"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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Exclusion diet plus prebiotics for [some] autism?

"To our knowledge, this is the first study where the effect of exclusion diets and prebiotics has been evaluated in autism, showing potential beneficial effects."

So said the results reported by Roberta Grimaldi and colleagues [1] and the findings of their study attempting to "understand the impact of diet on GM [gut microbiota] composition and metabolism in ASD [autism spectrum disorder] children and to investigate the modulating potential of B-GOS® intervention on these parameters."

The study by Grimaldi et al was research registered (see here) and included the 'gold-standard' research design: "A randomised, double-blind, placebo-controlled" study. Researchers divided 30 children diagnosed with an ASD into two groups (A and B), which were subsequently further divided into two groups depending on whether they followed an exclusion diet - "mainly gluten and casein free" - or an unrestricted diet based on the analysis of 4-day food diaries. Within those subdivided A and B groups, half received a placebo supplement of maltodextrin whilst the other half received a "prebiotic B-GOS® mixture" over a 6-week period. As well as including 'run-in', 'beginning of treatment' and 'end of treatment' periods, researchers also included a follow-up period of 2 weeks at the end of the study where various behavioural and physiological measures complemented their use during the experimental period.

Results: there were quite a few results reported as a function of baseline variables such as whether or not participants were following an exclusion diet or not, and as a function of the intervention(s). Behaviourally (probably most importantly), researchers reported that: "Results showed consistent reduction over time in anti-sociability score in children on the combination of the exclusion diet and B-GOS intervention, with the most apparent difference occurring at follow-up." This was measured using the autism 'rising' instrument called the A-TEC (see here) and also complemented other results based on the use of the autism spectrum quotient (AQ). As far as I can make out, all other behavioural and psychometric measures used - the "empathy and systemising quotient (EQ-SQ)... and the Spence’s Children Anxiety Scale-Parent version (SCAS-P)" - did not show any significant changes over the study duration.

Gastrointestinal (GI) symptoms were also examined during the Grimaldi study as per the use of "daily questionnaires for GI function and symptoms" and the utilisation of that fabulous graphical resource, the Bristol stool chart. Authors reported no significant changes/differences as a consequence of intervention, although: "Significantly lower scores of abdominal pain (P < 0.05) and bowel movement (P < 0.001) were reported in children following exclusion diets" at baseline. Interesting, in light of other independent results (see here).

Grimaldi and colleagues also provide quite a lot of data following their examination of fecal and urine samples taken over the course of their investigation. This is perhaps not unexpected given their previous research interests in this area and the proud reputation earned at one of the affiliated institutions. The results? Lots of them. Perhaps the most important intervention-wise was the finding of a "significant increase of Lachnospiraceae family" following B-GOS® intervention. The authors talk about this in terms of the production of butyrate (as per their previous research) and the (positive) reputation this stuff is starting to garner.

Other details? Well, going back to the baseline assessment of samples as a function of the use of an exclusion diet or not, there are some interesting findings. So: "Before prebiotic B-GOS® intervention, we evaluated the nutritional impact of exclusion diets (GFCF) and our results showed deficiency in vitamin D intake, which was significant in children on unrestricted diets." This kinda ties into other research which observed that the 'horror' that is a gluten-free, casein-free (GFCF) diet in relation to autism might actually not be that horrible in nutritional terms (see here). I'm also minded to bring in other recent research which suggested that a GF diet might be a bit of a 'fixer' when it comes to vitamin D deficiency issues under certain clinical circumstances [2]. I say this minus any sweeping generalisations or universal application to the label of autism.

Overall the Grimaldi findings are interesting and suggest further investigations are required on the use of prebiotics and diet in autism; perhaps complementing the still-growing interest in the gut microbiota and autism (see here for one example). Mindful also that diet can itself be seemingly affect gut bacterial composition too [3]. As they stand however, the current results aren't yet a glowing endorsement of B-GOS® intervention 'for' autism, mindful of the small participant group eventually included for study and the relatively short-term nature of the Grimaldi trial. We'll see where this goes... although next time, I'd also like to see a more prominent statement about any harms or side-effects encountered or not during the study period. I assume 'not' in the current study but...

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[1] Grimaldi R. et al. A prebiotic intervention study in children with autism spectrum disorders (ASDs). Microbiome. 2018 Aug 2;6(1):133.

[2] Zingone F. & Ciacci C. The value and significance of 25(OH) and 1,25(OH) vitamin D serum levels in adult coeliac patients: A review of the literature. Dig Liver Dis. 2018 Aug;50(8):757-760.

[3] Berding K. & Donovan SM. Diet Can Impact Microbiota Composition in Children With Autism Spectrum Disorder. Front Neurosci. 2018 Jul 31;12:515.

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