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)

When health and hygiene equals just too clean

For most of us in the Industrialised world we have certain luxuries. Luxuries like a roof over our head to keep out the elements, and in particular those savage Winters we have been having recently, radiators and air conditioning to keep us at the right temperature all year round, just about any food imaginable within walking distance for most and a life relatively free from rodents and pests to hopefully keep us free from lots of not-so-nice disease-causing bacteria and viruses. It sounds pretty good doesn't it?

What if however I was to suggest to you that our warm, clean, pest-free lives might actually be the cause of some ill-health. That our modern obsession with all things clean and sterile might be counter to what we were originally made for. Would I be spoiling things? Welcome to the hygiene hypothesis and the suggestion that modern health and hygiene might just be too clean.

I am sure that most people will have heard about the hygiene hypothesis in some shape of form. The theory is that our collected efforts to eradicate anything and everything which might not meet with our exacting standards of cleanliness and 'sterility' might actually be putting our immune system in infancy out of a job, with some possible consequences to our health later in life. Whilst the theory remains just a theory, there is some evidence to corroborate this interesting view including some interesting stories about life down on the farm. I was drawn in particular to this recent article and the suggested link between asthma and Helicobacter pylori (also covered here) following my recent posts about asthma and allergy in relation to autism.

The article by Arnold and colleagues looked at exposure patterns to H. pylori in mice and how early exposure to the bacterium seemed to guide immune response to asthma-inducing allergens: the earlier that mice were exposed to H. pylori, the less they reacted to the allergens, a process modified by regulatory T-cells. When I first read this article, the first thing that went through my mind was H. pylori and its relationship to peptic ulcers and that Nobel prize for Medicine awarded in 2005 leading to triple therapy. H. pylori = bad, and eradication of H. pylori = good.

Not so, at least in mice, according to this recent article. I am of course minded to say that correlation does not necessarily imply causation and further replication of the results is required, not least in how such findings relate to humans. I do however appreciate the notion that the various bacteria that traditionally colonised us, having perhaps been modified time after time to survive in places like the human gut, might have quite a lot of effects in relation to health and moderating our risk of things like allergic disease. I partially covered this in a previous post on that lovely helminthic therapy (not for those of a squeamish disposition).

I don't for one minute advocate rolling babies and young children in dirt and detritus or adopting a pet pig just to ensure that they have their full allocated early exposure to bacteria (and viruses) to potentially help with later health. I do however follow the view that children should be allowed to be children; to roll in the short grass being careful of those pesky ticks, make those mud pies and for parents not to be too put off by the appearance of the odd dirty fingernail here and there. Soap and water was good enough for most of us, not forgetting to wash behind the ears. How about a visit to an exhibition on the history of dirt for a real insight?

As if to prove a point, take a look at this young lad from a few years back... I wonder if he ever suffered from an allergy?