The gut microbiome and autism... so far (continued)

Building on other reviews of the peer-reviewed science literature looking at the intestinal microbiota in relation to autism (see here), the paper published by Feitong Liu and colleagues [1] provides an updated 'where we're at' position in relation to the "potential evidence for the characteristic dysbiosis of gut microbiota in ASD [autism spectrum disorder] patients compared with healthy controls (HCs)." Just before you say anything, those are the authors words not mine; I'm not a fan of the word 'patients' nor use of the term 'healthy control' to denote not autism - not autistic, but there you go.

Language use aside, the Liu paper covers quite a lot of the peer-reviewed science talking about gut bacteria and autism up to March 2018. Their systematic review took in data from 16 studies - human studies "that compared the composition of gut microbiota in ASD patients and HCs using culture-independent techniques." Researchers had also previously registered their intention to conduct this review as per their PROSPERO entry (see here).

So what did their systematic review reveal? Well, they talked about how most studies looked at the intestinal microbiota via the examination of stool samples, although a couple relied on gut biopsy samples instead. Coincidentally, I spotted a bit of an error in the Liu paper in relation to their study reference numbering in one of the results sections, and how the Luna study (see here) and Williams study (see here) which relied on biopsy samples were replaced by other 'stool as a sample media' studies in the Liu write-up. It's only a small point and doesn't detract from the paper overall. The included studies also covered various different populations in a geographic sense as well as taking into account a mix of participants (with autism) in terms of the presence of gastrointestinal (GI) issues and the use of 'special' diets. Indeed, we are told that: "As restricted diet is very common in ASD patients, we tried to extract the information of eating habit in ASD and control group." Yes it is common, and yes it can have sometimes very negative effects (see here). Finally, all the studies included for review were "identified and assessed as medium (6–7) to high (8) quality" suggesting that the data were pretty reliable in a methodological sense.

Some key points emerged: "Overall, the changed structure of gut bacterial community in terms of β-diversity was observed coherently in ASD patients compared with HCs." Beta-diversity basically translates into 'between samples diversity' and in this case represents autism vs. not-autism controls. Out of the 16 studies included in their systematic review, Liu et al reported that "ten studies analyzed β-diversity (unweighted UniFrac distance, weighted UniFrac distances, and Bray-Curtis)." Six of those 10 studies "consistently reported that the microbiota of ASD patients clustered significantly apart from that of HCs." Ergo, there is evidence - some evidence - that the gut microbiome is significantly 'different' in autism compared with not-autism in a group sense. Some evidence at least.

Also: "Consistently, ASD patients had elevated abundance of Proteobacteria rather than HCs. In addition, Bifidobacterium, Blautia, Dialister, Prevotella, Veillonella, and Turicibacter were consistently decreased, while Lactobacillus, Bacteroides, Desulfovibrio, and Clostridium were increased in ASD patients relative to HCs."  Bear also in mind that Liu et al talked about various other bacterial species that were, in individual studies, elevated or depressed in the groups with autism, and how important such information might be. Such bacterial changes in terms of diversity or individual species predominating might also have knock-on effects as a result of the different chemical messages that different bacteria produce. One example: "Bacteroides is an abundant genus at all ages, from infants to adults. It is the main producer of propionate in the gut, and the abundance of propionate in feces correlates strongly with the abundance of Bacteroides." It probably won't surprise you to hear that propionic acid (propionate) has also got some research history when it comes to autism (see here) and indeed, with caveats, continues to do so [2]. Other examples are included in the Liu paper, including the 'chemical of the moment', butyrate (butyric acid) (see here). This complements other recently published research [3] too. And let's not forget how such bacteria and their chemical messaging also has some important 'effects' on things like gut barrier function and gut immune function, as part of the 'new triad' when it comes to autism and the gut (see here).

"Microbiome reconstitution could be a potential therapy to ASD patients in future." That's another topic raised in the Liu study on how "remodeling gut microbiota with diet, antibiotics, prebiotics, probiotics, and FMT [fecal microbiota transplant]" could be an option. Actually the future is now, as a quick scour of the autism research literature shows that some of these options are already being / have been investigated (see here and see here for examples). We do need a lot more information on the hows-and-whys of such therapeutic options; importantly covering safety, effectiveness and maybe highlighting the possible mechanisms involved, but there is already existing literature in this area.

As well as highlighting some of the shortcomings of the current research literature discussing the intestinal microbiota and autism, the Liu study provides a nice overview of this topic as things currently (up to March 2018) stand. Whether such information can eventually be 'manipulated' to improve things like quality of life in the context of autism remains to be seen...

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[1] Liu F. et al. Altered composition and function of intestinal microbiota in autism spectrum disorders: a systematic review. Translational Psychiatry. 2019; 43.

[2] Shams S. et al. Systemic treatment with the enteric bacterial metabolic product propionic acid results in reduction of social behavior in juvenile rats: Contribution to a rodent model of autism spectrum disorder. Dev Psychobiol. 2019 Jan 28.

[3] Wang M. et al. Alterations in Gut Glutamate Metabolism Associated with Changes in Gut Microbiota Composition in Children with Autism Spectrum Disorder. mSystems. 2019 Jan 29;4(1). pii: e00321-18.

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Scurvy in a child with autism following a ketogenic diet

"We report a case of a 5-year-old patient with autism, who presented with scurvy secondary to the dietary restrictions of a ketogenic diet."

That was the aim of the paper by Syed Amir Ahmad and colleagues [1] who continue an important theme in autism research and clinical practice circles pertinent to the seeming over-representation of illnesses of malnutrition in relation to autism (see here).

The 'value added' bit to the Ahmad findings is the observation that scurvy - a disease caused by insufficient vitamin C in the diet - was seemingly present as a result of "the dietary restrictions of a ketogenic diet" (where a ketogenic diet represents a high fat, low carbohydrate eating schedule). I assume said diet was put in place in light of some previous research suggesting that a ketogenic diet (KD) may be 'useful' for some children on the autism spectrum (see here and see here) from a behavioural perspective or where indicated following the detection of an inborn error of metabolism for example.

Scurvy is something of a pet topic on this blog (see here and see here). Described as a rare disease, the growing [research] literature on autism and scurvy indicates that it is perhaps not as rare as many people think or would like it to be. One of the big issues in this area is that more screening needs to be done for scurvy in relation to a diagnosis of autism, particularly when children (and adults) on the autism spectrum might have a limited or restricted diet (see here).

"This case emphasizes the importance of vitamin supplements in patients consuming a special diet." I wholeheartedly agree with that conclusion made by the authors. I say this in the context that supplementation with various vitamins, minerals and nutrients where autism is present and a 'special diet' is being followed is already a good idea (see here). The fact that some of those nutrients being supplemented might themselves have an 'effect' of on the behaviour of some children (see here and see here for examples) is also something important to mention.

the bottom line: screen and keep screening for health issues like scurvy when autism is diagnosed.

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[1] Ahmad SA. et al. Florid Scurvy in an Autistic Child on a Ketogenic Diet. Pediatr Emerg Care. 2018 Nov 19.

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Autism research really needs to study the prevalence and treatment of scurvy in autism

The results published by Melinda Saavedra and colleagues [1] describing another case report where scurvy was [eventually] diagnosed as appearing alongside autism represents yet another 'call to action' on this topic.

I've covered this issue quite a few times before on this blog (see here and see here and see here), and quite frankly it's reached the point where autism research really needs to step up and formally study the prevalence of scurvy in relation to autism. Indeed given the almost universal reports of medical science not initially recognising that scurvy can be no stranger to autism, the time has also come to "announce [to] the pediatrician and other professionals dedicated to primary health care about scurvy as a potential consequence of restrictive diets in children with autism spectrum disorders."

This time around the clinical focus was on a 4 year old boy who was brought to clinical attention as a result of "hip pain and refusal to walk, associated with petechiae and bruising of the lower limbs." The clues were all there that scurvy could be a cause of such symptoms, but it was only when it was revealed that the child had "selective feeding habit" that the penny seemed to finally drop. Indeed: "Levels of Vitamin C in blood were measured and without waiting for results he started treatment with 300 mg per day of ascorbic acid." Lo and behold, his vitamin C results were found to be low, and vitamin C supplementation eventually did the trick. Of vital importance, the pain associated with scurvy also showed improvement and he was discharged from clinical care with a maintenance dose of vitamin C and some nutritional advice.

'Selective feeding patterns', 'picky eating' or whatever you want to call it, is an issue that is not stranger to autism (see here). It's reasonable to assume that where such feeding issues continue into the longer-term, and dependent on what foods are consumed as part of such a restrictive pattern, there are likely to be biological consequences for the person concerned as a function of what nutritional inadequacies follow. Indeed, I daresay that such a pattern follows what is being noticed in connection with other food-related conditions in the longer term (see here). Set in this context, a lot more research and importantly, clinical practice, needs to focus on the hows-and-whys of such behaviours and their remediation. There is no longer any excuse for allowing diseases of the past such as scurvy and also others like rickets, to plague the children of today, vulnerable children of today, where healthy food in most parts of the world, is not in short supply.

Oh, and bear in mind that 'picky eating' might not be the only reason why scurvy might appear alongside autism [2]. We need lots more data.

And also, as I write this [3]...

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[1] Saavedra MJ. et al. Scurvy due to restrictive diet in a child with autism spectrum disorder: case report. Arch Argent Pediatr. 2018 Oct 1;116(5):e684-e687

[2] Hasan Al-Breiki S. et al. Scurvy as the tip of the iceberg. Journal of Dermatology & Dermatologic Surgery. 2014; 18: 46-48.

[3] Caldwell KJ. et al. Child With Autism and a Limp. Ann Emerg Med. 2018 Oct;72(4):493-495.

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Eating difficulties in adolescents with CFS/ME

I tread quite carefully when discussing the paper by Sarah Harris and colleagues [1] (open-access available here) on the potential causes and effects of 'eating difficulties' when it comes to adolescent chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME).

Careful because (i) I don't want to confuse eating difficulties with eating disorder (they are not one and the same) and (ii) the suggestion that some of the young adults included for study "recognised how their eating difficulties were exacerbated and maintained by psychological factors of low mood and anxiety" could potentially play into the concept of 'psychosomatic', something that quite a few people are trying to move on from when it comes to ME/CFS. I count myself in the camp describing CFS/ME as a real organic disease (or spectrum of diseases) potentially manifesting in various physiological and [secondary] psychological ways (see here).

A few details first: 11 teens were included for study (aged between 13-17 years). All had a diagnosis of CFS/ME but I'm not exactly sure which of the numerous criteria around were used to make that diagnosis. They were all "drawn from a CFS/ME specialist hospital service providing regional support for assessment and treatment of over 300 children a year" so I am assuming that someone, somewhere had confirmed the diagnosis (somehow). Interviews were arranged around the topics of "the adolescents’ experience of eating; the factors they felt caused and exacerbate eating difficulties and what they believed were helpful strategies" and various primary themes were pulled out from the transcripts.

Results: some interesting issues emerged, not least that quite a few participants "perceived their eating difficulties were caused by abdominal symptoms." 'Abdominal symptoms' is quite a nebulous term but specifically issues like bloating, indigestion and stomach cramps/pain were frequently mentioned. Also: "Nausea prior to eating often caused the adolescents to perceive that eating would make it worse or induce vomiting." My first thoughts on reading about these symptoms was a previous post on some research suggesting that 'abdominal discomfort syndrome' might be part and parcel of a subgroup of those with ME/CFS (see here). That and a possible role for certain foods [2] (see here also)...

Next: "Seven adolescents noticed a change in smell or taste (or both)" potentially impacting on their eating behaviours. Alongside perceived changes in the sensation of food texture said to accompany the onset of their CFS/ME, this also seemed to tie into some of the eating difficulties described. As odd as it might sound, the sorts of changes being described by this small participant group with CFS/ME to me sounded very similar to what has been talked about with the autism spectrum in mind. Many (many) moons ago I published a small opinion piece on eating difficulties associated with autism [3] and well, let's just say some not dissimilar themes cropped up. I'm not saying CFS/ME is autism or vice-versa, but it does intrigue me about the possibility of overlap (see here).

When it came to the idea of 'intervention' for such eating difficulties, the Harris paper also includes some information. "Adolescents frequently excluded various dietary items such as diary, gluten and sugar, claiming these created greater digestive disturbances, although they had not been given a medical explanation for this." Having already mentioned the Rowe paper on cow's milk protein intolerance, I don't want to stick too long on this aspect of intervention. All I will say is that there is nothing in the peer-reviewed literature at present to say that a diagnosis of CFS/ME is protective against genetic/biological issues with certain foods... and that also includes dietary gluten for example (see here).

Insofar as the other techniques possibly helpful with the eating difficulties described in this group, the authors talk about distraction and relaxation strategies as being potentially useful and also the involvement of healthcare professionals such as dietitians to help overcome some of the difficulties experienced. These all sound pretty reasonable intervention options. Again, drawing on some of the autism research literature (again, with no wild claims of association being made) I wonder if there might be some 'connection' between those sensory issues previously described and other clinical aspects such as anxiety as part and parcel of abdominal manifestations for example (see here)?

If there is a bottom line from the Harris data it is that a diagnosis of CFS/ME is certainly not protective against eating difficulties when it comes to young adults. I would like to see this research built upon in future in various ways; first and perhaps foremost is the testing of those presenting with abdominal symptoms for various digestion and/or food-related conditions (i.e. coeliac disease and the rather 'shades of grey' borders of non-coeliac gluten sensitivity for example). I don't want to make connections when none might exist but I'd also be minded to suggest that those trillions of wee beasties that call our gut home (the gut microbiota) might also be a target for further inspection too (see here) in light of their potential connection to all-things gut related. The sensory aspects hinted at in the Harris data are also deserving of quite a bit more study too. Without blowing my own trumpet too much, sensory features accompanying 'overlapping fatigue syndromes' is something else I've also discussed in the peer-reviewed literature [4].

In short, don't dismiss eating difficulties and their potential correlates when it comes to CFS/ME...

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[1] Harris S. et al. A qualitative investigation of eating difficulties in adolescents with chronic fatigue syndrome/myalgic encephalomyelitis. Clin Child Psychol Psychiatry. 2016 May 23. pii: 1359104516646813.

[2] Rowe PC. et al. Cow's Milk Protein Intolerance in Adolescents and Young Adults with Chronic Fatigue Syndrome. Acta Paediatr. 2016 May 13.

[3] Whiteley P. et al. Feeding patterns in autism. Autism. 2000; 4: 207-211.

[4] Whiteley P. et al. Correlates of Overlapping Fatigue Syndromes. Journal of Nutritional & Environmental Medicine. 2004; 14:

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Harris S, Gilbert M, Beasant L, Linney C, Broughton J, & Crawley E (2016). A qualitative investigation of eating difficulties in adolescents with chronic fatigue syndrome/myalgic encephalomyelitis. Clinical child psychology and psychiatry PMID: 27215228