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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Open label study of probiotics and autism

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Intestinal dysbiosis, irritable bowel syndrome and ME/CFS

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

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

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

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

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

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

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

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

Unexpected improvement in core autism symptoms following a probiotic?

The paper by Enzo Grossi and colleagues [1] (open-access) is definitely worthy of a post today and the suggestion that the "appropriate use of probiotics" might be something to consider for at least some diagnosed as being on the autism spectrum.

Accepting that I'm slightly curious as to what would be considered 'inappropriate use of probiotics', the Grossi paper describes the clinical journey of a boy aged 12 diagnosed with an autism spectrum disorder (ASD) accompanied by learning (intellectual) disability who was concurrently diagnosed with coeliac disease (CD). The CD diagnosis was a slightly complicated affair given that whilst he presented with the relevant 'genetics' of CD (HLA genotypes) and "a slight elevation of transglutaminase antibodies" a gluten-free diet seemingly did very little in terms of clinical benefits and when it came to the "blood-specific tests for celiac disease" they were always negative. I'll come back to some of these points shortly but his chronic gastrointestinal (GI) symptoms that were first thought to be CD related were subsequently put down to irritable bowel syndrome (IBS).

In light of the IBS diagnosis and given some pretty important research suggesting that specific probiotic formulations might have treatment-potential for some IBS (see here), a probiotic intervention was prescribed: VSL#3. What happened next is intriguing...

After a few weeks of probiotic treatment, some 'apparent improvements' were noted in the boy's behavioural presentation. This led the authors to start looking more systematically at whether said improvements could be charted and possibly tied into his probiotic use. We are told that the various components of his behavioural plan that had been in place for some 6 years were continued without "any particular change." Use of the gold-standard assessment tool that is the ADOS - Autism Diagnostic Observation Schedule - was employed over a period of about a year-and-a-half to covering the period of probiotic use. Data for two ADOS assessments were available before the probiotic was installed and four assessments were carried out during and post-intervention. The results suggested that scores relevant to social affect (the DSM-5 term describing issues with social and communicative domains) changed over the intervention period in line with some of the observations made of this boy. Further: "This change was surprising since in our assessment records over several years, the patient status had remained steadily unchanged." It should also be noted that the GI symptoms, the initial target of probiotic use, also reduced "as expected."

Yes, I know that this is a case report (and N=1) and given what we (think we) know about autism, such results can by no means be generalised to all autism. There could also be a million and one other variables potentially accounting for the results including something called puberty potentially playing a role (see here) given the age of the boy. One needs to be cautious.

But... these are still potentially important results for quite a few different reasons. Going back to the description of CD being diagnosed and then un-diagnosed, regular readers might know about my interest in something called non-coeliac gluten sensitivity (NCGS) when it comes to something like autism (see here). The suggestion being that although a diagnosis of autism is not protective against a diagnosis of CD, the still emerging peer-reviewed data seems to suggest something slightly more gluten-fuzzy when it comes to at least some autism. That elevated levels of tissue transglutaminase are also not an uncommon finding in relation to [some] autism (see here) adds to the curiosity in this area.

Bowel or GI issues occurring alongside autism? Well, I've said it before and I'll say it again: GI issues (both functional and pathological) are over-represented when  it comes to autism (see here). You can call it IBS or similar other bowel related label but the fact of the matter is that such issues are not uncommon and lots more resources need to be poured into looking at and importantly, treating such issues save any further health inequalities appearing alongside the label of autism. It makes good sense that if something like IBS is diagnosed, and the various meta-analyses suggest that probiotics might be one part of an intervention strategy for IBS, their use where IBS clusters with autism should be the same as when autism is not part of the equation. Simple as.

The Grossi case report also highlights how gut and brain, with a healthy portion of gut microbiome, might show some important links for some on the autism spectrum [2]. This is by no means 'a new thing' (see here) and to some extent, justifies the various studies where gut bacteria for example, have been looked at in the context of autism (see here for example). That such a connection might also include issues with gut permeability (see here) is another important detail and is evidenced by the possibility that probiotics may also work on the gut membrane [3] as well as those trillions of wee beasties that call us home.

In short, more research on the use of probiotics with autism is very much implied (and indeed is already in progress). Watch this space.

To close, first we had Mr Pharmacist from The Fall. Now we have Oxymoronic from NOFX. Spot the difference...

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[1] Grossi E. et al. Unexpected improvement in core autism spectrum disorder symptoms after long-term treatment with probiotics. SAGE Open Medical Case Reports. 2016; 4: 2050313X16666231.

[2] Inoue R. et al. A preliminary investigation on the relationship between gut microbiota and gene expressions in peripheral mononuclear cells of infants with autism spectrum disorders. Biosci Biotechnol Biochem. 2016 Sep 1:1-9.

[3] Mennigen R. et al. Probiotic mixture VSL#3 protects the epithelial barrier by maintaining tight junction protein expression and preventing apoptosis in a murine model of colitis. Am J Physiol Gastrointest Liver Physiol. 2009 May;296(5):G1140-9.

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Grossi, E., Melli, S., Dunca, D., & Terruzzi, V. (2016). Unexpected improvement in core autism spectrum disorder symptoms after long-term treatment with probiotics SAGE Open Medical Case Reports, 4 DOI: 10.1177/2050313X16666231

Bipolar disorder in irritable bowel syndrome (IBS): real gut-brain axis stuff

"Our results support a significantly higher prevalence rate of BD [bipolar disorder] in IBS [irritable bowel syndrome] patients than in controls."

So said the results of the meta-analysis and systematic review published by Ping-Tao Tseng and colleagues [1] (open-access available here) based on the suggestion that "both IBS and BD may, at least partially, share a similar mechanism of pathophysiology" specifically with immune function in mind.

Building on previous research suggesting that (a) various psychiatric comorbidity might be over-represented in IBS (see here) and (b) that gastrointestinal (GI) inflammation and immune activation might not be unstrange bedfellows in at least some cases of BD (see here), the old gut-brain axis receives some important support from these latest findings. Bipolar disorder (BD) I should explain, is characterised by episodes of depression and mania and vice-versa.

The hows and whys: some 170,000 people diagnosed with IBS and 190,000 not-IBS controls were included from 6 studies that met the authors' criteria for inclusion. Two of the six studies originated from Taiwan and that oh-so-useful resource that is the National Health Insurance Research Database (NHIRD). In those diagnosed with IBS: "The prevalence rate of BD was significantly higher in the IBS patients than in the HCs [healthy controls] (OR = 2.48; 95% confidence interval [CI]: 2.35–2.61; P < 0.001)." The authors also suggested that they "could not find any significant association between the comorbidities of DM [diabetes mellitus]/hypertension and the prevalence rate of BD in IBS patients."

The authors provide one or two caveats regarding their results, not least that a meta-analysis is only as good as the studies it includes (see here for another example of how this might play out). They stress the observation-only link between BD and IBS in their paper "rather than any mechanistic explanation of the comorbidity of these 2 diseases." So, there is more to do in this area. Interestingly too, they also talk about what their findings might mean for the practice of prescribing antidepressants in cases of IBS. To quote: "We suggest that clinicians and researchers start to investigate the possibility of a phase-shift to manic episodes in IBS patients treated with antidepressants." Indeed.

I'm gonna conclude with two further points that might provide some avenues for further scientific investigation in this area. First is the idea that treating [some] IBS with specific probiotic formulations seems to be in the research and clinical ascendancy these days (see here). The question is what effect (if any) such treatments might have on accompanying BD symptoms? Y'know taking into account that those trillions of wee beasties that call our gut home (the gut microbiota) might be doing so much more than just digesting food and making the odd nutrient or two? At this point I might also bring to your attention the case report from Grossi and colleagues on IBS, probiotics and autism [2] that will be gracing this blog soon. This is made all the more interesting by the suggestion that bipolar disorder might not be an unstrange diagnostic bedfellow with autism (see here). Second is the potentially intersecting research talking about states such as [some] mania as perhaps being linked to bacterial infections (see here). Stay with me on this one, but is it at all possible that infection - possibly a GI-related infection - might affect both bowel and behaviour at the same time? What can we do about this? Questions, questions, questions...

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[1] Tseng PT. et al. A meta-analysis and systematic review of the comorbidity between irritable bowel syndrome and bipolar disorder. Medicine (Baltimore). 2016 Aug;95(33):e4617.

[2] Grossi E. et al. Unexpected improvement in core autism spectrum disorder symptoms after long-term treatment with probiotics. SAGE Open Medical Case Reports. 2016; 4: 2050313X16666231

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Tseng PT, Zeng BS, Chen YW, Wu MK, Wu CK, & Lin PY (2016). A meta-analysis and systematic review of the comorbidity between irritable bowel syndrome and bipolar disorder. Medicine, 95 (33) PMID: 27537599

On probiotics and irritable bowel syndrome (IBS)

Granted, I am taking a slight departure from the material typically discussed on this blog by introducing the paper by Yan Zhang and colleagues [1] who reported the findings of a meta-analysis examining "the efficacy of different probiotic types, doses and treatment durations in IBS [irritable bowel syndrome] patients diagnosed by Rome III criteria via a meta-analysis of randomized controlled trials (RCTs)." The results however - "Probiotics are an effective pharmacological therapy in IBS patients" - were important enough for me to think about discussing, particularly in the context that IBS might not be stand-alone condition (see here) and some recent research in progress [2] (see here for my take) that could illustrate some wider relevance.

The Zhang paper is open-access so doesn't need any grand rewriting from me in terms of methods or findings but a few things stick out. First is the fact that quite a few different probiotic preparations have been experimentally examined with IBS in mind. From the 21 studies looked at by Zhang et al, we have some recurring themes including different types of Lactobacillus acidophilus and Lactobacillus rhamnosus for example being included in the preparations. The inclusion of a preparation called VSL#3 also caught me eye in light of some discussions about a potential 'antibiotic brain' recently on this blog (see here) and what might reverse this in mice. Of additional note was the use of an old friend: Saccharomyces boulardii that continues to impress [3].

Second, and related to the first point, are the authors conclusions that: "Single probiotics, a low dose, and a short treatment duration were more effective with respect to overall symptom response and QoL [quality of life]." The authors provide some rather interesting forest plots illustrating how the analysed data helped them reach this conclusion; albeit bearing in mind that "the effects of individual probiotic species" were not analysed in the current meta-analysis. In other words, some preparations seem to work pretty well but we don't know enough about which ones used under which circumstances.

Finally, I noted that the whilst the use of a placebo was an important eligibility criteria for inclusion in their meta-analysis - "the studies were randomized controlled trials (RCTs) that compared probiotics with placebo" - the authors did not shy away from the fact that: "An appreciable placebo effect was detected in some studies, which may have minimized the effects of probiotics." Placebo effects and IBS is something again, that has been discussed before on this blog (see here) bearing in mind I'm not saying that IBS is 'all in the mind' or anything like that.

Set within the context of other recent meta-analyses concluding that: "There were alterations of gut microbiota in IBS patients and it implied that alterations of gut microbiota might be involved in the pathogenesis of IBS" [4] one shouldn't necessarily be surprised that there may have been effects from the use of probiotics in cases of IBS. Assuming that an oral probiotic is able to survive the stomach environment and actually colonise [parts of] the gastrointestinal (GI) tract (if only for a defined amount of time) the cost-effectiveness of this intervention coupled with the low rates of side-effects makes for impressive reading in terms of the treatment of at least some cases of IBS.

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[1] Zhang Y. et al. Effects of probiotic type, dose and treatment duration on irritable bowel syndrome diagnosed by Rome III criteria: a meta-analysis. BMC Gastroenterology. 2016; 16: 62.

[2] Santocchi E. et al. Gut to brain interaction in Autism Spectrum Disorders: a randomized controlled trial on the role of probiotics on clinical, biochemical and neurophysiological parameters. BMC Psychiatry. 2016 Jun 4;16:183.

[3] Szajewska H. & Kołodziej M. Systematic review with meta-analysis: Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea. Aliment Pharmacol Ther. 2015 Oct;42(7):793-801.

[4] Zhuang X. et al. Alterations of gut microbiota in patients with irritable bowel syndrome: A systematic review and meta-analysis. J Gastroenterol Hepatol. 2016 Jun 14.

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Zhang Y, Li L, Guo C, Mu D, Feng B, Zuo X, & Li Y (2016). Effects of probiotic type, dose and treatment duration on irritable bowel syndrome diagnosed by Rome III criteria: a meta-analysis. BMC gastroenterology, 16 (1) PMID: 27296254