). Second, vitamin D is also a topic of growing interest when it comes to autism (see here and see here for examples). We can um-and-ah about whether such reports of deficiency/insufficiency in the context of autism are 'autism-specific' or just following the trends noted in various other populations (see here and see here). But that does not alter the vitamin D findings observed across various populations and studies with autism in mind. Adding the two observations together in the context that vitamin D deficiency is likely to affect more than just bone metabolism (something else noted in relation to some autism) and one arrives at the possibility that autism + inflammatory bowel disease (specifically UC, and active UC) *might* be something to look at with vitamin D supplementation in mind. Might...

Music, and my brood have finally bumped into the Greatest Showman, and one song seems to be a particular favourite...

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[1] Garg M. et al. The effect of vitamin D on intestinal inflammation and faecal microbiota in patients with ulcerative colitis. J Crohns Colitis. 2018 May 3.

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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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Low grade intestinal inflammation and autism

The suggestion that low grade intestinal inflammation might be related to some autism comes from the findings reported by Katarina Babinská and colleagues [1] (open-access available here).

Researchers set out to "assess the concentrations of fecal calprotectin in a sample of children with ASD [autism spectrum disorder] and to investigate the correlations of this inflammatory marker with the core behavioral symptoms of ASD."

Faecal calprotectin (FC) is a measure of the amount of calprotectin in a stool (poo) sample. It's typically released in response to the presence of inflammation and, here in Blighty at least, is indicated as "an option to support clinicians with the differential diagnosis of inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS) in adults with recent onset lower gastrointestinal symptoms for whom specialist assessment is being considered." 

In terms of research history looking at autism and FC, there is some peer-reviewed science on the topic; also having been included as a parameter in the important paper by Laura de Magistris and colleagues [2] talking about 'leaky gut' in the context of some autism (see here) and how "FC was elevated in 24.4% of patients with autism and in 11.6% of their relatives." Such research is set in the more general context that bowel or gastrointestinal (GI) issues are absolutely no stranger to a diagnosis of autism (see here).

This time around Babinská et al measured FC (via ELISA) in some 87 children diagnosed with an autism spectrum disorder (ASD) aged between 2 and 17 years of age. The authors use the term 'low functioning' to describe this portion of their participant group but I'm rather less enamoured with such labels (see here) despite the well-deserved focus on a group very much under-represented in autism research and other areas. Alongside, over 50 age-matched controls (not-autism) and 29 siblings of children with ASD also provided samples for analysis and comparisons.

Results were not exactly as cut-and-dried as one might have expected. So: "In non-relatives significantly lower values of fecal calprotectin were observed than in both subjects with ASD and their siblings." What this means is that based on group results, those with autism and the siblings of those with autism seemed to manifest higher levels of FC than non-related controls. Based on individual results, where elevated levels of fecal calprotectin was set at 50 µg/g of feces or higher according to test producers guidance as being a level of concern, the frequency of such a finding was greater in those with autism (22%) and their siblings (20%) than in non-related controls (9%) but this difference was reported as 'non-significant'.

Authors also did a little work on another important area in relation to bowel symptoms/pathology and autism: how *might* something like intestinal inflammation 'interact' with the behavioural signs and symptoms of autism? Well, we are told that those diagnosed with autism "had to meet criteria for ASD" on two gold-standard diagnostic tools: the Autism Diagnostic Observation Schedule – second edition and the Autism Diagnostic Interview-Revised (ADI-R). Data from the ADI was examined in the context of the FC findings and lo and behold: "In the group with ASD significant correlations of fecal calprotectin with all domains of the ADI-R diagnostic tool were found: qualitative abnormalities in reciprocal social interaction and communication, restrictive and repetitive patterns of behavior." I say this bearing in mind that similar analyses between FC values and ADOS ratings do not seem to have been either done or reported on for some reason.

When the authors talk about low grade intestinal inflammation as potentially being relevant to some autism, they seem to be accurate insofar as the measured levels of FC in some participants and the *correlation* with autism scores on one of the gold-standard assessment instruments. That being said, there is quite a bit more to do in this area before anyone gets too carried away with the results as they stand. So for example, all that chatter about inflammatory bowel disease (IBD) being related to some autism (see here and see here) did not seem to register in this particular study insofar as the guidance on FC being a marker for possible IBD, albeit based on higher levels of FC being detected: "Active, symptomatic inflammatory bowel disease 200 – 40,000 mg/kg."

I also note that the authors report an important limitation when it came to their research: "Additional factors that might have been a cause of elevated FC levels, such as nutritional or gastrointestinal factors were not analysed." Nutritional factors eh? Y'mean like milk type for example [3] or other dietary and/or environmental factors such as the implementation of a gluten-free diet [4] positively affecting FC levels? Indeed, there are lots of potential factors that could cause a 'false-positive' when it comes to elevated FC such as infections like C. diff or gastrointestinal conditions such as coeliac disease, many of which have shown some important connections to autism (see here for example).

It looks like there is still much more research to do in this area but investigations should definitely continue.

To close, my brood have just discovered the brilliant film 'The Great Escape'. As well as setting up many, many discussions about war, bravery and captivity, they've also commented on the theme tune...

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[1] Babinská K. et al. Fecal calprotectin levels correlate with main domains of the autism diagnostic interview-revised (ADI-R) in a sample of individuals with autism spectrum disorders from Slovakia. Physiol Res. 2017 Dec 30;66(Supplementum 4):S517-S522.

[2] de Magistris L. et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 2010 Oct;51(4):418-24.

[3] Ho S. et al. Comparative effects of A1 versus A2 beta-casein on gastrointestinal measures: a blinded randomised cross-over pilot study. Eur J Clin Nutr. 2014 Sep;68(9):994-1000.

[4] Balamtekın N. et al. Fecal calprotectin concentration is increased in children with celiac disease: relation with histopathological findings. Turk J Gastroenterol. 2012;23(5):503-8.

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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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Probiotics are "a good choice in remission of inflammatory bowel diseases" (says review)

The systematic review and meta-analysis published by Mahboube Ganji-Arjenaki & Mahmoud Rafieian-Kopaei [1] provides the blogging fodder today, on the topic of  "the efficacy of probiotics in attaining clinical response on patients with various types of IBD [inflammatory bowel disease]."

Probiotics, in case you've not heard, include a range of bacterial and yeast species thought to have some sort of health benefit by acting on the multitude of microorganisms that call us (predominantly our digestive tract) home. Inflammatory bowel disease (IBD) typically means one of two conditions: ulcerative colitis (UC) and/or Crohn's disease (CD). Both IBD conditions involve inflammation of parts of the gastrointestinal (GI) tract, in which many of those previously discussed microorganisms reside in. Putting the two concepts together - probiotics and IBD - and it stands to reason that they might have some [variable] interaction with one and another.

The authors surveyed the current peer-reviewed science literature on the topic of probiotics 'for' IBD, grouped the results together and set about trying to come up with some summary statements based on the statistical results obtained. Bearing in mind that the term 'probiotic' includes quite a few different bacterial/yeast species, both alone and in combination, they came up with a few take-home messages.

First: "Probiotics are beneficial in IBD, especially the combination ones in UC." Given what traditional treatment options are currently available for UC (see here), the idea that popping a few pills, most of which are readily available without a doctor's prescription, containing bacteria and/or yeasts must represent a rather good deal for those diagnosed with UC. I say this minus any medical or clinical advice from me: please, consult you medical physician before making any such changes.

Second: I note that two particular 'preparations' are mentioned in the review text: Saccharomyces boulardii and VSL#3. Both of these products (yes, I know S. boulardii is a strain of yeast) have had previous airtime on this blog for various different reasons (see here and see here for examples). Both of them also have some pretty good evidence when it comes to other bowel-related conditions and states as told again by the all-powerful meta-analysis/systematic review (see here).

Finally I note that the safety profile of these preparations seemed to be pretty good based on the trial data included for study. That's not to say that they are completely side-effect free [2] (particularly in the context of the use of immunosuppressants for potentially treating UC for example) but their risk profile seems at least to be on a par with more traditional pharmacotherapies.

What's more to say? Well, just before I finish I do want to try and relate some of the Ganji-Arjenaki - Rafieian-Kopaei findings back to the core material of this blog: autism. I say this with some cautions but: (a) science has told us a few times that inflammatory bowel disease does seem to be over-represented when it comes to a diagnosis of autism (see here), and (b) discussions should be turning to 'what can we do to help' when it comes to IBD accompanying autism, given that presentation might be slightly less 'mainstream' in such cases [2] (see here for my take on this study). I've also already touched upon the study by Grossi et al [3] (see here) talking about how a probiotic formulation seemed to affect both gut and behaviour in a case report and what that could mean for [some] others diagnosed with an autism spectrum disorder (ASD). Such findings asks science to do a lot more to see if a dual diagnoses of autism and IBD represents an important target for probiotics as an extension to work on autism and more 'functional' bowel complaints either already completed or still underway (see here and see here).

And bear in mind that outside of any gut-brain notions specifically with IBD and autism in mind (see here), there is evidence to suggest that effective medical treatment of IBD might generally extend to quite a few domains [4] which I daresay are just an important in the context of autism as they are to not-autism...

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[1] Ganji-Arjenaki M. & Rafieian-Kopaei M. Probiotics are a good choice in remission of inflammatory bowel diseases: A meta analysis and systematic review. J Cell Physiol. 2018 Mar;233(3):2091-2103.

[2] Lee M. et al. Association of Autism Spectrum Disorders and Inflammatory Bowel Disease. J Autism Dev Disord. 2017 Nov 23.

[3] Grossi E. et al. Unexpected improvement in core autism spectrum disorder symptoms after long-term treatment with probiotics. SAGE Open Medical Case Reports. 2016;4:2050313X16666231.

[4] Mählmann L. et al. Psychological wellbeing and physical activity in children and adolescents with inflammatory bowel disease compared to healthy controls. BMC Gastroenterology 2017; 17: 160.

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Inflammatory bowel disease and autism (again)

"Children with ASD [autism spectrum disorder] were more likely to meet criteria for Crohn’s disease (CD) and Ulcerative colitis (UC) compared to controls."

So concluded Maunoo Lee and colleagues [1] following their "retrospective case-cohort study" of the US Military Health System database. Having previously published their findings as a conference abstract [2], authors gave their data the full peer-reviewed publication treatment covering nearly 300,000 people: ~48,000 children diagnosed with ASD and ~240,000 matched (not-autism) controls.

Alongside gathering data on the frequency of ICD-9 diagnostic codes for CD and UC - both defined as inflammatory bowel diseases (IBDs) - researchers also examined prescription data for treating/managing such bowel conditions. They observed differences in the prescription rate ratio (PRR) *potentially* reflective of either a more severe or more difficult to control form of IBD in children diagnosed with ASD. In short, and hopefully without making too many sweeping generalisations, IBDs are seemingly over-represented when it comes to a diagnosis of autism, and may be more likely to have an atypical pathological course.

Of course all of this is not new news. I've talked about other research that has reported similar things in relation to IBDs and autism (see here) alongside the 'now-not-questioned-so-much' data on the over-representation of functional bowel problems in relation to autism (see here). There's still a way to go in research and clinical terms to try and answer questions about how such bowel issues come about in relation to autism and whether one might consider some IBDs as being potentially 'novel' in relation to 'some' autism (see here). But the days of bowel problems in autism being some sort of fringe issue seem to well and truly gone, as perhaps 'suffering' as a result of such bowel issues can hopefully start to be addressed and other potential 'effects' (see here) investigated further minus hype, generalisation and/or fear...

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[1] Lee M. et al. Association of Autism Spectrum Disorders and Inflammatory Bowel Disease. J Autism Dev Disorders. 2017. Nov 23.

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"psychiatric comorbidity may be the earliest manifestation of the onset of IMID in some individuals"

IMID shown in the title of this post refers to immune-mediated inflammatory diseases such as inflammatory bowel disease (IBD), multiple sclerosis (MS) and rheumatoid arthritis (RA) and formed quite an important part of the findings reported by Ruth Ann Marrie and colleagues [1] (open-access available here). This work adds to an area of increasing importance on how the physical and psychological/psychiatric might very well be linked by the immunological (see here for discussions on other recent work from this authorship group).

Similar to their last publication [2] Marrie et al relied on data out of the "the Canadian province of Manitoba" and included some 12,000 diagnosed cases of IMID. The aim of their study this time around was "to estimate the incidence of several psychiatric disorders, including depression, anxiety, bipolar disorder and schizophrenia, in the 5-year periods pre- and post-IMID diagnosis." Further: "We hypothesised that the incidence of psychiatric comorbidity would be higher in the incident IMID than in the matched general population cohorts pre- and post-IMID diagnosis."

Results: "the incidence of psychiatric comorbidity was increased in the IMID cohorts in the 5–10 years before IMID diagnosis." Minus too many sweeping generalisations, there is something potentially rather 'stunning' about such findings and the idea that for some at least, psychiatric findings might be a prelude to something rather more somatic a few years down the line. Authors also noted that post-IMID diagnosis, there was also a possible *connection* to receipt of a psychiatric label too.

Explanations? Well, with the requirement for quite a bit more independent analysis in this area of science, there are a few possibilities to consider. Authors talk about a possible "prodromal period for the IMID in which inflammation has developed sufficiently to increase the risk of psychiatric disorders but not to precipitate typical clinical manifestations of IMID." You'll note the use of the word 'inflammation' in that last sentence pertinent to the idea that inflammation as a component of immune function might well be doing lots and lots of different things (see here).

They also mention the possibility that "psychiatric disorders and IMID may share common aetiologic factors." So, drawing on a little autism research here, and how autism genes might not necessarily be just genes for autism (see here) and how such genetic overlap may include some of the genetics of immune function (see here), the feeling is that such sentiments could be pertinent to other labels too. Of course it's also important to note that outside of just structural genetics, there may be other non-genetic factors that could exert a possible effect such as the availability of certain nutrients for example (see here).

And there is another important point raised by Marrie and colleagues: "the occurrence of psychiatric disorders pre-diagnosis of IMID could potentially be conceptualised as early symptoms of IMID rather than as distinct comorbid conditions." This is something rather appealing to me following my reading of the research literature in this area down the years. Yet again drawing on research in autism, I've often thought that at least of the 'comorbidity' that is over-represented alongside a diagnosis of autism might actually be a lot more 'central' to some presentations. Take for example all the chatter about gastrointestinal (GI) issues being present alongside [some] autism (see here). Minus all the fluffy psychological explanations for the presence of various bowel issues alongside a diagnosis of autism, there is evidence that the bowel might be quite a bit more central to quite a few cases of autism under specific circumstances (see here). Further extending such work I note that bowel issues also might carry relevance to other behavioural/psychiatric diagnoses too (see here). If also proven in the context of 'psychiatric IMID' (if I can call it that), such a move away from notions of comorbidity towards more core issues has implications not just for screening and assessment but also management and treatment too...

Reiterating that quite a bit more work needs to be done on the whole 'immune system doing more than just traditional immune system things', I continue to find this area of research absolutely fascinating.

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[1] Marrie RA. et al. Rising incidence of psychiatric disorders before diagnosis of immune-mediated inflammatory disease. Epidemiol Psychiatr Sci. 2017 Nov 3:1-10.

[2] Marrie RA. et al. Increased incidence of psychiatric disorders in immune-mediated inflammatory disease. J Psychosom Res. 2017 Oct;101:17-23.

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Psychiatric disorders accompanying "immune-mediated inflammatory disease"

I wasn't actually that surprised at the results published by Ruth Ann Marrie and colleagues [1] (open-access available here) observing that: "Individuals with IMID [immune-mediated inflammatory diseases], including IBD [inflammatory bowel disease], MS [multiple sclerosis] and RA [rheumatoid arthritis] are at increased risk of psychiatric comorbidity."

On more than one occasion on this blog I've talked about how the psychiatric and the somatic are seemingly intertwined (see here and see here for examples) for whatever reason(s). The current results from Marrie et al however add further weight to calls to study "a common underlying biology that may be best elucidated by studying different psychiatric disorders and different IMID together."

So, based on the use of "population-based administrative (health) data" based in a region of Canada, authors identified nearly 20,000 participant records of people diagnosed with IMID. They compared this IMID group with almost 100,000 not-IMID "age-, sex- and geographically-matched controls" with regards to "the incidence of depression, anxiety disorder, bipolar disorder and schizophrenia in each of the study cohorts." The authors noted that: "To estimate incidence of psychiatric disorders after the diagnosis of the IMID of interest, the first claim for the psychiatric disorder had to occur after the index date for the IMID, and be preceded by a five-year period with no claims for that psychiatric disorder."

Results: The incidence of CMD (comorbid mental disorder) was increased in the IMID group compared with the non-IMID control group. This observation survived adjustment for other potential variables of interest such as region of residence and socioeconomic status (although authors did note that: "Female sex, urban residence, and lower SES were associated with increased incidence of psychiatric disorders.") Looking at the individual IMID, authors reported that: "Depression and anxiety affected the MS population more often than the IBD and RA populations."

What's more to say? Well, aside from more research being required to look at the connection(s) between immune function and psychiatric presentations there is an argument for enhanced screening for psychopathology as and when IMID are diagnosed. Perhaps intriguingly, there is also the idea that where the two systems coincide, new intervention and treatment regimes *might* show some promise as the per the idea for example, that some kinds of depression might be sensitive to certain anti-inflammatory compounds (see here).

To close, what else but more insight into the potential Last Jedi?

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[1] Marrie RA. et al. Increased incidence of psychiatric disorders in immune-mediated inflammatory disease. J Psychosom Res. 2017 Aug 1;101:17-23.

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SHANK3 and intestinal barrier function might have implications for some autism...

According to the Spectrum Wiki, SHANK3 - SH3 and multiple ankyrin repeat domains 3 - is described as "a leading autism candidate gene, with mutations occurring in between 1 and 2 percent of individuals with autism spectrum disorder."

Providing instructions for making the SHANK3 protein, alterations to the structure or function of the SHANK3 gene can have some quite far-reaching consequences, notably including disrupting communication between neurons in the brain.

A recent paper published by Shu-Chen Wei and colleagues [1] provides some further discussion on how issues with SHANK3 may very well extend beyond just 'brain function' and indeed, may overlap with reports of an over-representation of bowel disease in the context of autism (see here). In effect, a *possible* genetic association between autism and inflammatory bowel disease. Possibly...

Wei et al initially relied on a mouse model of SHANK3 disruption, something that has also reached autism research [2]. Said mouse model was artificially exposed to dextran sulfate sodium, a compound that creates experimental colitis mimicking human inflammatory bowel conditions such as ulcerative colitis. Various measures were employed to explore the interaction between colitis in the SHANK3 knockout mice pertinent to the expression of intestinal permeability, hyperpermeability of which is also known as 'leaky gut' in some quarters. Gut permeability issues are 'on the radar' when it comes to at least some autism (see here). Researchers also looked at SHANK3 expression in a cohort of human participants diagnosed with an inflammatory bowel disease called Crohn's disease.

Results: "SHANK3 knockout resulted in a leaky epithelial barrier phenotype, as demonstrated by decreased transepithelial electrical resistance, increased paracellular permeability, and increased Salmonella invasion." Going back to the idea that genetic issues identified as being potentially pertinent to some autism might extend beyond just 'effects on the brain' this is an important finding. Much like in other identified genetic conditions manifesting autism or autistic traits, the indications are that intestinal issues might be part and parcel of some autism where SHANK3 issues have been identified (see here and see here for other examples under other genetic conditions).

Further: "Overexpression of SHANK3 enhanced ZO-1 expression, and knockdown of SHANK3 resulted in decreased expression of ZO-1." ZO-1 refers to zonula occludens-1, something called a tight junction protein which serves an important function in intestinal barrier biochemistry. In effect, ZO-1 and other tight junction proteins seal the space - paracellular space - that is part of the intestinal barrier. The implication being that under expression of SHANK3 seems to have a detrimental effect on metabolites involved in intestinal barrier integrity; something also noted when it came to Wei and colleagues looking at "colonic tissue of patients with Crohn's disease" with ZO-1 in mind.

I used the words 'might have implications for some autism' in the title of this post but hasten to add that much more investigation is still required. Yes, SHANK3 seems to have a place in the aetiology and pathology of 'some autism' but further confirmatory research is required. Not least that, as far as I am aware, no-one has actually looked at intestinal barrier function directly in cases of Phelan-McDermid syndrome a primary outcome of SHANK3 genetic issues, despite some chatter about gastrointestinal issues potentially being no stranger to such a diagnosis [3]. I would also like to see a little more done on the measurement of something like zonulin where SHANK3 is mentioned in the context that zonulin seems to have a connection to intestinal barrier integrity. Whether, similar to other preliminary work looking at autism and zonulin (see here), there may be merit in testing when SHANK3 issues are likewise identified.

And while we're on the topic of mouse models and possible connections to autism, it's worth noting the findings reported by Groves and colleagues [4] talking about what vitamin D deficiency might do to certain mouse behaviours in the context that vitamin D has some autism research history too...

Music to close, and not to make light of SHANK3 but it does conjure up the sound of quite a famous song...

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[1] Wei SC. et al. SHANK3 Regulates Intestinal Barrier Function Through Modulating ZO-1 Expression Through the PKCε-dependent Pathway. Inflamm Bowel Dis. 2017 Oct;23(10):1730-1740.

[2] Yoo J. et al. Shank mutant mice as an animal model of autism. Philosophical Transactions of the Royal Society B: Biological Sciences. 2014;369(1633):20130143.

[3] Kolevzon A. et al. Phelan-McDermid syndrome: a review of the literature and practice parameters for medical assessment and monitoring. Journal of Neurodevelopmental Disorders. 2014;6(1):39.

[4] Groves NJ. et al. Adult vitamin D deficiency exacerbates impairments caused by social stress in BALB/c and C57BL/6 mice. Psychoneuroendocrinology. 2017 Sep 6;86:53-63.

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Autism, ageing and comorbidity

I'm not spending too much time today on the findings published by Elizabeth Wise and colleagues [1] but did want to bring them to your attention. Looking at the presentation of "comorbidities and behavioral and neuropsychiatric symptoms" in relation to autism in the context of ageing, some important details were noted. Not least that "GI [gastrointestinal] disorders (68.9%) and seizure disorders (23%) were common, and 25.7% of the sample had a BMI [body mass index] >30" when looking at their 74 strong cohort of adults diagnosed with autism (DSM-5 autism by all accounts).

It's not new news that the label of autism rarely exists in some sort of diagnostic vacuum (see here and see here for other examples). The fact that GI disorders (whether functional or more pathological), epilepsy and/or seizure disorder and excess BMI have been picked out by Wise et al ties into an extensive peer-reviewed research body highlighting such issues. What is still missing from quite a lot of that literature is the hows-and-whys of such over-represented comorbidity and importantly, what can be done to manage/ameliorate them (see here for example) given that sometimes they can be just as 'disabling' as a diagnosis of autism itself.

Wise and colleagues also noted that: "the point prevalence of behavioral and neuropsychiatric symptoms (BNPS) declined significantly for 12 of 13 BNPS over a mean of 25 years while many other features of ASD remained stable." Accepting the relatively small cohort studied, this is an interesting finding and ties into other research looking at what happens to something like psychiatric comorbidity in the context of ageing and autism (see here). There is a caution attached to the idea that behavioural and psychiatric comorbidity might be quite fluid across the lifespan in relation to autism insofar as sex/gender potentially being an important variable (see here).

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[1] Wise EA. et al. Aging and Autism Spectrum Disorder: A Naturalistic, Longitudinal Study of the Comorbidities and Behavioral and Neuropsychiatric Symptoms in Adults with ASD. J Autism Dev Disord. 2017. Mar 16.

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Wise EA, Smith MD, & Rabins PV (2017). Aging and Autism Spectrum Disorder: A Naturalistic, Longitudinal Study of the Comorbidities and Behavioral and Neuropsychiatric Symptoms in Adults with ASD. Journal of autism and developmental disorders PMID: 28303420

"A Putative Blood-Based Biomarker for Autism Spectrum Disorder-Associated Ileocolitis"

Contrary to Murphy's Law - 'never repeat a successful experiment' - replication or reproducibility is a cornerstone of good science. Today, I'm blogging about a piece of research that aimed to do just that as per the findings reported by Stephen Walker and colleagues [1] (open-access).

The title of this post has been borrowed from the title of the Walker paper to illustrate how moving on from the quite widely known 'fact' that functional gastrointestinal (GI) symptoms are over-represented when it comes to the label of autism (see here for example) so further research focus is required on more pathological bowel conditions potentially linked to autism too (see here). Yes, I know this potentially takes us into some uncomfortable territory but for those with autism suffering with various bowel issues (and I do mean suffering) this marks some important science for them and their families onward to the resolution of any further health inequalities.

The latest Walker paper follows on from their original findings [2] which have been previously covered on this blog (see here) observing that: "ASDGI children have a gastrointestinal mucosal molecular profile that overlaps significantly with known inflammatory bowel disease (IBD), yet has distinctive features that further supports the presence of an ASD-associated IBD variant, or, alternatively, a prodromal phase of typical inflammatory bowel disease." ASDGI by the way, referred to their small grouping of "twenty five consecutive ASDGI cases (6 autism; 19 autism spectrum disorder) with histopathologic findings of ileitis, colitis, or both."

This latest time around authors report on the extending of their 'initial findings' in "an additional case/control cohort." Further they "report a gene expression profile in peripheral blood that may reflect the presence of ASD-associated ileocolitis and provide a putative surrogate biomarker that, upon validation, would be of significant clinical relevance." Potentially, big words.

The paper is open-access but here are a few choice details:

• Biopsy samples - "a specimen from each of seven anatomic locations (from the terminal ileum to rectum)" - and blood samples were provided by 21 participants (patients) diagnosed with an autism spectrum disorder (ASD). All presented with gastrointestinal (GI) symptoms and all had "a history of normal development for at least 12 months followed by developmental regression and onset of gastrointestinal symptoms." All also had "histologically-confirmed ileitis, colitis, or both in at least one of seven collected and archived colonic biopsies." 
• A control group of 21 'typically-developing' children "without ASD who had gastrointestinal symptoms... but no identifiable histologic inflammation on any biopsies in either the ileum or colon" were also included for analysis.
• Part 1 of the study "compared whole genome gene expression profiles of inflamed ASD GI mucosal tissue (ASDIC+) to non-inflamed TD mucosal tissue (TDIC−) in biopsies from both the terminal ileum and colon." This is pretty much what was done by the authors during their first research voyage in this area. Part 2 was more novel insofar as blood gene expression profiles were compared between the groups. It's also important to note that: "blood was obtained from the same patients, and at the same time, as their respective mucosal tissue samples."
• Results: applying a statistical technique called Principal Component Analysis (PCA) looking at gene expression in those mucosal (bowel) samples, authors were again able to say that there were differences between inflamed and non-inflamed samples/groups. They also observed some potentially important differences in those blood samples too: "Nine of these DETs [gene transcripts that are differentially-expressed] were also differentially expressed in blood in our most recent cohort." You might ask what does this actually tell us about the autism+GI group? Well, nothing and something, insofar as it is not really being ethical to start taking bowel biopsies from children with autism without any indication to do so, which means that comparisons between non-GI and GI+ children with autism were not possible. The data do however suggest that a "putative peripheral marker could provide a proxy for gastrointestinal inflammation and also provide functional insights."
• Insofar as the details of what genes were being differentially expressed in ASDIC+ vs. TDIC- samples and how these overlapped with the previous study from the authors, there were some interesting candidates including "a key mitochondrial folate pathway gene, MTHFD2 (methylenetetrahydrofolate dehydrogenase (NADP + dependent) 2, methenyltetrahydrofolate cyclohydrolase)" hinting at an effect beyond just immune function and inflammation/inflammatory signalling. Authors modelled various combinations of these genes expressed (or not) to try and come up with some preliminary Receiver Operating Characteristic (ROC) curve analysis. Regular readers of this blog will probably have heard me talk about ROC analyses before (see here for example) with regards to the search for potential classifiers or biomarker profiles associated with autism. Bearing in mind the small participant numbers included in this study and the final figures arrived at, I'd suggest that quite a bit more work is required before anyone takes the reported findings as gospel just yet. But they are interesting...

So, there you have it. This is important work for two reasons: (i) more pathological bowel states can and do present alongside autism [3] (the diagnosis of autism is seemingly protective of very little as science is learning) and (ii) with the strong requirement for further investigations in this area, science is seemingly starting on a path to potentially identifying blood-based 'biomarkers' possibly useful in identifying those who might benefit from further screening for such bowel issues.

Given the history and debate in the area of bowel disease accompanying some autism, I'm not expecting giant fanfares to greet these results nor any big rush to try and prove/disprove these latest findings. That is an unfortunate truth and in the end, it is the children/adults with autism and significant GI issues who lose out as a consequence. The fact that this and the previous work by the authors is peer-reviewed science and not just speculation however will I think eventually be important, as talk about medical comorbidity accompanying autism continues at a pace [4] (see here too) and further moves towards 'what can we do about such issues?' eventually start to come to the forefront.

And just before I go, there may also be other research uses for biopsies as and when they have to be taken from children/adults under clinical investigation [5]...

To close, I note there is an election across the Pond. With all the nastiness that has followed the campaign, surely there's an easier way to pick the Leader of the Free World...

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

[2] Walker SJ. et al. Identification of unique gene expression profile in children with regressive autism spectrum disorder (ASD) and ileocolitis. PLoS One. 2013;8(3):e58058.

[3] Doshi-Velez F. et al. Prevalence of Inflammatory Bowel Disease Among Patients with Autism Spectrum Disorders. Inflamm Bowel Dis. 2015 Oct;21(10):2281-8.

[4] Vohra R. et al. Comorbidity prevalence, healthcare utilization, and expenditures of Medicaid enrolled adults with autism spectrum disorders. Autism. 2016. Oct 20.

[5] Kushak RI. et al. Analysis of the Duodenal Microbiome in Autistic Individuals: Association with Carbohydrate Digestion. J Pediatr Gastroenterol Nutr. 2016 Nov 2.

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Walker SJ, Beavers DP, Fortunato J, & Krigsman A (2016). A Putative Blood-Based Biomarker for Autism Spectrum Disorder-Associated Ileocolitis. Scientific reports, 6 PMID: 27767057

No unique patterns of gut issues in autism? Headline fail...

"This study supports the observation that children with autism who have symptoms of gastrointestinal disorders have objective findings similar to children without autism. Neither non-invasive testing nor endoscopic findings identify gastrointestinal pathology specific to autism, but may be of benefit in identifying children with autism who have atypical symptoms."

So concluded Rafail Kushak and colleagues [1] (them of "Lactase deficiency not associated with intestinal inflammation or injury is common in autistic children and may contribute to abdominal discomfort, pain and observed aberrant behavior" [2]) who undertook some important work around the topic of gastrointestinal (GI) issues being over-represented in cases of autism (see here). Some media on their recent findings can be read here (see here).

Looking at the results of 61 children diagnosed with autism and presenting with GI issues and data from 50 non-autistic individuals also being assessed for GI problems, researchers examined whether there were any differences between the groups on a range of measures including disaccharidase activity, intestinal inflammation and gut permeability (the so-called 'leaky gut'). They reported finding some discrepancies between the groups - including "mild levels of mucosal inflammation on intestinal biopsy" for some of those with autism -  but nothing that seemed to point to a 'GI fingerprint' specifically relevant to just autism. They concluded that where GI issues appear alongside autism, the same level of assessment and care should be afforded as it is when GI issues are present outside of autism. Tim Buie, one of the study authors, had said as much quite a few years back.

I would draw attention to a few important points included in the Kushak study. First, are the participant groups. This was a study comparing children with and without autism who were both under investigation following the presentation of GI issues. They were not comparing children with autism with GI issues with non-autistic children without gut issues. I say this just in case anyone assumes that the findings point to no significant gut issues being identified in those with autism. That is absolutely not the case. Headlines might need some adjustment.

Second, the results reported are to some degree at odds with other findings published by independent groups - specifically those reported by Stephen Walker and colleagues [3] (see here for my take). Although perhaps not exactly overlapping in terms of methods and outcomes, Walker et al concluded that their data was evidence that "ASDGI children have a gastrointestinal mucosal molecular profile that overlaps significantly with known inflammatory bowel disease (IBD), yet has distinctive features that further supports the presence of an ASD-associated IBD variant, or, alternatively, a prodromal phase of typical inflammatory bowel disease." I might add that at the time of writing this post and despite the Walker findings being published some 3 years ago, no-one has taken up the research gauntlet to try and replicate/challenge the Walker publication. That IBD might be over-represented when a diagnosis of autism is received is also an important point to make (see here).

Finally, mention of the words "leaky gut" in the Kushak report are a continued welcome sign. That measurement via "rhamnose/lactulose test and measured by HPLC-MS" did not appear to differentiate kids with autism with GI issues vs, kids without autism with GI issues is an important addition to the debate in this area. I know discussions of intestinal permeability with autism in mind can furrow brows in certain quarters but there is a growing recognition that (a) this is a real phenomenon (see here) and (b) for at least some people on the autism spectrum, gut permeability issues are present (see here). That gut permeability issues might be a 'later life event' when detected in 'some' autism (see here) is also worth re-iterating as is the idea that 'treating' gut permeability might be something that many people are already doing without even knowing it (see here).

Now, about that study on the use of dietary intervention for children with autism WITH bowel issues...

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[1] Kushak RI. et al. Evaluation of Intestinal Function in Children with Autism and Gastrointestinal Symptoms. J Pediatr Gastroenterol Nutr. 2016 Feb 20.

[2] Kushak RI. et al. Intestinal disaccharidase activity in patients with autism: effect of age, gender, and intestinal inflammation. Autism. 2011 May;15(3):285-94.

[3] Walker S. et al. Identification of unique gene expression profile in children with regressive autism spectrum disorder (ASD) and ileocolitis. PLoS ONE. 2013; 8: e58058.

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Kushak RI, Buie TM, Murray KF, Newburg DS, Chen C, Nestoridi E, & Winter HS (2016). Evaluation of Intestinal Function in Children with Autism and Gastrointestinal Symptoms. Journal of pediatric gastroenterology and nutrition PMID: 26913756