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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A poo(p) transplant for depression and anxiety?

Contrary to the title of this post - "A poo(p) transplant for depression and anxiety?" - I don't think we are yet in a position to say that Fecal Microbiota Transplantation (FMT) is ready to go 'mainstream' as an approved treatment for depression and/or anxiety. I do however, think that the findings reported by Shunya Kurokawa and colleagues [1] provide evidence for a further, more controlled, scheme of research on this topic.

Based on their following a small-ish group of patients diagnosed with "either Irritable Bowel Syndrome (IBS), Functional Diarrhea (FDr) or Functional Constipation (FC) who underwent FMT for the treatment of gastrointestinal symptoms and observation of psychiatric symptoms" authors report results before said poo(p) transplant and after 4 weeks based on ratings on various instruments pertinent to the presentation of depression and anxiety. Alongside "intestinal microbiota were measured" with a particular focus on the level of diversity of species that were present in pre- and post-FMT samples. I might also mention at this point, how something like IBS is not without it's own 'psychological' correlates as per other research (see here and see here).

Following an 'open-trial' methodology and including only a "small sample size with no control group", researchers reported some significant improvements in relation to those depression and anxiety symptom scores for some. Importantly too, they noted that potential FMT effects on mood seemed to be independent of effects on "gastrointestinal symptom change." Similarly: "There was a significant correlation between baseline Shannon index and HAM-D [Hamilton Rating Scale for Depression] score, and a correlation between Shannon index change and HAM-D improvement after FMT." This suggests that bacterial diversity might be something to look at as potentially explaining the psychological effects of FMT.

Reiterating that the Kurokawa findings are preliminary and hence, require quite a lot more further (independent) study, I find this topic to be an interesting one. Although there may be some 'consumer resistance' to the idea of FMT, for some people, this type of intervention is nothing short of life-saving (see here). The idea that a similar type of transplant *might* also hold some benefits for conditions/labels outside of something like Clostridium difficile (C. difficile) infection has already been noted in the peer-reviewed science literature (see here and see here for examples), including conditions characterised by behaviour and psychology. This alongside a growing interest in how mood and temperament might have some important connection to those trillions of wee beasties (the gut microbiome) that call us all home (see here). We'll see where this goes...

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[1] Kurokawa S. et al. The effect of fecal microbiota transplantation on psychiatric symptoms among patients with irritable bowel syndrome, functional diarrhea and functional constipation: An open-label observational study. J Affect Disord. 2018 Apr 12;235:506-512.

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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

C-section and the microbial transplant

I'm pretty sure that the paper by Maria Dominguez-Bello and colleagues [1] speaks for itself when describing the results of "a pilot study in which infants delivered by C-section [Caesarean section] were exposed to maternal vaginal fluids at birth." If you need a graphic, some coverage of the research in the New York Times helpfully provides a visual aid (see here).

The long-and-short of it is that following some concerns that infants delivered via C-section might be missing out on some valuable exposure to their mother's microbial passengers [2] as a function of their by-passing the birth canal and beyond, the use of a "vaginal microbial transfer" might be an option. Detailing results based on a small number of births - 11 born by C-section (planned or elective) and 7 via the more traditional route - researchers report what happened when 4 of the C-section infants were swabbed with previously collected gauze containing mum's bacterial passengers. Swabbing by the way, was done on various parts of the infant's body.

The authors concluded that: "Similarly to vaginally delivered babies, the gut, oral and skin bacterial communities of these newborns [swabbed C-section infants] during the first 30 d[ays] of life was enriched in vaginal bacteria—which were underrepresented in unexposed C-section–delivered infants." That being said, the results appeared to show that whilst swabbing was good at delivering a microbial transplant for C-section infants, it was no substitute for the real thing (a vaginal birth) bacterially-speaking. I might also add that important variables such as breastfeeding (or not) can also influence the constitution of our gut bacteria (see here).

There is some media chatter about this study and onwards what the longer-term effects might be in terms of health and well-being in the context of how our bacterial masters may show various health/disease links [3]. I'd be interested to see how this cohort and other larger ones fare as a result. I do however, have a word of caution to add to proceedings alongside others it seems (see here).

Accepting that a vaginal microbial transfer is not the same as the more 'popular' talking point that is a faecal microbiota transplant, and that the bacteria that colonise the gut may not necessarily be the same as that colonising other parts of the body, I'm minded to direct readers to a post not-so-long-ago covering weight gain following poo(p) transplant (see here). I don't think the specific 'obesogenic' bacteria were isolated in the case report by by Neha Alang and Colleen Kelly [3] or indeed, whether other elements such as the gut virome may have exerted some effect on patient weight gain following "receiving stool from a healthy but overweight donor." But one question might be to ask whether a similar 'process' could potentially be pertinent to the swabbing of C-section infants?

OK, I appreciate that there has been some research discussion about how C-section babies *might* be slightly more prone to obesity in later life (see here). But if one assumes that outside of the typical risk factors linked to obesity, there may be a microbial link too, is it not inconceivable that an early-days microbial transplant from a mum who is herself overweight or obese at the time of birth might potentially 'transmit' the basis of such weight problems to offspring too? Indeed, with all the chatter about microbes and mood these days (see here for example) one could potentially stretch the 'bacterial association' even further...

I'll leave you with those thoughts and some (new) music from the Leppard (hopefully really not a "nuclear waste of time").

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[1] Dominguez-Bello MG. et al. Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer. Nature Medicine. 2016. Feb 2.

[2] Biasucci G. et al. Cesarean delivery may affect the early biodiversity of intestinal bacteria. J Nutr. 2008 Sep;138(9):1796S-1800S.

[3] Alang N. & Kelly CR. Weight Gain After Fecal Microbiota Transplantation. Open Forum Infect Dis. 2015; 2: 1.

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Dominguez-Bello MG, De Jesus-Laboy KM, Shen N, Cox LM, Amir A, Gonzalez A, Bokulich NA, Song SJ, Hoashi M, Rivera-Vinas JI, Mendez K, Knight R, & Clemente JC (2016). Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer. Nature medicine PMID: 26828196

Poo transplant and weight gain: a case study

The case report detailed by Neha Alang and Colleen Kelly [1] (open-access) reporting on "new-onset obesity after receiving stool from a healthy but overweight donor" has already garnered some significant press attention (see the BBC entry for example). Reporting on that seemingly most undesirable but in some cases life-saving of measures - the fecal microbiota transplant (FMT) - whereby some of those trillions of wee beasties which inhabit our deepest, darkest recesses are transferred from one person to another, the authors add a cautionary caveat to our current fascination with such a technique.

The Alang/Kelly paper is open-access but a few pointers might be in order:

Interesting viewing @ Paul Whiteley

• "A 32-year-old female with recurrent CDI [Clostridium difficile infection] underwent FMT". As per my previous mention of being a potentially 'life-saving' measure, FMT for CDI (recurrent CDI) is something which is now formally indicated, as per the directions from NICE here in Blighty. Such recommendations came on the back of quite a volume of science which suggested effectiveness particularly in hard to treat cases of CDI (see here).
• For this patient, quite a few avenues of treatment had been previously tried but with little success. "After extensive discussion, the patient elected to undergo fecal transplant. As per the patient’s request, her 16-year-old daughter was chosen as the stool donor." Said donor was, we are told: "∼140 pounds (BMI of 26.4), but it increased later to 170 pounds." BMI by the way, stands for body mass index and 140 pounds is equivalent to about 63 kilograms rising to about 77 kilograms in new (weight) currency. 
• Results: well, FMT worked in that the mother: "improved and did not suffer a further CDI recurrence after FMT". But... "The patient presented again 16 months after FMT, and reported an unintentional weight gain of 34 pounds. She weighed 170 pounds and had become obese (BMI of 33)." Diet and exercise seemingly did very little to aid in weight loss and also after 3 years post FMT she "developed constipation and unexplained dyspeptic symptoms."
• The authors concluded that there was a link between her weight gain and FMT treatment and further instigated a policy: "to use nonobese donors for FMT."

Repeating the fact that this is a single case report and so cannot really inform about any generalisable relationship between a poo(p) transplant and weight gain/loss and that correlation does not necessarily imply causation, this is an interesting paper. The first thoughts running through my mind when reading this paper was a comment from Dr Emily Deans a few years back about poo transplants and ensuring: "if you ever have a fecal transplant, make sure it is from a slender, non-asthmatic, happy person!" Although said in jest, it appears that Dr Deans may have been on the money with at least part of her prediction.

Insofar as the possibility of a connection between the use of FMT and weight gain/loss, well, we have kinda seen evidence emerging that gut bacteria might be doing far more than just helping us digest our food or making the odd vitamin or two. I've covered something on the mouse - Akkermansia muciniphila weight study before on a sister blog (see here) and how in a mouse at least, certain types of bacteria might be implicated in energy homoeostasis. You could ask whether some profiling of the donor stool might be indicated in future attempts at FMT covering something like A. muciniphila and other potentially important species bearing in mind, the relationship is likely to be complex and not just limited to one type of gut bacteria being 'present or not'.

The other intriguing point that also arises from the Alang/Kelly paper is the idea that weight gain/loss might not solely be driven by the classical 'food in, energy out' relationship which many people cling to as an explanation of our current obesity statistics. Again, I've talked about this idea before on this blog (see here) and how factors such as sleep and gut bacteria might come into play in some cases, albeit with a lot more research required including some genetic input into proceedings. Probiotics (to 'alter' gut bacteria) for weight management is still a relatively new area of investigation despite some intriguing initial results [2].

More controlled studies are of course implied in this area. I might also advance the idea that a little more focus on other residents of the gastrointestinal (GI) tract might also be indicated in future work including the emerging idea of the gut virome and 'bacteriophages' (viruses attacking bacteria) as per what is being doing in other areas of interest to this blog [3]. That and further work on another of my preoccupations, gut barrier integrity bearing in mind things might not be entirely straight-forward [4].

Then to some music: Shame Shame Shame (shame on you).

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[1] Alang N. & Kelly CR. Weight Gain After Fecal Microbiota Transplantation. Open Forum Infect Dis. 2015; 2: 1.

[2] Sanchez M. et al. Effect of Lactobacillus rhamnosus CGMCC1.3724 supplementation on weight loss and maintenance in obese men and women. Br J Nutr. 2014 Apr 28;111(8):1507-19.

[3] Yolken RH. et al. Metagenomic Sequencing Indicates That the Oropharyngeal Phageome of Individuals With Schizophrenia Differs From That of Controls. Schizophr Bull. 2015. Feb 9.

[4] Kless C. et al. Diet-induced obesity causes metabolic impairment independent of alterations in gut barrier integrity. Molecular Nutrition & Food Research. 2015. Feb 10.

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Alang, N., & Kelly, C. (2015). Weight Gain After Fecal Microbiota Transplantation Open Forum Infectious Diseases, 2 (1) DOI: 10.1093/ofid/ofv004

Gut dysbiosis in treated coeliac disease: time for a probiotic or worse?

"Our findings indicate that dysbiosis of microbiota is associated with persistent gastrointestinal symptoms in treated celiac disease patients and open new possibilities to treat this subgroup of patients."

That was the summary of the paper published by Pirjo Wacklin and colleagues [1] who looked at the bacterial constitution of the duodenal microbiota [the bacteria which inhabit us] in a small group of participants diagnosed with coeliac (celiac) disease who "had been following a strict GFD [gluten free diet] for several years and had restored small bowel mucosa and negative celiac autoantibodies." Based on an analysis of bowel symptoms recorded using the Gastrointestinal Symptom Rating Scale, researchers reported that despite the use of a gluten free diet - universally indicated for coeliac disease (CD) - a proportion of their cohort still presented with "persistent symptoms" and it is within this cohort they were aiming to see whether: "abnormal intestinal microbiota may be associated with persisting gastrointestinal symptoms in treated celiac disease patients."

I'm applying for a villain loan. I go by the name of Vector.

"The treated patients with persistent symptoms had a higher relative abundance of Proteobacteria (P=0.04) and a lower abundance of Bacteroidetes (P=0.01) and Firmicutes (P=0.05)." That and "their microbial richness was reduced." All of this led authors to conclude that for some with CD, a gluten free diet might just be the start of a management schedule to alleviate symptoms and improve quality of life.

This is not the first time that CD (both treated and untreated) has been discussed with the gut microbiome in mind. The paper from De Palma and colleagues [2] (open-access) hinted that there may be more to see based on analyses of fecal samples for IgA-coated bacteria compared to results from asymptomatic controls. Granted the results do not directly overlay with the recent Wacklin findings but it's a start at least. Likewise the paper from Sellitto and colleagues [3] (open-access) (covered in a previous post on a sister blog) might also be pertinent to add to the discussion with their findings of "significant differences between the developing microbiota of infants with a genetic predisposition for CD and those from infants with a non-selected genetic background." I might add that the delayed introduction of gluten bit to their paper has not seemingly been borne out by subsequent larger scale research (see here).

Then to the next question leading from the Wacklin results: do issues with gut bacteria mean that altering gut bacterial communities might be an intervention option? Well, one might certainly consider something like the use of probiotics to try and 'change' the bacterial make-up as a possibility. Indeed, type 'probiotics and celiac disease' (non-UK spelling) into PubMed and you get an array of papers talking about how probiotics might already have a role for some with CD. I've previously talked about the paper from Sarno and colleagues [4] on this blog (see here) and "a novel effect of probiotics in the prevention of undigested gliadin peptides toxic effects". Tomorrow on this blog, I have a post scheduled tomorrow about the paper from Duar and colleagues [5] on probiotics potentially degrading gluten peptides. One might also entertain the possibility that certain probiotics might also affect related systems such as abnormal intestinal permeability too...

Insofar as probiotics potentially affecting GI symptoms in CD, the paper by Smecuol and colleagues [6] provides some preliminary data suggesting that there may be more to see in this area. Based on their examination of "the probiotic Bifidobacterium natren life start (NLS) strain", authors concluded that under placebo-controlled conditions: "those randomized to B. infantis experienced a significant improvement in Gastrointestinal Symptom Rating Scale (P = 0.0035 for indigestion; P = 0.0483 for constipation; P = 0.0586 for reflux)". And yes, their results were based on the same Gastrointestinal Symptom Rating Scale used by Wacklin and colleagues.

Rather more speculatively, and with specific regard to the the 'or worse' bit of the title of this post is another possible means that one might think about altering the gut microbiota: the fecal microbiota transplantation or stool transplant. Now just before anyone gets the wrong idea here, I'm not talking about some sort of DIY transplant for CD as per other media reports (see here). What I do think is worthwhile however is for some brave researcher(s) to perhaps entertain the idea that transplanting bacteria from one person to another might have some potentially important effects in cases of CD as per it's use in other areas of medicine (see here) and onwards think about putting some actual science to the anecdotes. I'll say no more on this matter (at least for now).

Music to close: Roxanne by The Police.

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[1] Wacklin P. et al. Altered Duodenal Microbiota Composition in Celiac Disease Patients Suffering From Persistent Symptoms on a Long-Term Gluten-Free Diet. The American Journal of Gastroenterology. 2014. November 18.

[2] De Palma G. et al. Intestinal dysbiosis and reduced immunoglobulin-coated bacteria associated with coeliac disease in children. BMC Microbiol. 2010 Feb 24;10:63.

[3] Sellitto M. et al. Proof of concept of microbiome-metabolome analysis and delayed gluten exposure on celiac disease autoimmunity in genetically at-risk infants. PLoS ONE. March 2012.

[4] Sarno M. et al. Lactobacillus paracasei CBA L74 interferes with gliadin peptides entrance in Caco-2 cells. Int J Food Sci Nutr. 2014 Jul 17:1-7.

[5] Duar RM. et al. Identification and characterization of intestinal lactobacilli strains capable of degrading immunotoxic peptides present in gluten. J Appl Microbiol. 2014 Nov 6. doi: 10.1111/jam.12687.

[6] Smecuol E. et al. Exploratory, randomized, double-blind, placebo-controlled study on the effects of Bifidobacterium infantis natren life start strain super strain in active celiac disease. J Clin Gastroenterol. 2013 Feb;47(2):139-47.

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Wacklin, P., Laurikka, P., Lindfors, K., Collin, P., Salmi, T., Lähdeaho, M., Saavalainen, P., Mäki, M., Mättö, J., Kurppa, K., & Kaukinen, K. (2014). Altered Duodenal Microbiota Composition in Celiac Disease Patients Suffering From Persistent Symptoms on a Long-Term Gluten-Free Diet The American Journal of Gastroenterology DOI: 10.1038/ajg.2014.355

The gut microbiota and ME/CFS

Continuing a common theme of gut bacteria on this blog, most recently with autism in mind, my attention today turns to a paper by Frémont and colleagues* looking at the gut microbiota in cases of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS).

Cross my palm @ Wikipedia 

This is not the first time that those trillions of bacterial masters of ours have cropped up on this blog with CFS/ME in mind as per my recent post on yuck factor 10 and the fecal microbiota transplant (FMT) with CFS/ME in mind (see here).

Frémont et al utilised the most commonly used tool of the bacteriologists trade, high-throughput 16S rRNA gene sequencing (see here for an overview** and here for some issues with the method), to classify bacteria derived from a lovely sample medium - stool samples - provided by 43 participants diagnosed with ME/CFS compared with 36 asymptomatic controls.

They reported a few interesting things.

• Because samples were provided by both Belgian and Norwegian participants (both ME/CFS and control groups), the authors reported differences in the type of bacteria between the different country samples. I'm guessing that quite a lot of this variation has to do with environmental factors such as food preferences and the like as per what other studies have shown. We also know for example that what you eat can have a fairly important effect on what bacteria you have in your gut (see here).
• "Norwegians showed higher percentages of specific Firmicutes populations" when looked at as a whole in comparison to the Belgian samples.
• When comparing Norwegian CFS/ME participants with their fellow asymptomatic country-people "patients presented increased proportions of Lactonifactor and Alistipes, as well as a decrease in several Firmicutes populations". Readers who clicked on the link for more information about Alistipes might recognise the name carried by a particular species, A. finegoldii named in honour of one Sydney Finegold, a regular on the autism-gut bacteria research scene. 
• "In Belgian subjects the patient/control separation was less pronounced, however some abnormalities observed in Norwegian patients were also found in Belgian patients". Not too much more to add there aside from the suggestion that searching for diagnosis-wide biomarkers for a heterogeneous condition like CFS/ME perhaps suffers from the same methodological ills as has been talked about with the autisms in mind (see here). That and the whole brain CFS/ME vs gut CFS/ME subgroup discussions that I've had on this blog. 

Appreciating that this was a relatively small scale study in terms of participant numbers, I'm intrigued by this study and its results. Heterogeneity in presentation and all the myriad of other factors which can and do affect gut bacteria are important interfering factors in any kind of research in this area. Indeed if one compares the gut microbiome with some of the other -omes such as the genome or epigenome, one starts to appreciate the similar issues involved in building up a picture of the underlying pathology behind a condition like CFS/ME in terms of no one gene or epigenetic factor probably working in isolation covering all cases. So it is probably true for the gut microbiome too.

That being said, unlike genes and to a lesser extent the epigenome, where differences are identified in the various phylum/class/order/family/genus/species of bacteria present potentially even in just subgroups of the condition, one would assume that some corrective intervention could be put in place which might, just might, affect the presentation of symptoms. Indeed the authors speculate on "treatments based on gut microbiota modulation (antibiotics, pre and probiotics supplementation)" which brings me to the paper by Groeger and colleagues**** and back to the original paper by Borody and colleagues***** and indeed outside of CFS/ME, that interesting case study on antibiotics and autism which I discussed recently (see here) [no medical advice is given or intended].

To close, Muscial Youth and a blast from the 80s past.

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* Frémont M. et al. High-throughput 16S rRNA gene sequencing reveals alterations of intestinal microbiota in myalgic encephalomyelitis/chronic fatigue syndrome patients. Anaerobe. 2013 Jun 19. pii: S1075-9964(13)00092-9. doi: 10.1016/j.anaerobe.2013.06.002.

** Trichopoulou A. et al. Disparities in food habits across Europe. Proceedings of the Nutrition Society. 2002; 61, 553–558.

*** Větrovský T. & Baldrian P. The Variability of the 16S rRNA Gene in Bacterial Genomes and Its Consequences for Bacterial Community Analyses. PLoS ONE. 2013; 8(2): e57923. doi:10.1371/journal.pone.0057923

**** Groeger D. et al. Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut. Gut Microbes. 2013 Jun 21;4(4).

***** Borody TJ. et al. The GI microbiome and its role in Chronic Fatigue Syndrome: A summary of bacteriotherapy. Journal of the Australasian College of Nutritional and Environmental Medicine. 2012; 31: 3-8.

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Frémont M, Coomans D, Massart S, & De Meirleir K (2013). High-throughput 16S rRNA gene sequencing reveals alterations of intestinal microbiota in myalgic encephalomyelitis/chronic fatigue syndrome patients. Anaerobe PMID: 23791918

The gut microbiome and chronic fatigue syndrome

I've hinted before on this blog and its sister blog about how one of the most unappealing of interventions - fecal bacteriotherapy - is starting to make some waves in managing various conditions. I know its not everyone's cup of tea but the concept of transplanting whole stools or specific types of enteric bacteria from one person to another is actually providing some well needed relief for quite a few people.

Insert here.... @ Wikipedia  

If it sounds like an undesirable treatment option, put yourself in the shoes of someone who for example is suffering as result of infection due to C. difficile and the potential consequences that this can entail after other treatment options have been exhausted and then wonder again. Better still, have a look at that probiotic yoghurt drink that is sitting in your fridge and ponder the question: where did the 'special' bacteria included in this drink originally come from? (hint: 'donor zero' is probably smiling at all of us).

Whilst fecal bacteriotherapy is moving into more mainstream medicine circles for conditions linked to things like C.diff, various other states and diseases are also starting to be discussed with the s--t transplant in mind. One person in particular is leading these discussions, Dr Thomas Borody, following his groundbreaking work on triple therapy for H.pylori infection (see here), and some discussions on 'emerging' applications* (no pun intended). Indeed Dr Borody is quite the leading light when it comes to fecal bacteriotherapy.

I was particularly interested to read the paper by Borody and colleagues** looking at the potential application of bacteriotherapy to cases of chronic fatigue syndrome (CFS). Regular readers might already know of my tendency to stray into the research domain of CFS (and ME) on this blog and beyond not least because quite a bit of the research there seems to overlap with what I talk about with autism in mind (e.g. immune function, mitochondrial issues, even HERVs..).

Anyhow, with many thanks to Sarah Finlayson, one of Dr Borody's co-authors, for sending me a copy of their paper, a few points are worth noting:

• This is a paper which kills two birds with one stone. On the one hand, there is quite a nice summary of CFS and the gut microbiome (hopefully this link still works for non-members). On the other hand, the paper describes the experiences of 60 patients with CFS attending Dr Borody's clinic some time in the mid-1990s and in receipt of transcolonoscopic (TC) and rectal infusions of "anaerobic bacterial culture". Distinct from the 'full works' of of a stool transplant or 'fecal microbiota transplantation (FMT)', bacteriotherapy involves the 'fusion of a mixture of 13 non-pathogenic enteric bacteria" which include those of the Bacteroidetes, Clostridia and E.coli families/phyla/species.
• Every participant received at least one TC infusion; most also received a second rectal infusion (n=52); a small number received two days of additional rectal infusion (n=3). Actually, as you'll see in a minute, there was a bit more to this than what is mentioned in the methods section of the paper.
• Results: it is slightly difficult to gauge what specific results were achieved from this trial given that participants were judged to be responders or non-responders at 4 weeks based on some fairly nebulous criteria. So for example, responders signified "a resolution of CFS symptoms (sleep deprivation, lethary/fatigue)" but without the paper actually saying how these outcomes were measured or what tools were used. I'd hazard a guess that it was a case of participant interview or questionnaire but I can't confirm this. 
• On the basis of this responder / non-responder coding, 35 (58%) were judged responders to bacteriotherapy. This figure improved when initial non-responders (n=15) were given a second TC infusion "followed by rectal infusion (n=4) or an oral course of cultured bacteria (n=6)"; up to 42 / 60 (70%) responders.
• Gastrointestinal (GI) symptoms were reported to be resolved in 37 of the 42 final responders.
• Follow-up of participants some 15-20 years later (12 of the original cohort) suggested that over half of them remained free of their CFS symptoms; although importantly, some relapsed (5/12) between 18-36 months post-bacteriotherapy.

I probably don't need to highlight the fact that this was very much an observational case-series study over anything like a clinical trial. My initial excitement at reading this paper was very slightly dampened by the way results were reported and those all-important missing details regarding how the authors measured change over the period of baseline vs. bacteriotherapy. Even the reported resolution of GI symptoms leaves me asking questions like: what GI symptoms, how were they measured and who did the measuring? There are gaps in this work, make no mistake of that. Bear however in mind issues such as when this study was initially carried out and how the diagnostic criteria of CFS might not necessarily have been as well-defined as they are today. Just sayin.

I can also imagine some people are reading this post and thinking what the .... ! How can a condition like CFS be sensitive to a bacterial transplant, and what about those methods used to introduce such a therapy... yeah right. Bear in mind however that our nether regions are actually quite good routes of drug administration bypassing for example, hostile environments like the stomach and onward the first-pass effect. Indeed the question should be: would you prefer this to the insertion of a naso-gastric tube as is the other option when delivering bacteria to where it is needed? Your choice...

Having said all that I am still interested in this line of inquiry. The authors for example, suggest a possible link between "the resolution of gastrointestinal and CFS symptoms" and how this "supports the theory of a possible gastrointestinal-associated etiology, potentially arising from alterations to the bowel flora". I kinda speculated about the many faces (Man-E-Faces?) of CFS in a previous post on HERVs and ME (see here) and how the spectrum of CFS/ME might be just that, a spectrum. It strikes me that one could very easily investigate this possible sub-types issue within a well-defined population.

There is obviously more to do in this area of endeavour. As per a recent article I played a small hand in writing, the gut microbiome is a relatively uncharted area of medicine in terms of its links to health and wellbeing and indeed our often varied response to the pharmaceutics we all take potentially as a result of our gut bacterial composition. There are obvious important questions to ask about safety (the gut virome anyone?) and efficacy of interventions like bacteriotherapy particularly when applied to conditions of unknown origin like CFS/ME. Indeed, the desperation of some sufferers makes them very vulnerable to all kinds of potential intervention options which might not necessarily be right for them.

But that's not to say there isn't already research movement (no pun intended) in the area of the gut microbiome and CFS/ME as per Sanjay Shukla study (detailed here) which should be reporting quite soon. That added to the Michael Maes suggestion of issues with gut permeability in cases of CFS/ME (sound familiar?) makes for quite a few hypotheses being open for testing with much greater focus on rigour in research methodology.

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* Borody TJ. & Khoruts A. Fecal microbiota transplantation and emerging applications. Nat Rev Gastroenterol Hepatol. 2011; 9: 88-96.

** Borody TJ. et al. The GI microbiome and its role in Chronic Fatigue Syndrome: A summary of bacteriotherapy. Journal of the Australasian College of Nutritional and Environmental Medicine. 2012; 31: 3-8.

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Thomas Borody, Anna Nowak, & Sarah Finlayson (2012). The GI microbiome and its role in Chronic Fatigue Syndrome: A summary of bacteriotherapy Journal of the Australasian College of Nutritional and Environmental Medicine, 31 (3)