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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Paediatric Acute-onset Neuropsychiatric Syndrome (PANDAS) misdiagnosed as autism: some implications

Credit: BBC Website 25 January 2019

The BBC website recently ran with an interesting story headed under the title: "Mother's appeal after boy diagnosed with autism when he just needed antibiotics." It was an interesting piece that drew attention once again to an increasingly important condition known as Paediatric Acute-onset Neuropsychiatric Syndrome (PANDAS) also called PANS.

Classically triggered by Streptococcal infections, PANDAS/PANS is typically characterised by quite an abrupt change in behaviour to include things like "clinically significant obsessions, compulsions and/or tics" alongside things like anxiety, sensory issues, aggression and a corresponding loss of academic abilities. Treatment is often multi-disciplinary; but in the most part intervention includes the use of various types of antibiotics clinically indicated to treat strep infections. This also follows a wider research-based thread suggesting that strep infections *might* have some important links to various neuropsychiatric conditions (see here).

The BBC piece specifically focused on how the young boy highlighted was "repeatedly diagnosed as having autism and severe anxiety" and how following a PANDAS diagnosis, and after just two days of antibiotic treatment, the mother of the young boy "felt like Jack was back." I'll also mention that the mum of Jack was herself a medic, a psychiatrist, and so was perhaps more attuned than most people about clinical diagnoses like autism and anxiety. It also emphasises how she kept on questioning...

Mention of the label autism in the BBC story got me thinking about quite a few things. Although still relatively sparse, there are some isolated reports in the peer-reviewed science literature observing that something like PANDAS/PANS can be "misdiagnosed as autism spectrum disorder" [1] in some circumstances. Such a notion complements some still emerging views that: (i) there may be many different routes to a diagnosis of autism (pertinent to the notion of 'the autisms'), (ii) autism is not universally an inborn genetic condition/state/diagnosis present from birth or early infancy, and (iii) autism for some people, is not necessarily a lifelong condition or label or state. Having discussed those views quite a bit on this blog (see here and see here and see here respectively) and noted some 'resistance' in some quarters to them, it is important that stories such as the one about Jack are continually highlighted. Not least because for him at least, his mother's determination and tenacity ultimately led to a new [accurate] diagnosis and subsequent treatment tailored to his particular circumstances. I daresay that other children (and even adults) who perhaps share Jack's clinical picture remain undiagnosed and untreated out there; something which represents a significant health inequality for them and their families. I might also add that the autism-anxiety diagnostic mix discussed in the BBC piece also complements the idea that the word 'comorbidity' may not be entirely accurate for the experience of [some] anxiety in the context of [some] autism (see here).

Jack's story begs the question: just how many people have been diagnosed with autism yet are 'suffering' with undiagnosed PANDAS/PANS? There's a research study there for someone brave enough there; alongside further study on whether elucidating the mechanisms of PANDAS/PANS when seemingly mimicking the signs and symptoms of autism & anxiety *could* be beneficial for at least some other parts of the wider autism spectrum...

Continue questioning and continue investigating seem to be the key lessons, as once again we are reminded that a diagnosis of autism should be a starting point and not 'the finishing line'.

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[1] Goncalves MVM. et al. Pediatric acute-onset neuropsychiatric syndrome (PANS) misdiagnosed as autism spectrum disorder. Immunol Lett. 2018 Nov;203:52-53.

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Middle ear infection and autism (again)

"Autism was more common in children who had had an otitis media infection or who had been treated with antibiotics."

Minus any sweeping generalisations, that was the conclusion reached in the study by Theresa Wimberley and colleagues [1] continuing some important research themes (see here and see here) examining any "interplay among otitis media, antibiotics, and the subsequent risk of developing autism."

Just in case you don't already know, otitis media infection refers to an infection of the middle ear that "causes inflammation (redness and swelling) and a build-up of fluid behind the eardrum." Aside from the use of painkillers, the seriousness of certain otitis media infections can sometimes mean that antibiotics are prescribed to combat any underlying bacterial infection or even in some cases, grommets inserted as treatment.

Wimberley et al report results based on "the entire Danish population", well, over three-quarters of a million children "followed from birth (January 1, 1997 to December 31, 2008) until December 31, 2012." They calculated various 'risk of autism' statistics as a function of a previous medical diagnosis of otitis media and "antibiotic prescriptions redeemed at Danish pharmacies." Yes folks, yet again those big data Scandinavian population registries have been used to good research effect.

Results: "The absolute risk of autism before age 10 was increased among children with otitis media (1.2% for females and 3.3% for males) and in children who had redeemed an antibiotic prescription (0.6% and 2.7% for females and males) compared to children without a history of otitis media and antibiotics usage (0.4% for females and 1.9% for males)." Researchers also reported finding "little evidence of a synergistic effect between otitis media infections and treatment with antibiotics" despite them being over-represented in relation to autism. They also caution that cause-and-effect cannot be inferred from their observational results.

What more can one say about the Wimberley findings? Well, echoing the idea that correlation is not the same thing as causation, I'd say that there is quite a bit more research to do on this topic. Further investigations are required into the possible mechanisms through which autism may manifest at least partially as a result of a history of ear infection (or indeed vice-versa). Mention of antibiotics also brings in areas of additional research interest such as the gut microbiome and what antimicrobials might 'be doing' to the trillions of passengers that are carried in the deepest, darkest recesses of the human body. I'm also minded to suggest that alongside antibiotic use to potentially treat infections like otitis media, researchers might also want to focus in on other medicines that might be accessed in such case such as over-the-counter pain relief in light of other *associations* that have been made (see here).

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[1] Wimberley T. et al. Otitis media, antibiotics, and risk of autism spectrum disorder. Autism Res. 2018 Oct 3.

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"specific microorganisms interact with some ME/CFS symptoms" and intervention could follow?

The quote titling this post: "specific microorganisms interact with some ME/CFS symptoms" and intervention could follow? comes in part from the findings reported by Amy Wallis and colleagues [1]. They reported that, following an open-label study design including 44 eligible patients diagnosed with ME/CFS [myalgic encephalomyelitis/chronic fatigue syndrome], a few potentially important details emerged. Not least that: "antimicrobial and probiotic treatment showed concurrent reduction in enteric Streptococcus counts and improvement in some neurological symptoms." Mmm...

The authors on the Wallis paper have some research form in this area [2] (see here for a previous blogging take on this work) talking about how use of a antibiotic - erythromycin (400 mg) - delivered over a 6-day period seemed to have some important effects on "gram-positive faecal Streptococcus" and also, for some, a positive impact on sleep quality. The caveat being once again, that this was another open-trial so potentially liable to various confounding variables. Still, there was one particularly positive thing to see in this previous trial, the use of actigraphy to collect objective data on sleep-wake cycles (something sadly lacking from various other studies of ME/CFS).

This latest time around it was all about comparing "the treatment response of male and female ME/CFS patients using a combined antibiotic and probiotic intervention aimed at reducing Streptococcus." The trial was registered (see here) and indeed, prospectively registered. The focus was on "sleep, mood and cognitive symptoms" also taking into account sex/gender as a potentially important variable. Alongside the use of an antibiotic, this time researchers also introduced a probiotic into the study protocol on alternate weeks - "Two capsules of Pro4-50 d-lactate free multistrain probiotic." As well as sleep continuing to be a focus for study, a battery of other parameters were also studied over the 4-week period of study covering various aspects of cognition ("word memory, story memory, spatial working memory, visual learning, verbal fluency, processing speed, cognitive flexibility and planning"), fatigue ("General Fatigue subscale from the Multidimensional Fatigue Inventory, MFI-20") and interestingly, 'brain fog'.

Results: the first thing that struck me about the Wallis results was the fact that the attrition (drop-out) rate was zero. Accepting that this was a rather short study, every participant (27 females and 17 males) completed the study protocol and had full results. That's not bad at all. It also makes statistical analyses sooo much easier.

Next, despite the authors reporting that "some sleep" parameters seemed to show some positive changes following the intervention, I'm minded to point out a key statement made in their text: "The primary outcome for sleep, actigraphic sleep efficiency, revealed similar mean scores at baseline... and post... with a small effect estimate... indicating no change in objective measurement of sleep efficiency." Given the 'open trial' nature of the experiment being described combined with the short experimental time, one therefore needs to be cautious about other, more self-report observations included for study. Cautious but not necessarily dismissive.

Then: "Streptococcus count was the only microbial variable that showed a large effect for time... with a reduction from baseline... to post." This is perhaps not unexpected given the use of an antibiotic that targets that specific type of bacteria. That being said, not everyone on the study showed the same 'direction' of effect, as per the statement: "individual variability of treatment response was highlighted by the proportion of participants who increased in Streptococcus counts at post." I guess this might imply that things are complicated when it comes to bacteria and antimicrobial use. Like just about every other medicine in use these days, not everyone will show the same clinical response to the same medicine.

Finally, bearing in mind an important aim of the Wallis study to undertake "sex comparisons", the results pretty much suggested that things are not so clear-cut when it comes to ME/CFS. So: "Analysis of the change in scores from baseline to post for male and female subgroups (sex-time interactions) revealed no large effects and thus did not support a sex-specific response to the treatment."

What we have with the Wallis paper and results is a well-described study, albeit with an inherent issue: the use of an open-label trial. I'm not saying there isn't value in such results; merely that one needs to be cautious about any findings produced (this comes from someone who has used similar trial designs). I might also add that whilst the authors talk about "Change in mean scores for all clinical outcomes (sleep, mood, cognitive and other) [that] were in the direction of improvement at post-intervention" this is not the same as statistically significant findings no matter what your views are on the current system employed. When joined to that open-label study design employed, such 'in the right direction' views needs to be kept to a minimum without further, more controlled investigations, to back them up...

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[1] Wallis A. et al. Open-label pilot for treatment targeting gut dysbiosis in myalgic encephalomyelitis/chronic fatigue syndrome: neuropsychological symptoms and sex comparisons. Journal of Translational Medicine. 2018; 16: 24.

[2] Jackson ML. et al. Sleep quality and the treatment of intestinal microbiota imbalance in Chronic Fatigue Syndrome: A pilot study. Sleep Science. 2015;8(3):124-133.

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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

Infections treated with anti-infective agents linked to schizophrenia?

Identify everyone born in Denmark between 1985-2002. Identify those treated "in the primary care setting" for an infection. Identify those diagnosed with schizophrenia and affective disorders. Look-see whether there is an overlap between infection or treated infection and schizophrenia / affective disorders. Report results.

That's basically the study published by Köhler and colleagues [1] (a name that has appeared on this blog before) who concluded that: "Infections treated with anti-infective agents and particularly infections requiring hospitalizations were associated with increased risks of schizophrenia and affective disorders, which may be mediated by effects of infections/inflammation on the brain, alterations of the microbiome, genetics, or other environmental factors."

Mention of Denmark as being the source material for such a discovery means, yet again, that those various Scandinavian population registries are proving their 'big data' scientific worth. Indeed, such resources really do put countries such as Blighty to shame insofar as tracking the health of the Nation and at the same, providing science with lots and lots of research nuggets.

Taking into account various "confounders", authors report that alongside a possible connection between infection or treatment for infection being 'associated' with schizophrenia / affective disorders there was "a dose-response and temporal relationship" further substantiating their findings. Indeed, those who had to be hospitalised for infection (a serious infection then) were at much greater risk of subsequently being diagnosed with schizophrenia or affective disorders. This tallies with other research on this topic (see here).

One more thing: "The excess risk was primarily driven by infections treated with antibiotics, whereas infections treated with antivirals, antimycotics, and antiparasitic agents were not significant after mutual adjustment." Interesting. This suggests that bacterial infections or their treatments, e.g. antibiotics seem to be important factors in relation to the subsequent risk of schizophrenia and/or affective disorders. Again, this is not the first time that this point has been raised (see here and see here) and provides some corroborative evidence as to why the microbiome was mentioned by authors in relation to possible mechanisms to account for their findings.

I could start talking about how this research is further evidence for a role for the immune system and/or inflammatory processes in relation to psychiatric labels (see here for example) but you've probably heard it all before I'm sure. What we are also starting to understand with some confidence, is that infection and the effects of it's treatment might go way beyond just the somatic...

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[1] Köhler O. et al. Infections and exposure to anti-infective agents and the risk of severe mental disorders: a nationwide study. Acta Psychiatr Scand. 2016 Nov 21.

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Köhler O, Petersen L, Mors O, Mortensen PB, Yolken RH, Gasse C, & Benros ME (2016). Infections and exposure to anti-infective agents and the risk of severe mental disorders: a nationwide study. Acta psychiatrica Scandinavica PMID: 27870529

Antibiotic brain part 3

"This study demonstrates an association between antibiotic use in the first year of life and subsequent neurocognitive outcomes in childhood."

So said the findings reported by Slykerman and colleagues [1] who relied on data from the Auckland Birthweight Collaborative Study (an initiative set up to determine whether "internationally recognized risk factors for small-for-gestational-age (SGA) term babies were applicable in New Zealand") to examine the suggestion that early life antibiotic use might be associated with a "detrimental effect on later neurocognitive outcomes."

Relying on maternal report of antibiotic use among offspring "between 12 months and 3.5 years of age" researchers compared data with that derived from "Intelligence test scores and measures of behavioural difficulties" when children were 3.5, 7 and 11 years of age. They found that antibiotic use during the first 12 months of life was high in their cohort (70%) and that: "Those who had received antibiotics had more behavioural difficulties and more symptoms of depression at follow up." I've highlighted the 'relying on maternal report' bit because although parents are typically the experts on their own children (yes, they are), the reliance on parental report is not the same as reliance on objective medical or prescribing records for antibiotic use and important information on antibiotic type, dose and reason for such use that they typically contain. Indeed, I might also stress that correlating antibiotic use and developmental outcome whilst interesting should also be mindful of the myriad of other variables that might play a role, including the idea that 'behavioural difficulties' often don't present until later infancy for whatever reason. Be careful with single associations.

But... I've labelled this post 'Antibiotic brain part 3' because I feel that the Slykerman findings are another important piece of evidence potentially pertinent to the idea that antibiotics may be pretty good at tackling bacterial infection but that also that they may have some quite potent effects on behaviour and development as well as physiology (see here for antibiotic brain part 1 and antibiotic brain part 2).

What's the possible mode of action linking [early] antibiotic use and behaviour and development? Well, far be it from me to speculate too much but I'm minded to bring in the idea that those trillions of wee beasties that inhabit our deepest, darkest recesses (the gut microbiome) might play some role in any process. Minus hype [2] we're for example, already finding out how gut bacteria 'might' show some important behavioural connections (see here for example) and specifically how certain strains of bacteria might link to important states such as depression (see here and see here). It's not outside the realms of possibility that 'swallowing a grenade' (although not literally) designed to kill bacteria rather willy-nilly, might influencing either bacterial diversity in the gut or impact on specific strains that could be consider more rather than less beneficial.

One more idea for science to perhaps consider relates to why antibiotics were given in the first place. If for example we assume that ear infection might be a common reason, could it not be that the actual symptoms over and above the [antibiotic] treatment might be the more important variable in relation to 'behavioural difficulties'? [3]

There is much more to do in this area, but alongside the dangers of antibiotic resistance perhaps science might also be more open to the idea that antibiotics might do so much more than just impact on physiology?

To close, for those in Blighty who might remember Hastings, 1066 and a certain Tapestry, things were a whole lot more complicated/gory that you might have expected...

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[1] Slykerman RF. et al. Antibiotics in the first year of life and subsequent neurocognitive outcomes. Acta Paediatr. 2016 Oct 4.

[2] Bik EM. The Hoops, Hopes, and Hypes of Human Microbiome Research. Yale J Biol Med. 2016 Sep 30;89(3):363-373.

[3] Niclasen J. et al. Associations between otitis media and child behavioural and learning difficulties: Results from a Danish cohort. Int J Pediatr Otorhinolaryngol. 2016 May;84:12-20.

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Slykerman RF, Thompson J, Waldie KE, Murphy R, Wall C, & Mitchell EA (2016). Antibiotics in the first year of life and subsequent neurocognitive outcomes. Acta paediatrica (Oslo, Norway : 1992) PMID: 27701771

Hospitalisation for mania following antibiotic exposure?

"Individuals hospitalized with acute mania have a markedly increased rate of bacterial infections, as evidenced by the recent prescription of antimicrobial agents. The prevention and effective treatment of bacterial infections may be important interventions for the management of individuals with mania."

That was the research bottom-line reported by Robert Yolken and colleagues [1] (yes, that Robert Yolken) who continued a theme of how immune function/response might be something pretty important when it comes to all-things psychiatry and in particular, when it comes to diagnoses like mania (see here). Some media interest in this work can be seen here.

On this occasion, the name of the game was to investigate "whether individuals hospitalized with acute mania have evidence of bacterial infections as determined by the prescription of systemic antimicrobial agents." Antimicrobial agents normally means antibiotics; evidence of their use was searched for in over 230 people "hospitalized for acute mania in either an inpatient unit or a day hospital" compared with some 550 controls.

Researchers reported that among their cohort there was "a substantially increased rate of recent antimicrobial prescription, defined as exposure within three days of ascertainment." 'Substantial' in this respect meant 18 of 234 hospitalised people (~7%) compared with 7 of 555 controls (~1%). Interestingly, authors also reported that the site of bacterial infection for which antimicrobials were given was most commonly urinary tract infection for women "while the respiratory tract and mucosal surfaces were the most common sites in men." Mention of the the urinary tract as a source of infection brought me back to another post a while back (see here) and some intriguing data about urinary tract infection and risk of acute psychosis.

This latest Yolken data further add to the growing body of research suggesting that either cause or effect, the immune system does seem to be associated with various behavioural and psychiatric labels. My reading of this work suggests that the authors favour the idea that the infection itself (or response to infection) might be the more important aspect to any relationship but I'm not so sure that things are so straight-forward. Indeed, on the other occasions where I've talked about infection and psychiatry, the use of antibiotics - particularly recurrent prescriptions of antibiotics - might not be without possible side-effects (see here) in certain contexts.

There is more to do in this area, not least with regards to possible mechanisms of effect and whether the "prevention and effective treatment of bacterial infections may be important interventions for the management of individuals with mania." I would also hope that given the 'when you swallow a grenade' sentiments associated with antimicrobial use, the trillions of wee beasties that call us home (the gut microbiota) might also figure in any future research strategy.

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[1] Yolken R. et al. Individuals hospitalized with acute mania have increased exposure to antimicrobial medications. Bipolar Disorders. 2016. 17 July.

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Yolken R, Adamos M, Katsafanas E, Khushalani S, Origoni A, Savage C, Schweinfurth L, Stallings C, Sweeney K, & Dickerson F (2016). Individuals hospitalized with acute mania have increased exposure to antimicrobial medications. Bipolar disorders PMID: 27425597

Antibiotic brain part 2

"Mouse study finds link between gut bacteria and neurogenesis" went the press release accompanying the paper by Luisa Möhle and colleagues [1] (open-access). Describing the results of a mouse study - that's MOUSE study - researchers reported that "treatment of adult mice with antibiotics decreases hippocampal neurogenesis and memory retention."

The antibiotic mix used on study mice was quite an aggressive one: "ampicillin plus sulbactam (1.5 g/l; Pfizer), vancomycin (500 mg/l; Cell Pharm), ciprofloxacin (200 mg/l; Bayer Vital), imipenem plus cilastatin (250 mg/l; MSD), and metronidazol (1 g/l; Fresenius)" and was delivered to mice via their drinking water for 7 weeks. Unsurprisingly, this antibiotic mix pretty much savaged the gut microbiome of participant mice (when you swallow a grenade and all that) and, when compared with untreated mice, the depletion of gut bacteria caused by the antibiotic mix seemed also to impact on measures of mouse cognitive functions as well as "proliferating cells in the hippocampus." A potential gut-brain axis no less...

The reason I titled this post 'antibiotic brain part 2' is because the results so far seemed to overlap pretty well with other similar experiments discussed on this blog (see here) talking about potential cognitive impairments in mice treated with quite an aggressive course of antibiotics. But there was more to see in the Möhle paper...

"Voluntary Exercise Rescues Neurogenesis Levels Despite Antibiosis" and "Probiotics Fully Restore Neurogenesis" were additional findings reported by the authors, as use of a running wheel seemed to have some important positive effects, as did use of the probiotic mixture VSL#3 "a commercially available probiotic mixture consisting of the following eight bacterial strains: Streptococcus thermophilus, Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, and Lactobacillus delbrueckii subsp. Bulgaricus." It was particularly timely that the paper by Grant & Baker [2] also mentions probiotics and exercise as being potentially linked in their review paper. Researchers also reported that alongside those cognitive and structural brain findings, levels of a particular type of white blood cell (monocyte) called LY6Chi were also lower in antibiotic-treated mice. A few additional experiments later including "transfer of Ly6Cpos monocytes" and it looked like these cells might indeed play an important role in the findings reported.

Reiterating that this was a mouse study and how one has to be slightly careful of extrapolating findings from mice to humans (see here), the Möhle results are pretty interesting. I note in the press release, the authors have talked about the possibility of investigating whether "probiotic treatments will improve symptoms in patients with neurodegenerative and psychiatric disorders." I would second the idea that there is further research implied in that area, minus any hype. Let's also not forget that this study also suggested that exercise might be a useful strategy too...

Wearing my autism research hat and following on from some important responses when I initially tweeted about the Möhle paper, I do also wonder whether there are other implications potentially linked to such findings. Of course "female 6-to 8-week-old C57BL/6 wild-type mice" are not young children, but I can't help wonder whether early aggressive use of antibiotics discussed by more than one parent of a child eventually diagnosed with autism to combat an ear infection for example (see here) might have some role to play. Appreciating that antibiotics range in type and frequency of use, and under quite a few circumstances show more positive effects in relation to cases of autism and beyond (see here), the possibility of an artificial reprogramming of something like the gut microbiome at certain critical stages could be considered an important possibility. I don't say that as some sort of sweeping generalisation given that many children receive antibiotics during infancy for various different reasons and not all are or 'become autistic' as a result. But rather, that as one variable among several, further inspection of the possibility of a link between the gut-gut bacteria-brain elements is warranted...

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[1] Möhle L. et al. Ly6Chi Monocytes Provide a Link between Antibiotic-Induced Changes in Gut Microbiota and Adult Hippocampal Neurogenesis. Cell Reports. 2016; 15: 1-12.

[2] Grant MC. & Baker JS. An Overview of the Effect of Probiotics and Exercise on Mood and Associated Health Conditions. Crit Rev Food Sci Nutr. 2016 May 31:0.

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Luisa Möhle, Daniele Mattei, Markus M. Heimesaat, Stefan Bereswill, André Fischer, Marie Alutis, Timothy French, Dolores Hambardzumyan, Polly Matzinger, Ildiko R. Dunay, & Susanne A. Wolf (2016). Ly6Chi Monocytes Provide a Link between Antibiotic-Induced Changes in Gut Microbiota and Adult Hippocampal Neurogenesis Cell Reports : 10.1016/j.celrep.2016.04.074

More [metabolomic] evidence for dysbiosis and some autism?

The paper by Xiyue Xiong and colleagues [1] (open-access available here) took my attention recently and some further evidence contributory to the idea that the trillions of wee beasties that call our gastrointestinal (GI) tract home - collectively known as the gut microbiome - might have some important links to at least 'some' autism.

Describing the results of "a GC/MS based metabolomic approach"  - GC-MS being gas chromatography-mass spectrometry and metabolomic(s) being the analysis of 'small molecule metabolites found in biological fluids such as blood, saliva and urine' - the authors report results based on analysis of urine specimens for some 62 children diagnosed with an autism spectrum disorder (ASD) compared to 62 'not-autism' controls. Bearing in mind that quite a few of the compounds normally found in urine are linked to the goings-on in the gut microbiome, the authors ensured that "Children included in the study had no antianaerobic drug use history" (i.e. certain types of antibiotics were not used).

Results: "Three compounds identified as 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), 3-hydroxyphenylacetic acid (3HPA), and 3-hydroxyhippuric acid (3HHA) were found in higher concentrations in autistic children than in the controls." I was rather interested in the HPHPA finding in particular given that it has previously appeared on this blog in relation to autism and the gut microbiome (see here) following other peer-reviewed findings [2]. The watchword on that previous post was 'dysbiosis' and how alterations in the relative levels of certain gut bacterial species might have some rather intriguing outcomes [3]. The idea therefore being that the action of certain types of bacteria on the proposed starting material for HPHPA (the aromatic amino acids phenylalanine and tyrosine) might influence metabolism and lead to elevations in this metabolite. At this point I'll also refer you to some other musing on research on another aromatic amino acid (tryptophan) that might also be 'autism-relevant' (see here).

Indeed to further test the idea of a gut microbial link to the elevations noted in HPHPA and related metabolites, Xiong et al provide further details: "Fifty HPHPA-positive autistic children (9/50 patients 3HPA-positive and 17/50 patients 3HHA-positive) were selected for oral vancomycin treatment at standard age-appropriate dosages (50 mg/kg/d, 30 days as one therapeutic course) followed by supplement therapy with Bifidobacterium agent (Bifidobacterium BB-12, 2 pills a day)." Use of vancomycin - a quite powerful antibiotic indicated for the treatment of 'Clostridium difficile–associated Disease' [4] among other things - is not unheard of in autism research and practice circles (see here) and this time around there were significant decreases in the levels of HPHPA and related metabolites "which indicated that these compounds may also be from gut Clostridium species." Further, when vancomycin was stopped: "3–6 months later, the concentration of HPHPA almost recovered to its initial level in 3 patients and recovered to 0.08–0.45 times their initial values in 12 patients." Authors also noted that some behavioural scores might have been affected by the use of vancomycin that could be construed along the same lines as when Sandler et al reported on the use of vancomycin with 'regressive-onset autism' in mind [5].

The authors also add in some details about how "measurements of the three metabolites are strong predictors of ASDs and support the potential clinical utility for identifying a subgroup of ASDs subjects in whom disordered phenylalanine metabolism may be a salient characteristic." On this point I'm not convinced that on the basis of 60 or so children and with 3 metabolites in mind (out of the thousands that we excrete everyday influenced by all manner of 'internal' and 'external' forces) there is biomarker potential for 'all autism' just yet. I am in agreement that 'disordered phenylalanine metabolism' for a subgroup on the autism spectrum is a possibility based on the use of 'phenylalanine mopping up' compounds in other peer-reviewed work (see here) for example. But much more research is indicated...

These are interesting results that, yet again, require independent replication. Because I am a bit of stickler when it comes to all-things metabolomics (especially where mass spectrometry is involved) I might be inclined to mention about how adjustment using creatinine might have issues when it comes to autism (see here) which could affect the final quantification of metabolites. I might also suggest that the GC-MS system used and the urine sample pre-treatment applied before analysis could be 'up-graded' taking into account more accurate detection methods (e.g. q-ToF mass spectrometry with liquid chromatography separation) with a greater focus on features like accurate mass.

But don't let me put you off from the idea that marrying metabolomics and microbiomics could be a good autism research idea. Although on the topic of whether we might be able to 'alter' our microbiomes/metabolome in ways other than the use of potent antibiotics, the jury is still out [6] bearing in mind how diet might affect results...

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[1] Xiong X. et al. Urinary 3-(3-Hydroxyphenyl)-3-hydroxypropionic Acid, 3-Hydroxyphenylacetic Acid, and 3-Hydroxyhippuric Acid Are Elevated in Children with Autism Spectrum Disorders. Biomed Res Int. 2016;2016:9485412.

[2] Shaw W. Increased urinary excretion of a 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), an abnormal phenylalanine metabolite of Clostridia spp. in the gastrointestinal tract, in urine samples from patients with autism and schizophrenia. Nutr Neurosci. 2010 Jun;13(3):135-43.

[3] Rogers GB. et al. From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways. Molecular Psychiatry. 2016. April 19.

[4] Shen EP. & Surawicz CM. Current Treatment Options for Severe Clostridium difficile–associated Disease. Gastroenterology & Hepatology. 2008;4(2):134-139.

[5] Sandler RH. et al. Short-term benefit from oral vancomycin treatment of regressive-onset autism. J Child Neurol. 2000 Jul;15(7):429-35.

[6] Kristensen NB. et al. Alterations in fecal microbiota composition by probiotic supplementation in healthy adults: a systematic review of randomized controlled trials. Genome Medicine. 2016; 8: 52.

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Xiong X, Liu D, Wang Y, Zeng T, & Peng Y (2016). Urinary 3-(3-Hydroxyphenyl)-3-hydroxypropionic Acid, 3-Hydroxyphenylacetic Acid, and 3-Hydroxyhippuric Acid Are Elevated in Children with Autism Spectrum Disorders. BioMed research international, 2016 PMID: 27123458

Antibiotic brain? Cognitive impairment by antibiotic-induced gut dysbiosis

"The present study shows that intragastric treatment of mice with an antibiotic mix impairs novel object recognition, but not spatial memory. This behavioral change is associated with a disruption of the microbial community in the colon, distinct alterations of the colonic and circulating metabolite profile and particular changes of neurochemical brain activity."

Those were the headlines attached to the paper published by Esther Fröhlich and colleagues [1] (open-access available here) who put further scientific flesh on the bones of the suggestion that those trillions of wee beasties (the gut microbiota) that call our gastrointestinal (GI) tract home, might be doing some much more than helping us digest our food or producing the odd nutrient or two. I say 'our' but should however point out that this was a study of mice not people.

Not content with the current evidence pertinent to establishing "causality in gut microbiota-brain relationships", researchers devised a plan to study various aspects of the effects of "antibiotic-induced gut dysbiosis" looking at the effects of an antibiotic mix on "(i) gut microbial community, (ii) metabolite profile in the colon, (iii) circulating metabolites, (iv) expression of neuronal signaling molecules in distinct brain areas and (v) cognitive behavior." All this carried out in adult mice, some of whom were given an antibiotic mix consisting of "ampicillin..., bacitracin..., meropenem..., neomycin... and vancomycin" who were then put through their paces with regards to a series of mouse cognitive tests before being sacrificed and further investigations carried out on their brain, blood and GI tract. I'll hasten to point out that I can't think of many typical occasions when such a combination of antibiotics together would be administered to people, so bear that in mind.

Results: well, first and foremost, authors were largely able to rule out any direct effect from the antibiotics themselves on brain function as a consequence of not detecting any metabolites of the antibiotics in the brains of those brave mouse participants. This despite the fact that "ampicillin had some oral bioavailability." Next, and as expected, the antibiotic mix "vigorously changed the microbiome." If you want some background on this, have a look at the interesting discussion piece on 'swallowing a grenade' from a while back (antibiotics not real grenades!). Researchers also reported that as a consequence of the disruption of normal gut bacterial service following antibiotic use, there was a shift in the types of metabolites produced by the surviving gut bacteria. So: "the levels of the short-chain fatty acids (SCFA) acetate, butyrate and propionate as well as of trimethylamine, adenine and uracil were significantly diminished by antibiotic treatment." This harks back to my opening sentiments about gut bacteria doing more than just helping digest food.

Next: "Antibiotic-treated mice had a significantly lower memory index than vehicle-treated mice."Vehicle-treated refers to those who did not receive the antibiotic mix. But, whilst one aspect of memory - novel object recognition - seemed to have been affected by antibiotic receipt, other aspects were seemingly not. The authors go on to report that various "neurochemical alterations" might be linked to the cognitive results reported including changes to "tight junction proteins, brain-derived neurotrophic factor, N-methyl-D-aspartate receptor subunit 2B, serotonin transporter, NPY system and corticosterone."

These are interesting findings and, as the authors conclude: "add to the understanding of the microbiota-gut-brain axis and highlight the potential and limitation of antibiotic-induced gut dysbiosis as model system to probe causality in the interaction between gut microbiota and brain." Accepting that there is a significant level of 'hype' around the possibility of a bacteria-gut-brain axis, this type of science is a welcome addition to the peer-reviewed literature and cries out for further independent replication.

Ideally, I would like to see a lot more research looking at the potentially important links between gut bacteria and behaviour in human participants. Obviously I'm not talking about dissecting people in the same way that Fröhlich et al sacrificed their mice, but I'm sure other study designs and methodologies could be introduced minus the need for death. Certainly the application of metabolomics to antibiotic use research could be quite revealing. Harking back to other research talking about toddler temperament potentially *correlating* with gut bacteria (see here) or even the extremes of psychosis appearing alongside acute urinary tract infection (see here), there are plenty of research avenues to pursue. The suggestion that recurrent antibiotic exposure might play some role in the experience of depression and/or anxiety (see here) would also seem to be as good a starting point if any when it comes to moving from mouse studies to human studies. Oh, and I'd minded to say that we might also want to look at gut barrier function too (see here)...

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[1] Fröhlich EE. et al. Cognitive Impairment by Antibiotic-Induced Gut Dysbiosis: Analysis of Gut Microbiota-Brain Communication. Brain Behav Immun. 2016 Feb 23. pii: S0889-1591(16)30040-X.

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Fröhlich EE, Farzi A, Mayerhofer R, Reichmann F, Jačan A, Wagner B, Zinser E, Bordag N, Magnes C, Fröhlich E, Kashofer K, Gorkiewicz G, & Holzer P (2016). Cognitive Impairment by Antibiotic-Induced Gut Dysbiosis: Analysis of Gut Microbiota-Brain Communication. Brain, behavior, and immunity PMID: 26923630

Omega-3 fatty acids, 'antibiotic exposure-induced gut microbiota dysbiosis' and obesity

The findings reported by Kaliannan and colleagues [1] provide food for thought today and the suggestion that in mice at least: "elevated tissue levels of omega-3 fatty acids significantly reduce body weight gain and the severity of insulin resistance, fatty liver, and dyslipidemia resulting from early-life exposure to azithromycin (AZT)."

Azithromycin is an antibiotic quite commonly used for treating a number of bacterial infections. The idea that antibiotic use, and specifically the effects on the trillions of wee beasties that call our gut home (the gut microbiome), might impact on weight is not a new one. The precise mechanism(s) are still a point of some speculation. Evidence from various sources however (see here for example) seems to indicate that there may be something about the gut microbiome that seems to have an important bearing on weight gain and obesity.

Kaliannan et al started with the premise that "increased tissue levels of omega-3 fatty acids may prevent antibiotic-induced alteration of gut microbiota and obesity later in life." I know some people might be a little puzzled as to why supplementing a fat might actually stop someone (or at least something) from 'becoming fat', but these are times where the sweeping notion that 'fat makes you fat' is being re-analysed (see here). Using a specific type of mouse - "the fat-1 transgenic mouse model" [2] - that is "capable of producing n-3 fatty acids from the n-6 type, leading to abundant n-3 fatty acids with reduced levels of n-6 fatty acids in their organs and tissues, without the need of a dietary n-3 supply", researchers exposed mice to AZT during their earliest days. They found that this particular type of mouse that is able to synthesize its own omega-3 fatty acids, potentially showed some important effects as a result of its naturally high levels of omega-3 fatty acids in tissues. Further: "These effects were associated with a reversal of antibiotic-induced dysbiosis of gut microbiota in fat-1 mice."

Reiterating that this was a mouse study focused on a very specific type of mouse, these are interesting findings. It's not necessarily new news that "dietary lipids affect specific populations of gut microbes and their metabolic end products" [3] or that specific types of bacteria might also affect fat composition of host tissues [4] but more scientific flesh needs to be put on the bones of the relationship. Insofar as how these results might transfer outside of the fat-1 transgenic mouse, well, the authors speculate about "the potential utility of omega-3 supplementation as a safe and effective means for the prevention of obesity in children who are exposed to antibiotics." I would however be minded to suggest that quite a bit more investigation is needed before fish oils are routinely prescribed alongside/following antibiotics in early childhood to 'prevent' microbiota-associated obesity. That also agricultural methods used might be a relevant factor is food for thought [5] as is the focus on fish oils and Akkermansia muciniphila (see here) among other things.

But speaking of our microbial masters, I might also draw your attention to the paper by Laura Blanton and colleagues [6] talking about the other extreme of weight and gut bacteria. Feed the world eh?

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[1] Kaliannan K. et al. Omega-3 fatty acids prevent early-life antibiotic exposure-induced gut microbiota dysbiosis and later-life obesity. Int J Obes (Lond). 2016 Feb 15.

[2] Kang JX. Fat-1 transgenic mice: a new model for omega-3 research. Prostaglandins Leukot Essent Fatty Acids. 2007 Nov-Dec;77(5-6):263-7.

[3] Shen W. et al. Influence of dietary fat on intestinal microbes, inflammation, barrier function and metabolic outcomes. J Nutr Biochem. 2014 Mar;25(3):270-80.

[4] Wall R. et al. Metabolic activity of the enteric microbiota influences the fatty acid composition of murine and porcine liver and adipose tissues. Am J Clin Nutr. 2009 May;89(5):1393-401.

[5] Średnicka-Tober D. et al. Composition differences between organic and conventional meat: a systematic literature review and meta-analysis. Br J Nutr. 2016 Feb 16:1-18.

[6] Blanton LV. et al. Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children. Science. 2016. Feb 19.

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Kaliannan K, Wang B, Li XY, Bhan AK, & Kang JX (2016). Omega-3 fatty acids prevent early-life antibiotic exposure-induced gut microbiota dysbiosis and later-life obesity. International journal of obesity (2005) PMID: 26876435

Sleep as a target of antibiotic use in chronic fatigue syndrome?

"The primary finding from the study was evidence of an improvement in several objective sleep parameters in participants in whom the increased colonization of lactic acid producing organisms was resolved after antibiotic treatment."

Those were the words written by Melinda Jackson and colleagues [1] (open-access) who, during an open-label trial, looked at whether administration of an antibiotic (erythromycin 400 mg) over the course of 6 days might have some important effects on elements of sleep in a patient group diagnosed with chronic fatigue syndrome (CFS). Yes, sleep did seem to be [positively] affected was the finding. The suggested mode of action of antibiotic administration was linked to colonisation "with gram-positive faecal Streptococcus (determined by stool analysis and suggestive of abnormal gut functioning)" onwards to the idea that the those trillions of wee beasties that inhabit us all might show some specific connection to elements in cases of CFS.

From an initial study population of 70 recruited for study, data for 22 participants (who completed the trial and met study inclusion criteria) were reported on. Those 22 all had "increased colonization of Streptococcus sp. (defined as >3×105 cfu/g of faecal sample)" as a pre-requisite to taking part in the trial based on the results of a "faecal microbiota analysis (FMA)." Actigraphy and sleep diaries were kept for a week before antibiotic use, during use and for 8 days after. Various facets of CFS symptoms were also examined during points of the study.

Bearing in mind some 'malfunctions' affecting actigraphy results, the authors describe some interesting findings. First and foremost, is the idea that not everyone who took erythromycin showed the same profile (behavioural or biochemical). The authors talk about "responders" to the intervention (music to my ears) on the basis that: "Thirteen of the patients showed a reduction in Streptococcus counts after treatment, whereas four patients showed an increase level of Streptococcus and four patients had no change at the end of the trial." Outside of the idea that there may be some significant individual variation in the effects of antibiotics on gut flora (remembering the idea of 'swallowing a grenade'), questions abound as to why some people did not seem to be so affected by this strain of antibiotics whilst others did. Further: "While 13 participants showed a reduction in Streptococcus only 7 of these had a significant change as defined by a percentage distribution post-therapy of less than 6% of Streptococcus after antibiotic treatment." Mmm, indeed.

Second, and linked back to the idea of 'responders' and 'non-responders' on the basis of microbiological results are the findings that there were: "more improvement in actigraphic sleep with treatment in responders compared to non-responders from baseline to post-treatment 2." Indeed, we are told that responders tended to increase their total sleep time by about 40 minutes between baseline and end of study, whereas: "non-responders slept an average of 15 min less from baseline to post-treatment 2."

Finally, and quite importantly: "No significant change in any of the subjective measures was observed between baseline and the two follow-up points for responders versus non-responders." The subjective measures in question were linked to things like self-reported fatigue, mood and the such like. The authors have suggested that there may be some 'correlation' between a subscale on 'vigour' and "Streptococcus viable count" but when you're talking about 7 participants as your responder group, one has to be mighty careful of making too many sweeping generalisations.

Although this is a preliminary study, I'd like to think that the Jackson findings might eventually be worked up into a larger, more methodologically sound research agenda encompassing a placebo arm and the like. We know for example, that sleep patterns can be affected by CFS and that at least subjective measures of sleep may affect the presentation of elements of CFS [2]. That children and adolescents with CFS may be particularly vulnerable to sleep disturbances [3] is an area in specific need of further investigation. Moves therefore to improve sleep measures in CFS are perhaps to be welcomed mindful of the idea that persistent use of antibiotics is not exactly a great long-term strategy particularly in these days of growing antibiotic resistance. I could offer a possible alternative to antibiotic use that has been initially tried with CFS in mind (see here) but again, more research is indicated first and perhaps also some PR! Still, the focus on the gut microbiota and CFS/ME continues at a pace (er, maybe a should rephrase that) and with the promise of much, much more to come.

I'll also be talking about the paper by Collin and colleagues in the not-too-distant future so watch this space...

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[1] Jackson ML. et al. Sleep quality and the treatment of intestinal microbiota imbalance in Chronic Fatigue Syndrome: A pilot study. Sleep Sci. 2015 Nov;8(3):124-33.

[2] Russell C. et al. Subjective But Not Actigraphy-Defined Sleep Predicts Next-Day Fatigue in Chronic Fatigue Syndrome: A Prospective Daily Diary Study. Sleep. 2015 Dec 22. pii: sp-00453-15.

[3] Snodgrass K. et al. Sleep Disturbances in Pediatric Chronic Fatigue Syndrome: A Review of Current Research. J Clin Sleep Med. 2015 Jul 15;11(7):757-64.

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Jackson ML, Butt H, Ball M, Lewis DP, & Bruck D (2015). Sleep quality and the treatment of intestinal microbiota imbalance in Chronic Fatigue Syndrome: A pilot study. Sleep Science (Sao Paulo, Brazil), 8 (3), 124-33 PMID: 26779319