Autism research in 2023: a bit of a game-changing year

 So, autism research in 2023. It’s been quite a year. Let me (briefly) tell you why.

The autism numbers game: the only way is (still) up. Northern Ireland, where some great work is done to plot the annual (estimated) prevalence rate of autism spectrum disorder (ASD) in school-aged children, said 1 in 20 (or 5%) in 2023. The US CDC said an estimated 1 in 36 8-year olds (2.7%) were autistic in 2020. The CDC also said 1 in 47 4-year olds were autistic (2%). Scotland also recently produced data observing “The prevalence of autism was 2.60% (10,089 children) in 2022. This represents a 31.98% increase from the 2018 prevalence of 1.97% (7883 children).” That Scottish data, by the way, only covered those at primary school (aged 4ish-12ish years). Other sources too are still showing a growth in the prevalence of autism across other parts of the globe, including a near 5% rate of behaviours consistent with autism or ASD in the Hadza of Tanzania. All data on autism prevalence is still only heading in one direction: UP. 

Importantly, the old ‘all better awareness’ arguments are slowly fizzling out as the effects of those prevalence stats are starting to show on resources and infrastructure that seemingly haven’t kept pace with the growth in numbers. Indeed, one of the head people related to the CDC autism figures, went as far as to say that the stats don’t really support ‘better awareness’ as the primary driver given that the increase is showing across various different ‘levels’ of autism that are/were unlikely to be missed or thought to be something else. Certainly here in the UK, I don’t think I’ve ever read so many reports about school place shortages (particularly specialised school place shortages) as I have this year. And unfortunately, with an estimated 140,000 people (mostly children and young people) awaiting assessment in England alone, I fear the squeeze on resources is just going to get worse and worse. Anyone care to start asking ‘why the increase’ yet?

CDC says yes to ‘profound autism’. Speaking of autism ‘levels’ (as in DSM-5 autism levels of support or the ICD-11 condition combinations), the CDC did something else rather important this year: producing the first ever report on the rate of profound autism in the US. So, for data covering the years 2000-2016, and using the descriptor “classified as having profound autism if they were nonverbal, were minimally verbal, or had an intelligence quotient <50” they determined that 26.7% of those with autism fitted into the profound autism category. An estimated quarter of autistic people are profoundly autistic. That’s quite important.

There were mixed reactions to the CDC use of the term profound autism. Many people were happy to see it, given that it now lays the foundations for more research and more understanding that despite being united by a triad/dyad of symptom combinations, not everyone experiences autism in the same way. Look no further than the awful early mortality statistics following the deadly triad that is autism, wandering/elopement and water safety to see this in action. Of course autism by virtue of just being diagnosed, means support is required for everyone with the diagnosis. But that support will arguably differ depending on whether you possess things like communicative speech and language, present with things like self-injurious or aggressive behaviours and/or need 24-7 care to ensure that your daily needs are fulfilled. Indeed, I often think that the general lack of support post autism diagnosis is a big driver in the reticence to adopt the term profound autism in some quarters. But should people be so reticent? I mean we have similar distinctions when it comes to experiences of learning (intellectual) disability and nobody seemingly bats an eyelid there. 

There is however more to do on profound autism. This ties into other changes that are needed when it comes to assessing things like cognitive functions and communication (verbal or non-verbal) ability in relation to autism. That’ll follow as the term beds in and builds up more of a research base. Asperger syndrome gone, profound autism steps in.

What else? 

Non-persistence of autism in (some) young kids. 2023 also gave a lot more credence to the idea that the saying ‘all autism is lifelong’ probably isn’t as accurate as you might think. Looking at the developmental trajectories of around 200 kids, all diagnosed early with autism, saw about a third of them not continuing to meet the diagnostic threshold for autism/ASD at ages 5-7 years according to a big study. Other independent work also illuminated this topic and argued against the ‘just misdiagnosed’ suggestions that some people might make and that also the state of ‘autism free’ might have important implications for various other issues too.

This was a particularly important finding for me given our paper from a few years back talking about inborn and lifelong not necessarily being the most accurate phrases for all autism. It also accords with various other studies in related areas observing that diagnoses like ADHD and depression for example, aren’t lifelong labels for absolutely everyone either. Although I noted some people tried to talk about ‘masking’ and ‘camouflaging’ as being the reasons why young kids in that JAMA study didn’t meet the thresholds for autism having previously done so, I do have to ask whether they’ve ever seen autistic kids at this age. Indeed, any child at this age, who generally aren’t renowned for their developed social etiquette abilities covering masking et al (this is also the reason that the gold-standard autism assessment instrument, the ADI-R, codes 4-5 years separately from ‘current behaviour’). As to why autism doesn’t persist for some, well, we don’t know exactly. There was talk of intervention potentially playing a role (behavioural intervention) but it’s probably going to be a bit more complicated than just that. For now, we await further studies on this important topic including more longitudinal ones and perhaps also looking at the biology behind this phenomenon. If I was to speculate about why there is autism non-persistence for some, I might be inclined to say ‘look to infection’ for some, and how, more and more, we’re learning that infection and immune responses to infection can manifest as behaviour and developmental issues as well as in immune biology. Just me speculating, so pay no mind (although that autism in Hadza children study did nicely reignite my interest in how infections like malaria can, through various mechanisms, also seemingly lead to autism).

The gut-brain axis is important to autism. I know a lot of people already appreciate this, but seeing it in a peer-reviewed mega paper in 2023 adds a lot more weight to it. Said paper trawled through huge amounts of data about gut bacteria and the like, and concluded that there is something to see both as observation and also as potential intervention. Authors even mentioned the words ‘faecal matter transplant’ (FMT) in the context that what goes on in the gut doesn’t necessarily stay in the gut, and something that is rising in some autism research and other circles. Allied to the gut-brain axis stuff was the reporting from other mega review papers observing that gastrointestinal (GI) symptoms are present in roughly 55% of children with autism, compared with about a quarter of non-autistic children. Constipation comes out on top. So fixed to clinical advice about treating such issues published over 10 years ago, maybe now is the time to preferentially screen and treat such issues in the context of autism? Perhaps recognise that the gut and brain are connected for quite a few labels/conditions? More on that shortly.

Various medical issues are over-represented in autism. More important data points to the various clusters of medical (somatic) issues that seem to accompany autism across the age ranges. Ranging from cardiovascular conditions to immune-mediated conditions, various studies confirmed what quite a few people already knew. With my gluten research hat on (I don’t actually have a hat made of gluten), I was glad to see that the archetypal gluten-related autoimmune condition called coeliac disease was given mention. Who knows, between coeliac disease and the slightly greyish area of non-coeliac gluten issues that seem to be over-represented alongside autism, there’s further hope for wider screening and use of a gluten-free diet in the context of autism? Oh, and just before you inquire about the research base in this area, here’s a couple of meta-analyses from the last few years - see here and see here - saying it might be worth a shot (minus any clinical or medical advice given or intended).

And there was yet more research on the psychiatric and behavioural issues that seem to be over-represented alongside autism. Importantly, and I do think needs a lot more investigation, one study out of Canada stressed the need to look at comorbid psychiatric issues as being an important driver of suicidal behaviours in the context of autism. I know such behaviours are complex and often very individual with a heavy biopsychosocial tilt, but there’s a wealth of evidence out there already suggesting that depression, bipolar disorder, personality disorder and schizophrenia spectrum disorders all convey a heightened risk for suicidal behaviours. All those conditions are well over-represented alongside a diagnosis of autism (yep, an estimated 1 in 10 autistic people will potentially ‘transition’ to schizophrenia). Screen, screen and treat (including, where appropriate, more clinical emphasis on the archetypal anti-suicidal agent that is lithium used in the right context).

Late 2023 research entry: CM-AT results are really, really, really promising. I’ve been following the CM-AT story for quite a while on this blog and beyond. Basically, it concerns a pancreatic enzyme therapy designed for autism that has already crossed quite a few methodological trial hurdles. Then, in November 2023 lo and behold, the results of a double-blind, placebo-controlled trial that say, yes, following the gold-standard trial design, CM-AT is good for treating/managing irritability and agitation in the context of autism in pre-schoolers. Said treatment is also likely safe and effective. This is a potential game-changer and opens the door to things like regulatory approval. Also, exquisite evidence for the whole ‘behaviour is biology’ tenet and the important role of the gut-brain axis in autism, yet again.

There was so much more other science published this year, across all-manner of different topics. Certainly far too much for me to put into one blogpost. I’m a great believer in your citizen scientists and so would encourage everyone to look-see and take part. I can’t help but draw your attention to another paper that basically said the ‘person with autism’ vs ‘autistic person’ arguments typically seen on social media aren’t really worth a dime. Ask the person how they want to be addressed. Oh, and remember, people aren’t ‘neurotypes’ either. They’re people. 

And finally… Saying farewell to Donald.

Finally, [I can see you’re yawning] a non-sciency thing to mention. ‘Patient 1’ from the great Leo Kanner’s seminal paper describing autism - Donald Triplett - passed away. If you’ve ever read or watched ‘In a Different Key’ you’ll have read about him or seen him. Of all the things said about Donald in the various obituaries to him, I think the overwhelming idea that comes across is how much community was important to him; both being part of a supportive community and having a great community around him. Loads of lessons to be learned there. My advice: seek out those who wish to foster community, and there are lots of good people of this ilk. Here's to 2024 and beyond.

Roger Moore's eyebrows, ADHD and coeliac disease part 2

Consider this post an extension of some previous blogging chatter (see here) about how behaviourally defined diagnostic labels such as attention-deficit hyperactivity disorder (ADHD) seem to rarely exist in some sort of clinical vacuum. Part of that vacuum also potentially encompasses a range of somatic symptoms and/or diagnostic labels.

The findings reported by Vendel Kristensen and colleagues [1] set out to "assess self-reported symptoms of impaired concentration in coeliac disease before and after treatment with gluten-free diet, compared with healthy controls and patient controls." Coeliac (celiac) disease, in case you didn't know, refers to the archetypal 'gluten can affect biology' condition, where a certain genetic predisposition (or two) adds to gluten exposure to start a whole cascade of biological actions that impact on physical health and well being. Alongside things like bowel symptoms, there is an increasing recognition that coeliac disease (CD) also potentially brings with it certain psychological symptoms, particularly when it is not properly treated/managed (see here).

Kristensen et al asked some 30 people - "newly diagnosed coeliac patients" - to complete various questionnaires pertinent to the presentation of ADHD type symptoms, depression and anxiety and gut issues. These were compared with responses from those diagnosed with an inflammatory bowel disease (IBD) and controls (healthcare professionals).

They reported that those diagnosed with CD before implementation of a gluten-free diet had "significantly higher scores than healthy controls" in relation to the presence of self-reported ADHD and depression/anxiety symptoms. Further: "After a gluten-free diet, their scores improved and were not significantly different from healthy controls." That gluten-free diet by the way, was in place for a minimum of 12 months.

One has to be careful not to make too many sweeping generalisations from the Kristensen data. The data do not, for example, mean that all cases of ADHD are somehow the product of undiagnosed coeliac disease. Not even close. What do they do (cautiously) suggest, is that preferential screening for something like coeliac disease *might* be a good idea as and when ADHD is diagnosed or significant ADHD-like symptoms present. Such findings also resonate with the idea that certain dietary interventions to manage *some* ADHD could be a research area to consider (see here) and bring into play an interesting concept: the gut-brain axis.

Oh, and in case you were wondering about the 'Roger Moore's eyebrows' bit, well, he was the best James Bond wasn't he?

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[1] Kristensen VA. et al. Attention deficit and hyperactivity disorder symptoms respond to gluten-free diet in patients with coeliac disease. Scand J Gastroenterol. 2019 May 3:1-6.

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Probiotics for autism systematically reviewed

"Our review includes two randomized controlled trials, which showed improvement of ASD [autism spectrum disorder] behaviors, and three open trials, all which exhibited a trend of improvement."

So said the findings reported by Jun Liu and colleagues [1] and the results of their "updated systematic review" on the topic of probiotic 'therapy' in the context of behaviour and gastrointestinal (GI) functioning in autism.

The current scientific outlook for probiotic use in the context of autism looked to be pretty good on the basis of the Liu findings. They corroborate quite a few individual study results that have been fodder for this blog (see here and see here) and fit in well with an emerging pattern of research suggesting that the trillions of wee beasties that inhabit the gastrointestinal (GI) tract might be doing a lot more than just helping us digest food (see here and see here).

What else is required? Well Liu et al talk about more "rigorous trials" to answer questions like who on the autism spectrum might be a best responder to this type of intervention and what bacterial species might be most important. I'd also like to see a little more research on the hows-and-whys of such intervention (see here for example) and whether probiotics are as harmless as many have made them out to be.

Still...

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[1] Liu J. et al. Probiotic Therapy for Treating Behavioral and Gastrointestinal Symptoms in Autism Spectrum Disorder: A Systematic Review of Clinical Trials. Curr Med Sci. 2019 Apr;39(2):173-184.

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

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

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

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

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

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

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

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

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

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On gut bacteria and schizophrenia

Hot on the heels of my discussions about the possible *association* between gut bacteria and depression (see here), the results published by Peng Zheng and colleagues [1] (open-access) entered my Twitter feed recently, extending the gut bacteria 'connection' to schizophrenia.

The Zheng study represents yet more good scientific value for money as researchers initially sought to "compare the gut microbial communities of patients with SCZ [schizophrenia] and healthy controls (HCs) to evaluate whether microbiotal dysbiosis was linked with schizophrenic episodes or the severity of schizophrenic symptoms." They also "transferred gut microbiota from patients with SCZ into GF [germ free] mice to test whether SCZ-relevant behavioral phenotypes were transmissible via their gut microbiome". The study findings have been covered quite a few media outlets (see here).

The results: "seminal evidence that SCZ is associated with changes in gut microbiota composition that are both specific to SCZ and correlated with symptom severity." This translated into:

• reduced (alpha) microbial diversity in those with schizophrenia (n=63) compared with "healthy controls" (authors words not mine),
• the identification of certain bacterial differences between the groups: "the most significant deviations between SCZ and HC subjects occurred for the bacterial families Aerococcaceae, Bifidobacteriaceae, Brucellaceae, Pasteurellaceae, and Rikenellaceae",
• a *correlation* between the presence of some bacterial species and the 'severity' of symptoms of schizophrenia,
• behavioural changes in those mice who received a gut bacterial transplant from participants with schizophrenia,
• "Perturbed gut-brain amino acid and lipid metabolism in SCZ microbiota recipient mice." Gut bacteria produce chemicals (for messaging and the like), and those bacteria transplanted into germ-free mice produced a different cocktail of chemicals that showed up "in the SCZ microbiota compared to the HC microbiota recipient mouse samples." In particular: "lower glutamate and higher glutamine and GABA in the hippocampus."

As I said, the Zheng study was pretty good value for money on the basis of the results obtained. The authors note that their findings "provide a novel framework for understanding the mechanisms of SCZ through the MGB [microbiota-gut-brain] axis and may lead to new diagnostic and treatment strategies."

Caveats? Well, fairly small participant numbers is one thing, as was the potential influence of medication being taken by those with schizophrenia. Authors however mention that: "we found that the distributions of global microbial phenotypes did not vary between medicated and unmedicated patients with SCZ." I'll also point out the inherent 'difficulties' when talking about "SCZ-relevant behaviors in GF recipient mice" similar to that noted with regards to other diagnostic labels (see here). People are given labels like schizophrenia not mice.

But it's a good start and complements other work in 'related' areas talking about the gut-brain axis as being potentially pertinent to 'some' schizophrenia (see here and see here). Whether modifying gut bacteria via use of something like diet, probiotics or the horror that is the gut microbial transplant might relieve some of the signs and symptoms of schizophrenia is an area that requires quite a bit more investigation...

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[1] Zheng P. et al. The gut microbiome from patients with schizophrenia modulates the glutamate-glutamine-GABA cycle and schizophrenia-relevant behaviors in mice. Science Advances. 2019; 5: 2.

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On gut bacteria and depression

I'm kinda standing on the shoulders of giants with this post talking about the findings reported by Mireia Valles-Colomer and colleagues [1]. An editorial published in Nature [2] to coincide with the publication of the Valles-Colomer paper says just about everything that needs to be said on this research, which observed that: "Gut–brain module analysis of faecal metagenomes identified the microbial synthesis potential of the dopamine metabolite 3,4-dihydroxyphenylacetic acid as correlating positively with mental quality of life and indicated a potential role of microbial γ-aminobutyric acid production in depression." Yes folks, the idea that "microorganisms in the human gut could influence the brain" is moving from 'wild idea' to "wise pursuit".

The sequencing of DNA from donor stool samples as part of the Flemish Gut Flora Project ('You too are a walking bacteria colony' is the strap line) was the starting point for the Valles-Colomer study; stool samples provided by over 1000 participants. Researchers also accessed data on both self-reported and "physician-diagnosed depression" and set to work looking for any potentially important correlates between bacteria and psychology. The words "with validation in independent data sets (ntotal = 1,070)" are also (importantly) mentioned in the Valles-Colomer paper. Oh, and they also "mined the data to generate a catalogue describing the microbiota’s capacity to produce or degrade molecules that can interact with the human nervous system."

Results: "Butyrate-producing Faecalibacterium and Coprococcus bacteria were consistently associated with higher quality of life indicators." There's that word again: butyrate and yet more positive publicity for this compound (see here) and it's standing reaching almost 'bacterial sainthood'. Researchers also observed that two groups of bacteria were also reduced in those with depression: Coprococcus and Dialister alongside observing that this finding held "even after correcting for the confounding effects of antidepressants [use]." And then there was that 3,4-dihydroxyphenylacetic acid, also called DOPAC, finding, a metabolite of the neurotransmitter dopamine. I have actually mentioned DOPAC before on this blog (see here) in relation to what happens when rats are subjected to 'early immune stimulation' [2]. I don't think there is much overlap between that rat study and the Valles-Colomer paper (that rat paper was looking at DOPAC levels in brain tissue for example) but the suggestion from the authors that DOPAC levels were "correlating positively with mental quality of life" requires quite a bit more investigation.

Caveats? Well, out of their initial 1054 participant cohort, only 121 participants had "GP-reported depression." About half of these participants were taking antidepressants for their depression, the others weren't. The participant numbers aren't exactly tremendous for this portion of the study. Similar to something mentioned in other research (see here), I'm also minded to suggest that future research might perhaps consider looking at multiple stool samples taken over different occasions for the same person. This would perhaps establish whether gut bacterial populations are stable and whether that stability translates into stability of something like depressive symptoms too. I am likewise cautious that we don't jump ahead of ourselves here in terms of important issues like cause-and-effect and for example; whether there may be other important 'influencers' of gut bacteria when it comes to depression (see here and see here).

Lots more study is required on the suggestion of a gut bacterial *link* to depression [3], including that focused on the mechanics of any relationship (e.g. any involvement of the vagus nerve). If the link is further established, there are a number of potentially important implications: the possibility of a 'bacterial transferability hypothesis of [some] depression' (see here), intervention options focused on redressing balance in bacterial colonies (see here) and what such findings might do for the whole 'gut-brain axis' idea.

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[1] Valles-Colomer M. et al. The neuroactive potential of the human gut microbiota in quality of life and depression. Nature Microbiology. 2019. Feb 4.

[2] Editorial. Links between gut microbes and depression strengthened. Nature. 2019. Feb 4.

[3] Cheung SG. et al. Systematic Review of Gut Microbiota and Major Depression. Front Psychiatry. 2019;10:34.

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Elevated zonulin levels in ADHD = more hyperactivity and "impairment of social functioning"

"Children with ADHD [attention-deficit hyperactivity disorder] had higher serum zonulin levels and were more impaired in social functioning compared to controls."

So said the findings reported by Gonca Özyurt and colleagues [1] exploring a topic quite close to my research heart, zonulin and the assumption that "the level of zonulin increases when intestinal permeability is impaired."

Before heading further into the Özyurt findings, I'll perhaps refer you to some of my previous musings on the topic of zonulin (see here) and the hows-and-whys of this potentially important compound. It's rooted in the idea that intestinal permeability is perhaps rather more than it should be in some people with some labels (see here) and this *could* have some important implications for biochemistry and beyond; particularly the notion of a 'gut-brain' relationship (see here).

Özyurt et al examined zonulin in the context of attention deficit hyperactivity disorder (ADHD) based on the idea that: "Zonulin has been shown to be associated with social impairment in children with autism spectrum disorder" but such functions (and other attention-related behaviours) have not yet been looked at with ADHD in mind. Based on the examination of serum zonulin levels in some 40 kids diagnosed with ADHD and a similar number of not-ADHD controls, analysed via "enzyme-linked immunosorbent assay", researchers reported that: "Children with ADHD had higher serum zonulin levels and were more impaired in social functioning compared to controls." Also: "The level of zonulin was independently predicted with hyperactivity symptoms and SRS [Social Responsiveness Scale] scores in regression analysis."

Bearing in mind that the Özyurt study was a fairly small scale study that utilised a methodology that has its critics (see here), I'm cautiously interested in the presented findings. I don't want to say anything further about this at the present time; aside that is, from the need for quite a bit more data on this potentially interesting relationship...

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[1] Özyurt G. et al. Increased zonulin is associated with hyperactivity and social dysfunctions in children with attention deficit hyperactivity disorder. Compr Psychiatry. 2018 Oct 29;87:138-142.

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Open label study of probiotics and autism

"We concluded that probiotics have beneficial effects on both behavioral and GI [gastrointestinal] manifestations of ASD [autism spectrum disorder]."

So said the study results published by Sanaa Shaaban and colleagues [1] detailing observations from their "prospective, open-label study" following some 30 children diagnosed with an autism spectrum disorder (ASD) before and after 3 months of probiotic usage. The study details were posted in a clinical trials repository (see here) and note how various measurements were taken as participants took a preparation containing "100 × 106 colony forming units of three probiotic strains; Lactobacillus acidophilus, Lactobacillus rhamnosus and Bifidobacteria longum."

Including some notable authors on the paper who are seemingly not adverse to [scientifically] examining some of the more non-traditional interventions put forward with autism in mind (see here and see here), researchers caution about their latest findings. So: "this study is a single center with a small number of patients and a great deal of additional wide-scale randomized controlled trials are needed to critically confirm the efficacy of probiotics in ASD." Yes, indeed; blinding for example, is a rather important part of the scientific process and other studies 'in progress' have adopted such factors (see here). Set against a growing tide of research suggesting that those trillions of wee beasties that inhabit our deepest, darkest recesses (the gut microbiome) might have more than a passing connection to some autism - some aspects of autism - this area of study is crying out for quite a bit more attention (see here also) not least on hows-and-whys (see here). The way that someone might potentially 'impact' on the gut microbiome in a probiotic sense is also potentially important (see here).

I have only one further point to make about the Shaaban results in relation to the observations that behavioural signs and symptoms (as assessed by the ATEC) seemed to show a relationship with GI symptoms following probiotic use. I'm wondering whether this potential tie-up might learn something from work looking at probiotic use in something like irritable bowel syndrome (IBS) (see here) and onward what happens to psychiatric issues that are seemingly over-represented in cases of IBS (see here). I say that on the basis that bowel issues seem to be most definitely over-represented when it comes to a diagnosis of autism (see here) and the whole 'gut-brain axis' thing continues -across decades - to persist with autism in mind (see here)...

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[1] Shaaban SY. et al. The role of probiotics in children with autism spectrum disorder: A prospective, open-label study. Nutr Neurosci. 2017 Jul 7:1-6.

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Irritable bowel syndrome (IBS) as a risk factor for bipolar disorder

"Only irritable bowel syndrome (IBS) emerged as a risk factor for BD [bipolar disorder] supported by convincing evidence."

So said the results of the umbrella review of systematic reviews and meta-analyses by Beatrice Bortolato and colleagues [1] looking at the various environmental risk factors potentially linked to the diagnosis of bipolar disorder. I might add that this is a topic that has been discussed before on this blog (see here and see here for examples).

If the systematic review / meta-analysis represents the top of the research methodology hierarchy, a review including a number of systematic reviews and meta-analyses represents the cherry on top. Indeed, there is a growing trend of this kind of research (see here).

The authorship names included on the Bortolato paper are not unfamiliar to this type of study methodology (see here) and specifically, the focus on psychiatric and somatic variables often being intertwined. This time around attentions turned to bipolar disorder, previously called manic depression, and a survey of 16 research publications identified listing over 50 "unique environmental risk factors for BD." The report of a possible link (with 'convincing evidence') between IBS and BD consolidates the idea of a gut-brain axis. Authors also detailed a few other factors as showing weaker but not necessarily less important connections to BD including childhood adversity, obesity and asthma. Focusing in on asthma in particular - a condition again previously talked about in the context of BD - I am wondering whether there are quite a few more generalisations connected to this diagnosis within the context of psychiatric labels (see here and see here)?

Of course, more science is indicated on the hows-and-whys of connections such as the one between IBS and BD and the tantalising prospect of new intervention avenues if such a relationship is further confirmed. Minus any medical or clinical advice, I'm specifically thinking about how alterations to the gut microbiome accompanying cases of IBS might mean that talk of things like probiotics affecting the symptoms of IBS (see here) could be applicable to the presentation of [some] BD too. That and the idea that certain dietary elements might also be important to cases (see here and see here)...

To close, I know that the past few days have not exactly been ones for smiling, but if some smiles and laughter are what you need, then the animal kingdom can provide them...

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[1] Bortolato B. et al. Systematic assessment of environmental risk factors for bipolar disorder: an umbrella review of systematic reviews and meta-analyses. Bipolar Disord. 2017; 00: 1–13.

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Bortolato, B., Köhler, C., Evangelou, E., León-Caballero, J., Solmi, M., Stubbs, B., Belbasis, L., Pacchiarotti, I., Kessing, L., Berk, M., Vieta, E., & Carvalho, A. (2017). Systematic assessment of environmental risk factors for bipolar disorder: an umbrella review of systematic reviews and meta-analyses Bipolar Disorders DOI: 10.1111/bdi.12490

Intestinal dysbiosis, irritable bowel syndrome and ME/CFS

I don't want to spend too much time talking about yet another paper from the research tag-team that is Hornig & Lipkin [1] (open-access) on the topic of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). But this latest addition to their research repertoire (see here) is deserving of several comments.

Not least are the observations made by the authors - including one Brent Williams who some might remember from autism research history (see here) and Jose Montoya who has also made a mark in CFS/ME research circles (see here) - on how the collected wee beasties that inhabit our gastrointestinal (GI) tract might have some role to play when it comes to at least some cases of CFS/ME. Yes it's gut microbiome research time again.

The press release accompanying the paper by Dorottya Nagy-Szakal and colleagues can be seen here. The long-and-short of it was that: "Independent of IBS [irritable bowel syndrome], ME/CFS is associated with dysbiosis and distinct bacterial metabolic disturbances that may influence disease severity." Further: "Plasma cytokines did not define ME/CFS disease groups in our cohort." There could be some good reasons for that last sentence looking at immune-related molecules on the basis of other study results (see here) but further investigations are required.

I have to say that outside of the observations that particular types of bacteria seem to be more or less prevalent in cases of CFS/ME (yet again) I was rather more interested in the finding that over 40% of the cohort also met criteria for IBS. I say that on the basis that I've already talked about 'abdominal discomfort syndrome' as a feature of some CFS/ME (see here) alongside findings that certain foods *might* also play a role in the bowel symptoms accompanying CFS/ME (see here).

In these days of increasing pluralisation of spectrums (the autisms, the schizophrenias, etc) it is probably also quite useful to think about pluralising the diagnostic label CFS/ME too. Assuming we can get the diagnostic criteria right (see here) we could have a phenotype of CFS/ME that, for example, has a stronger bowel-related clinical signature than other forms. The further implications that the GI tract might play a role in CFS/ME in relation to either primary or secondary symptoms might also inform intervention. So, we kinda know that use of probiotics might be something to think about for some cases of IBS (see here). There is also some preliminary evidence that certain probiotics might also impact on some of the 'psychological' features (careful with that term) which can accompany CFS/ME [2]. The possibility of connections exist and therefore require further scientific exploration.

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[1] Nagy-Szakal D. et al. Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome. 2017; 5: 44.

[2] Rao AV. et al. A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome. Gut Pathog. 2009 Mar 19;1(1):6.

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Nagy-Szakal D, Williams BL, Mishra N, Che X, Lee B, Bateman L, Klimas NG, Komaroff AL, Levine S, Montoya JG, Peterson DL, Ramanan D, Jain K, Eddy ML, Hornig M, & Lipkin WI (2017). Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome, 5 (1) PMID: 28441964

A poo transplant for [some] autism?

I've talked about 'fecal microbial transplants' a.k.a the poo(p) transplant before on this blog (see here). That previous entry was about the more typical (and potentially life-saving) use of a poo transplant - where stool from one person is extracted, 'repackaged' and transferred to another person - albeit with caveats in terms of possible long-term side-effects. Now it appears that poo transplants are being investigated with something rather more central to the typical contents of the blog...

The paper by Dae-Wook Kang and colleagues [1] (open-access) has already been picked up by some media (see here) and it seems, also has a following from likely proponents and detractors particularly on social media. Including one James Adams on the authorship list, someone who is quite well-known in autism research circles (see here and see here for examples) alongside some other notable inclusions (Alessio Fasano, Thomas Borody, etc), the authors describe the results of small open-label study - I repeat, a small open-label trial - of 18 participants diagnosed with an autism spectrum disorder (ASD) who underwent a 10-week program characterised by the use of antibiotics, a bowel cleanse and then regular poo transplants for approximately 8 weeks. Additional information about the study and its results can be found here or if you wish, you can see the ClinicalTrials.gov entry here.

Tapping into a growing interest in how the gut (and its contents) might be important for at least some autism (see here for example) the aims of the trial were to "follow gut microbiota in healthy and treated children with ASD longitudinally as well as to evaluate an investigational new treatment, MTT [Microbiota Transfer Therapy], for its effectiveness in children with ASD in treating both GI [gastrointestinal] symptoms (primary outcome) and ASD-related symptoms (secondary outcomes), and to determine the effect of MTT on the gut microbiome."

The study included children diagnosed on the autism spectrum - ADI-R diagnosed - aged between 7-16 years old. All presented with moderate to severe functional bowel issues alongside their autism (something not unusual it seems). The authors also report using a control group of "20 age- and gender-matched neurotypical children without GI disorders" who were monitored but not treated as part of their study design.

The study first involved the administration of the antibiotic vancomycin for 2 weeks (something that has, on its own, some peer-reviewed research history with autism in mind [2]) used to 'profoundly suppress' pathogenic bacteria. Prilosec, the brand name for omeprazole was also administered towards the end of the bacterial washout phase initiated by the use of vancomycin. Prilosec is a medicine traditionally used to suppress stomach acid secretions and was used to "remove most remaining gut bacteria and vancomycin" and aid the passage and survival of the donor stool to the wider gastrointestinal (GI) tract. I say all that knowing that such medicines can affect the composition of the gut microbiota. Then came the bowel cleanse (Moviprep) complete with a fasting from food day, followed by the main [research] event: oral or rectal administration of donor stool and an initial high dose followed by maintenance doses. I know some people might be slightly uncomfortable with the idea of the rectal administration of medicines but there are some common-sense reasons behind this form of medicines delivery particularly where oral dosage forms (tablets, capsules) might not be well tolerated. As for the initial oral dosage form: "the participants began either oral administration of SHGM [Standardized Human Gut Microbiota] (2.5 × 1012 cells/day) mixed in a chocolate milk, milk substitute, or juice for 2 days (divided into three daily doses)." I have to say that whilst I initially envisaged Austin Powers and his 'tastes a bit nutty' scene, this was very much NOT how things actually were.

Alongside the donor stool formulation being trialled predominantly with regards to safety and initial efficacy, researchers also surveyed participants in relation to (i) effects on their gut microbiota (diversity and species present), (ii) the presentation of bowel symptoms/habits and (iii) behavioural outcomes covering autism-specific issues (via the CARS) and more general adaptive behaviours (via the Vineland scales for example). I was also happy to see a section included in their paper labelled 'virome bioinformatics' hat-tipping the idea that gut bacteria are not the only passengers we carry in our deepest, darkest recesses.

Results: well something certainly seemed to happen when looking at before, during and after results of this case series trial. First and foremost adverse effects were small and limited (hyperactivity, irritability) meaning that in the short term at least, the poo transplants and pre-poo transplant protocols were tolerated quite well. This is also evident in the 0% study attrition rate (i.e. everyone who started the study stayed in the study).

So: "Substantial changes in GI and ASD symptoms were observed. GI symptoms, as assessed by the GSRS [Gastrointestinal Symptom Rating Scale], significantly improved for abdominal pain, indigestion, diarrhea, and constipation." The authors report some significant differences in scores over the course of the intervention period such that: "The average GSRS score dropped 82% from the beginning to end of the treatment and remained improved (77% decrease from baseline) even 8 weeks after treatment stopped." That is a helluva placebo effect! Indeed, only 2 participants from the cohort were classified as 'non-responders' on the basis of their GSRS scores over the course of the study.

Also: "Beyond these GI improvements, ASD-related behavior also improved following MTT." The sorts of changes to CARS scores being reported were in the region of a 20% reduction in 'core ASD' symptoms at 8 weeks compared to baseline reports. Further, 8 weeks after the intervention had been completed the behavioural gains ("relative to baseline") were still evident based on CARS scoring. These ratings also did not depend on whether the poo transplant was administered orally or rectally.

The authors also discuss some not unexpected changes to gut bacterial profiles in their cohort over the intervention period. At baseline: "gut bacteria were significantly less diverse in children with ASD than neurotypical controls." This finding is in line with other study results from the authors (see here). Bacterial diversity did (slowly) change over the intervention period to a point where at 18 weeks after baseline median richness "was statistically indistinguishable between the ASD and control groups." This was noted in 16 of the 18 participants with ASD.

Finally: "Specific genera that significantly changed in their relative abundances with treatment included Bifidobacterium, Prevotella, and Desulfovibrio." The authors have chosen to zoom in on Prevotella as a consequence of their results - "the increase in the relative abundance of Prevotella after MTT is consistent with their potentially beneficial role in the gut of children with ASD" - but I'd like to see a little more work done on this before any grand claims are made. As to the virome/phage side of things: "phage richness and evenness did not significantly change following MTT given the timeframe of this study" so again, there is more science needed in this area too as to hows and why (nots).

OK, I think it is worth stressing again that this was an open-label study not a gold-standard, double-blind, randomised-controlled trial or anything like that. What this means is that these results are preliminary - very preliminary - and although quite promising, need scientific follow-up for a longer period. Whilst such results are seemingly pretty good evidence for the whole 'gut-brain axis' thing with regards to autism (see here) there are still questions that need answering, not least with regards to possible mechanisms linking gut bacteria changes to behaviour changes. Do these results, for example, point to some role for intestinal permeability changes given what is already being said about 'leaky gut' in the context of [some] autism (see here) and the growing interest in a relationship between gut bacteria and gut barrier integrity? How do gut bacteria 'communicate' with the grey-pink matter floating in the skull? Questions aplenty there be. There is also a certain degree of 'yuck factor; to contend with as a result of the use of a poo transplant in this context and what this might mean for future trials and possible 'rolling out' of such an intervention assuming effectiveness is confirmed. I can just see the headlines now...

But I don't want to take anything away from these novel findings and [with caveats] the significance of the results. When one considers how many people on the autism spectrum are suffering (yes, suffering) with bowel complaints, whether functional or something rather more pathological (see here), efforts to reduce pain and any additional burden they bring should be welcomed from wherever they emerge...

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

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Kang, D., Adams, J., Gregory, A., Borody, T., Chittick, L., Fasano, A., Khoruts, A., Geis, E., Maldonado, J., McDonough-Means, S., Pollard, E., Roux, S., Sadowsky, M., Lipson, K., Sullivan, M., Caporaso, J., & Krajmalnik-Brown, R. (2017). Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study Microbiome, 5 (1) DOI: 10.1186/s40168-016-0225-7

Gut barrier integrity meets blood-brain barrier integrity with autism in mind

"In the ASD [autism spectrum disorder] brain, there is an altered expression of genes associated with BBB [blood-brain barrier] integrity coupled with increased neuroinflammation and possibly impaired gut barrier integrity."

Although pretty enthused to see research linking names like Anna Sapone, Tim Buie and Alessio Fasano in the recent paper published by Maria Fiorentino and colleagues [1] (open-access), I was slightly less impressed with the use of the term 'the ASD brain' in their paper potentially joining two concepts that I've been quite interested in down my research years: gut barrier and blood-brain barrier function in the context of autism. Yes, I accept that those most precious of resources, donated brains from the deceased, represented some of the 'material' under scientific scrutiny, but if science has learned anything about autism down the years, it is that sweeping generalisations such as terms like 'the autism brain' don't reflect what the existing research tells us about the heterogeneity under the label. I might just as well use the term 'blogger brain' to denote some of my activities, but such a label tells you nothing about me aside from my pastime.

After that little rant, the paper from Fiorentino is an interesting one in that the goal was to "investigate whether an altered BBB and gut permeability is part of the pathophysiology of ASD." To do this, tissue from both brain and gastrointestinal (GI) tract donated by a small number of deceased and non-deceased participants who were diagnosed with autism, schizophrenia or nothing related (not-autism controls) were analysed "for gene and protein expression profiles." This work was undertaken on the basis of "the interconnectivity of the gut–brain axis, [that] suggests that inappropriate antigen trafficking through an impaired intestinal barrier, followed by passage of antigens or activated immune complexes through a permissive blood–brain barrier (BBB), can be part of the chain of events leading to neuroinflammation and thereby subsequent disease." I might add that the use of the word 'disease' in that sentence is, I think, aiming to describe the physiological effects of 'leaky barriers' not the diagnosis of autism. It is unfortunate however that 'disease' still continues to be banded around in the context of autism [2].

I think it's important to stress that the Fiorentino study was in effect two studies: one that looked at brain samples from one participant group who had died, and one that looked at GI samples from those who were still living (at the time of sample collection) and who presented with "GI symptoms undergoing esophagogastroduodenoscopy (EGD) for clinically indicated reasons." This was not a study where biological samples - brain and gut - came from the same person but rather a mash-up. Keep that in mind for now. The sorts of genes that were focused in on were those "associated with the formation, integrity, and function of the BBB and neuroinflammation" and included the claudins and something called MMP-9 and MMP-2 that have been discussed previously on this blog (see here) with leaky barriers in mind. The key words are 'barrier integrity' when it comes to the list of compounds that were under inspection.

Results: well it was good to see the authors list details of each of the participants from which tissue were used in their study. Brain tissue from the deceased with autism for example, is subject to quite a few factors that can influence the outcome of any results obtained; not least whether specific comorbidity accompanied their autism diagnosis and the nature of their death. Indeed, looking through the various case report numbers, I'm struck by how young many participants, particularly those diagnosed with autism, were at the time of their death. This ties into other discussions and debates (see here).

"Our molecular analysis of the BBB integrity and function shows an altered BBB in the ASD subjects evaluated." This was evidenced by elevations in the gene expression of MMP-9 and its proposed connection to disturbances of BBB integrity. Further: "Of the four claudins (i.e., CLDN-1, -3, -5 and -12) that to date are thought to be incorporated in the BBB... we found that two were significantly more expressed in the ASD brain as compared in HC [healthy controls]." Once again I might suggest the term 'healthy controls' is not an inappropriate one when it comes to determining not-autism or not-schizophrenia.

Then to analysis of those [independent] gut biopsy samples: "results, showing increased expression levels of pore-forming (66% of the ASD samples) and decreased levels of barrier-forming (75% of the ASD samples) TJ [tight junction] components in the duodenal samples, suggest an impaired gut barrier and serve as a proof of concept to support the hypothesis of a gut–brain axis dysfunction in a subgroup of ASD patients." So, those compounds linked to making the gut barrier more 'leaky' were seemingly increased in expression, and those linked to making the gut barrier less 'leaky' were reduced in quite a few of the samples from those diagnosed with autism. Mmm...

There is quite a bit more science included in the Fiorentino study but I think I've gone on long enough in this post. Suffice to say that the whole gut-brain axis thing with autism in mind gets a boost but more work is indicated, not least with larger sample groups and perhaps combining tissues from gut and brain from the same person. I would also like to see a little more done on this topic with some 'interventions' in mind, based on the other autism research that potentially links the authors (see here). Drawing for example, on a paper written by Prof Fasano titled: 'Zonulin, regulation of tight junctions, and autoimmune diseases' [3] suggesting that "gliadin, a storage protein present in wheat and that triggers celiac disease in genetically susceptible individuals, also affect the intestinal barrier function by releasing zonulin" one might see how far from being a set-in-stone state of affairs, dietary changes for some on the autism spectrum, might actually set in motion a host of biological changes pertinent to this area of work. And such changes might not be just confined to accepted gluten-related conditions either...

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[1] Fiorentino M. et al. Blood–brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders. Molecular Autism. 2016; 7:49.

[2] Simms MD. When Autistic Behavior Suggests a Disease Other than Classic Autism. Pediatr Clin North Am. 2017 Feb;64(1):127-138.

[3] Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. Annals of the New York Academy of Sciences. 2012;1258(1):25-33.

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Fiorentino, M., Sapone, A., Senger, S., Camhi, S., Kadzielski, S., Buie, T., Kelly, D., Cascella, N., & Fasano, A. (2016). Blood–brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders Molecular Autism, 7 (1) DOI: 10.1186/s13229-016-0110-z

Non-febrile seizures in children with autism vs unaffected siblings

"Children with idiopathic ASD [autism spectrum disorder] are significantly more likely to have non-febrile seizures than their unaffected siblings, suggesting that non-febrile seizures may be ASD-specific."

So said the findings from Lena McCue and colleagues [1] (open-access) continuing a research theme looking at one of the important 'comorbidities' that seems to be over-represented when it comes to a diagnosis of autism (see here). Idiopathic autism or ASD refers to autism as the primary diagnosis and not something tied to an existing condition where autism can also present. Non-febrile seizures are seizures without fever (where fever can very much result in seizures).

McCue et al "conducted a secondary analysis of data from a registry-based retrospective cohort study of 731 children with ASD and their 192 children unaffected siblings from the AGRE project for whom phenotypic data were collected." Data from around 320 families with at least one child diagnosed with an ASD (n=610) were compared with sibling data (n=160) in relation to the presence of non-febrile seizures. Siblings (not autism) were chosen as the control group because "siblings share, on average, fifty percent of genes as well as the same environment" so perhaps providing an alternative to just general population control groups.

Results: "The prevalence of non-febrile seizures in the ASD group was 8.2% (50/610) and 2.5% in the unaffected siblings (4/160)." What this tells us, aside from the increased frequency of non-febrile seizures in those children diagnosed with autism, is that so-called 'unaffected' siblings are not completely immune to seizures or seizure-linked conditions minus fever. Further: "the odds of having non-febrile seizures increased with age..., presence of GI [gastrointestinal] dysfunction..., and those with a history of febrile seizures had five times the odds of reporting non-febrile seizures."

I was particularly interested in the observations that: (a) gastrointestinal (GI) dysfunction, denoting functional bowel issues such as constipation or diarrhoea, were pretty well over-represented among the children with autism in this cohort, similar to other research (see here) and (b) said GI issues might itself/themselves 'up' the risk of non-febrile seizures in relation to autism. In these days of the 'gut-brain axis' where the grey/pinkish matter floating in the skull might not be totally separate and independent from the more mucus-y matter situated in the torso (see here for example), it strikes me as important that further investigations be carried out on how epilepsy might not just be a 'brain-thing'. We have for example, evidence pertinent to an autoimmune connection to some epilepsy (see here) that has implications for other autoimmune conditions affecting the gut too as per the notion that 'birds of an autoimmune feather may flock together'. That also one of the primary 'treatments' for epilepsy not responsive to the usual anti-epileptic medicines is the ketogenic diet (see here) is something else to consider when talking about gut and brain potentially being quite close neighbours.

"Our study found a five-fold higher lifetime prevalence of non-febrile seizures in children with idiopathic ASD from largely multiplex families compared to their unaffected siblings. These findings suggest that the reported non-febrile seizures may be ASD-specific and cannot be explained by genetic predisposition alone." With that conclusion from the study authors, one might similarly also suggest that the presence of autism in affected children vs. siblings also cannot be explained by genetic predisposition alone...

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[1] McCue LM. et al. Prevalence of non-febrile seizures in children with idiopathic autism spectrum disorder and their unaffected siblings: a retrospective cohort study. BMC Neurology. 2016; 16:245.

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McCue, L., Flick, L., Twyman, K., Xian, H., & Conturo, T. (2016). Prevalence of non-febrile seizures in children with idiopathic autism spectrum disorder and their unaffected siblings: a retrospective cohort study BMC Neurology, 16 (1) DOI: 10.1186/s12883-016-0764-3

Bifidobacterium longum 1714 attenuates stress?

It's been quite a week hasn't it? Indeed for quite a few people it's been a stressful few days so perhaps timely that I'm talking about the 'attenuation of stress' in today's post.

Despite the relatively small sample size included in the paper by by AP Allen and colleagues [1] there is something rather tantalising about their results suggesting that in healthy volunteers "consumption of B. longum [Bifidobacterium longum 1714] 1714 is associated with reduced stress and improved memory."

Tantalising because as well as further directing research attention towards the important relationship that is the gut-brain axis (see here for another example) the findings provide initial support for the concept of "psychobiotics—live microorganisms with a potential mental health benefit" set within a human (not mouse) context.

The Allen paper (who incidentally is on Twitter) is open-access and has previously provided signs that it was to be published (see here). Here are a few choice details:

Take 22 (male) volunteers aged between 18 and 40 years of age who fitted various inclusion/exclusion criteria including no "self-report habitually taking any probiotic products" and ask them to take B. longum 1714 for 4 weeks after giving them a placebo preparation containing just maltodextrin and magnesium stearate and no probiotic for 4 weeks. Deliver various physical, psychometric and self-report questionnaires/tests at various intervals covering things like the "Socially evaluated cold pressor procedure" (SECPT) and other measures and see how things pan out according to placebo/psychobiotic use and after "a 2-week post-probiotic follow-up."

Results: well, as per the opening paragraph of this post, there did seem to be some effects to be had potentially associated with B. longum administration. So, when it came to that 'put your hand in cold water' test (SECPT), participants as a group lasted slightly longer in the cold water than on previous testing occasions. When researchers looked at salivary cortisol levels (a measure of psychological stress) following this acute stress test, they observed some potentially important differences between the initial (baseline) test, the period covering placebo use and the period covering the psychobiotic use. This accompanied some differences in reported state anxiety. Such acute stress findings were also complemented by some subtle but potentially important differences in self-reported daily stress levels (lower) following the period of psychobiotic use (something that "returned to a higher level during the 2-week follow-up period"). The authors also report on some findings associated with testing cognition across the various phases of the study but I'm gonna stay focused on the stress part of things for now before anyone moves towards describing B. longum 1714 as some sort of nootropic of choice just yet.

Of course there is still much to do in this area before anyone gets too carried away with things (how about a few more blinded RCTs pitting placebo against psychobiotic?) but the results are interesting. You could argue that there may have been some influence of practice effects associated with some of the results given the short timescales but I'm gonna take the findings at face-value. More so when when set in the context of other microbial preparations also potentially dealing with certain types of stress under experimental conditions (see here for example).

Mode of action? Well, the authors mention the 'vagus nerve' as potentially being important given the suggestion of a connection between the trillions of wee beasties that populate our gut (the gut microbiota) and brain function(s). The specifics however are yet to be decided upon; and it is also worth noting that as part of the probiotic formulation called VSL#3, B. longum 1714 might have some important 'bowel' effects as per other findings (see here) onwards to behaviour(s) and labels (see here). I'm also intrigued by the finding that post-probiotic there was a suggestion of a waning of some of the previously reported effects implying that far from probiotics being accepted and 'assimilated' into our collected gut microbiota, there may be mechanisms at work tied to going back to the status quo.

"Further studies are warranted to evaluate the benefits of this putative psychobiotic in relevant stress-related conditions and to unravel the mechanisms underlying such effects." Wise words before anyone makes a run on B. longum 1714 or any related preparations but this is an interesting piece of research. Given also the so-far relatively good safety profile of various probiotics, there is an important argument for experimentally testing such stress relief and/or cognition-aiding properties under a wide range of contexts.

To close, we lost another one in 2016. There must be a helluva party going on upstairs...

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[1] Allen AP. et al. Bifidobacterium longum 1714 as a translational psychobiotic: modulation of stress, electrophysiology and neurocognition in healthy volunteers. Translational Psychiatry. 2016; 6: e939.

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Allen AP, Hutch W, Borre YE, Kennedy PJ, Temko A, Boylan G, Murphy E, Cryan JF, Dinan TG, & Clarke G (2016). Bifidobacterium longum 1714 as a translational psychobiotic: modulation of stress, electrophysiology and neurocognition in healthy volunteers. Translational psychiatry, 6 (11) PMID: 27801892