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9th Invest in ME International ME Conference, 2014 - Part 2: Pathogens and the Gut
Mark Berry continues his series of articles on the 9th Invest in ME International ME Conference in London, with the emphasis shifting from autoimmunity to pathogens and the gut ...
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An Introduction to the Microbiome and ME/CFS

Discussion in 'Phoenix Rising Articles' started by Phoenix Rising Team, Jan 13, 2014.

  1. Phoenix Rising Team

    Phoenix Rising Team

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    Bugs are not all bad, in fact many in our gut are essential to good health, but problems with these could help explain some diseases, possibly even ME/CFS. Simon McGrath takes an introductory look at the Microbiome - an area that is fast becoming a focus for several research teams looking at our own illness...

    [​IMG]
    Home for gut microbes; few survive in the stomach but they flourish in the small intestine and dominate the colon - 60% of the dry weight of poop is bacteria.

    The microbiome - the bugs that live in our gut and on our skin - has become a hot topic, not least because of the coverage of 'faecal transplants' that apparently cure life-threatening infections by restoring the microbiome with poop from healthy donors.

    There are some impressive stats around: with 100 trillion cells microbes outnumber our cells around 10:1 and there are around 5 million different gut microbe genes compared with around 25,000 human ones.

    If it's any consolation, we are 98%+ human by weight - since the microbes are tiny - but it's probably more accurate to think of ourselves as mobile ecosystems rather than as pure human beings.
    But what's this all got to do with ME/CFS? Well, Ian Lipkin and others think microbiome problems could be behind the chronic inflammation that is often linked to our illness, and which may even be revealed as a cause of the disease.


    Peering into the microbiome

    The microbiome refers to all the microbes in our gut and on our body: bacteria, fungi and single cell organisms (and even viruses). Technically, the microbiome refers to the collective genes of all the microbes (microbiome as in genome) while the microbes themselves are known as the microbiota, which is the term I'll use here.

    The microbiota isn't just applicable to the gut but can apply all over our bodies: armpits, mouth, nose, skin and more. However, most research and this article will focus on the gut microbiota - the biggest and most important area.

    We tend to think of microbes as nasty thing to be avoided, but the microbiota is surprisingly useful and probably essential to our survival, for reasons that include:

    • making nutrients available, including making K and B vitamins
    • helping protect us from disease by 'crowding out' harmful pathogens, much like a densely-planted garden border stops weeds from growing
    • helping our immune system develop properly
    So it's perhaps not surprising the microbiota is now being called 'the forgotten organ'. Like any organ it can malfunction and microbiota problems are increasingly being linked to diseases, including Inflammatory Bowel Disease and Type 2 Diabetes.



    The Good, the Bad, and the Somewhere in Between

    Thousands of different species can survive and thrive in the human microbiota, but most of us carry around 500 species. Our individual microbiotat normally remains stable over time, though each person's is distinct; even identical twins have different microbiota.

    While there are many, many species of bacteria, in some way they play only a few different roles. The good guys are called 'symbionts', clearly paying their way e.g. those that make B vitamins and vitamin K.

    The bad guys - the pathogens like cholera and amoebic dysentery - aren't really part of the microbiota at all. Neutral 'commensals' don't do anything directly good but don't harm us either, and may well help by simply crowding the unhelpful types, especially the 'pathobionts'. Actually, as well as 'crowding-out', some bacteria fight each other with lethal proteins.

    'Pathobionts' include the infamous superbug Clostridium Difficile (C. diff for short) that usually sits there harmlessly in small numbers. However, in some situations - such as when helpful and neutral bacteria have been decimated by antibiotics, pathobionts show their Dark Side e.g. C. diff can take over causing bloody diarrhoea, which can be fatal in people already in poor health - and this is why C. diff can be so deadly in hospitals.

    Microbiota and our immune systems

    More immune cells are in the gut than anywhere else in the body, which makes sense as that's where most bugs are too. But it isn't simply bugs and our immune system facing off against each other: it turns out that the immune system needs the microbiota both to develop normally and to keep to keep it on an even keel. Germ-free mice, raised in sterile conditions, have no microbiota and are prone to some gut inflammatory diseases. This seems to be linked to problems with gut immune cells - particularly regulatory T cells (T-regs, shown in the photo), which we know don't develop properly in germ-free mice. T-regs help keep the immune system from over-reacting and setting off chronic inflammation; in particular they quieten down T-helper cells that otherwise rev up the immune system.

    Out of balance

    Dysbiosis is the fancy term for the gut bacteria getting out of balance, particularly the relationship with 'pathobionts', those bacteria that are harmless enough in small doses but can wreak havoc if given their head. The diagram opposite shows how an imbalance can lead to inflammation, which is what seems to be happening in Inflammatory Bowel Disease(IBD): for some reason there aren't enough of the symbionts that produce key molecules that help regulate the immune system, and inflammation results. There is also evidence in IBD that the body produces antibodies against helpful 'commensal' bacteria, and killing off the commensals would help the harmful pathobionts flourish.

    Maybe, just maybe, microbiota problems are also behind the low levels of chronic inflammation and other immune dysfunction that is often seen in ME/CFS.

    [​IMG]

    Cause or effect?


    The central question in microbiota research is not are microbiota changes associated with diseases (they are in numerous cases)? But are the changes a cause of disease or simply a knock-on effect? The findings above for Inflammatory Bowel Disease suggest a causal role for microbiota, and the success of faecal transplant treatment for C. diff (see below) is the strongest evidence yet.

    Faecal Transplants: Hard to swallow

    [​IMG]The microbiota's big break in medicine was the faecal transplant to treat persistent infections - such a gross idea that the media could not resist covering it (or us resist reading it). Of course, gross is relative - patients suffering with intractable or even life-threatening C difficile infections often don't see it that way: "Because a fecal transplant is gross, but cramps and bloody diarrhea are aesthetically pleasing?", as one writer put it.

    Initially the reports of faecal transplant were simply anecdotal and I have to admit I thought it all sounded like woo science. Then came case studies and a systematic review of 317 cases found a 92% success rate. Finally a trial comparing faecal transplant against antibiotics for treating recurrent C. diff was stopped early because the faecal transplant was so much more effective than the antibiotic. Faecal transplants are entering the mainstream, but fortunately someone has just found a way to extract the bacteria from faeces and parcel them up in a simple pill: yum.​
    And there are also examples of a causal relationship between microbiota and more complex illnesses. The best known case is obesity in mice. Germ-free mice, raised in sterile conditions, have no microbiota and tend to be thinner than normal laboratory mice. One possible reason for this is that the gut microbiota break down complex carbohydrates that mice can't digest on their own, making more food available.

    When these germ-free mice are given microbiota from lean mice they put on some weight, but they put on much more weight when given bacteria from obese mice. So perhaps one factor behind obesity is that some people have microbiota that help them extract more energy from food, and so put on more weight.

    However, it is early days for such research and the relationship between disease and changes in microbiota remains uncertain.

    Microbiota and ME/CFS

    Gastrointestinal symptoms are common in ME/CFS and could be linked to microbiota problems, and even chronic inflammation. Research on the microbiota is just beginning to appear in the ME/CFS literature:
    • Professor Kenny De Meirlier's small 2013 study on the microbiota of patients from Norway and Belgium had mixed results with differences seen between Norwegian patients but not between Belgian patients and controls.
    • A recent paper details 60 CFS cases treated (in the 1990s) with colonic 'bacteriotherapy' and reported a 58% rate for "resolution of CFS symptoms", though it wasn't clear how the study measured outcomes.
    • Pilot results from a CAA-funded microbiome study by Dr Shukla indicated that the microbiome of CFS patients responds differently to exercise than healthy controls. Data from the full study is now being analysed.

    Two important new microbiome studies underway

    Invest in ME have raised £100,000 (wow) for a microbiome study aiming to establish 'whether microbe-driven inflammatory responses can provide an explanation for the pathophysiology of ME'. The study, run by the impressive Professors Tom Wileman at the University of East Anglia and Simon Carding at Norwich, began last October as a three-year studentship and initial results could emerge in 2015. They will be looking at the microbiota of ME patients including both bacteria and viruses, testing for leaky gut and using metabolomics to look at the metabolism of the whole microbiota.

    Professor Ian Lipkin is focused on the microbiota for the same reason, particularly because his latest study found evidence of abnormal immune response in ME/CFS patients - could the microbiota be the cause? A microbiome study is underway: they plan to use a CFI cohort of 50 patients and 50 carefully-matched controls, but the study is held up by a lack of funds because the work they want to do is very expensive..
    If you want to make a donation of funds direct to this study, you can do so here. The team would also like to look at blood samples as well as the microbiome, but have yet to secure funding for this work. There will hopefully be a Phoenix Rising interview with Ian Lipkin about his microbiome project coming very soon, so do stay tuned.

    It may seem strange that bugs in our guts - not specific bugs, but an imbalance between different types - could cause ME/CFS, but that's just the line of research that Invest in ME and Lipkin are pursuing, focusing on a possible link with chronic inflammation. Microbiota in ME/CFS research is now taking off, and patients are helping make it happen.

    [​IMG]

    BBC Gut Microbiota podcast (Weds 15 Nov; 28 minutes).

    Simon McGrath tweets on ME/CFS research: @sjmnotes




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  2. Simon

    Simon

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    The microbiome is a pretty-complex area but it does seem to be an area of great potential for studying ME/CFS: as Ian Lipkin says "I think that the microbiome is going to be where the action is".

    If the blog looks too much to read, it's still worth checking out the excellent 5-minute animated video


    And thanks to @Firestormm for editing/posting the blog.
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  3. Marco

    Marco Old blackguard

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    Thanks Simon (and Russell).

    That was very informative as well as witty - "cramps and bloody diarrhea are aesthetically pleasing?” - classic!

    Regarding these preliminary findings :

    "Pilot results from a CAA-funded microbiome study by Dr Shukla indicated that the microbiome of CFS patients responds differently to exercise than healthy controls. Data from the full study is now being analysed."

    .... it may not be relevant but I was reading up on exercise, heat intolerance and heatstroke and was surprised to find that fatalities due to heatstroke during strenuous exercise in high temperatures is not just due to the internal organs 'cooking' (which they do) but ro endotoxemia/sepsis due to LPS being released into the bloodstream as the gut mucosal barrier breaks down.

    Leaky gut or a similar mechanism could well result in low grade systemic inflammation in ME/CFS which could just be enough to 'kick things off'.

    I wonder how many find a connection between gut and other symptoms or even if dysbiosis always leads to noticeable symptoms?
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  4. Simon

    Simon

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    Hi Marco

    Thanks - I loved that quote too.

    Invest in ME are specifically looking for leaky gut in ME/CFS patients vs controls following exactly that thought that leaky gut could be triggering a low grade chronic inflammation. Ian Lipkin seems to think the microbiome is a prime candidate for causing chronic inflammation too, though he doesnt' seem to be pursuing the leaky gut hypothesis.

    As for dysbiosis always leading to noticeable symptoms, I doubt anyone knows yet: microbiome research is so new that it is probably impossible to argue that anything always leads to anything else.
  5. Marco

    Marco Old blackguard

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    Hi Simon

    The mechanism of LPS inducing systemic inflammation (and from there systemic multi organ symptoms) has been well studied in alcohol abuse (it helps to look beyond the ME/CFS field).

    Reviewed here :

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2842521/

    Leaky gut is common in alcohol abuse. I found it interesting that LPS is usually 'detoxed' by the liver but of course in alcohol abuse the liver is also often damaged. What happens then is that processing is switched to the much less effective lymphatic system and LPS concentrations and systemic inflammation build up and can (and do) impact on CNS microglia.

    I wonder what mechanism Lipkin has in mind if not LPS translocation? The enteric nervous system?

    I guess we'll just have to wait.
  6. Bob

    Bob

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    Thanks for all the info Simon.

    I didn't know that Invest in ME had raised £100,000 for a microbiome study (I did know they were raising money) and I didn't know that they were looking for viruses, testing for leaky gut and using metabolomics (I've not come across that word before now.) I also didn't know the details of where the study was being run, and by whom.

    I personally can't get very enthused about the study of gut bacteria, because I think changes in the gut microbiome are symptomatic of (for example) some other underlying immune issue, rather than being causative in nature. But the Invest in ME study seems to be investigating other worthwhile issues, rather than just the constitution of the microbiome, which I think may have more potential of leading to useful findings.

    I'd like to see them testing gut biopsies for viruses as well, to test the enterovirus hypothesis. (I don't know if this is part of the plan.)
  7. HowToEscape?

    HowToEscape? Senior Member

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    Did ya have to put the notion of fecal transplant (ok, gross but in certain cases necessary) together with the word "swallow" and a drawing of the character sticking it's tongue out? That's, uh, a little beyond just gross. Well intentioned, I know, but consider an edit for those who read this within 1000 hours of dinner ;-)
  8. Simon

    Simon

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    Cheers, Bob.

    I was surprised when Ian Lipkin decided to pursue a microbiome study, because I had felt like you it was probably a marginal issue, but if someone of his calibre is going down this route - despite the huge costs - then I suspect it could prove important. Whether microbiome changes are a cause or effect is they key question, though perhaps first it needs to be clearly demonstrated that there are consistent microbiome changs with the illness. We do know, eg from C. diff, that microbiome changes can have causal effects so I do think it's worth looking at the possibility.

    [edit: trying to clarify exactly what IiME are doing re enteroviruses, they may well be doing biopsies] I agree the enterovirus finding deserves replication attempts. Did you see the comment from Cort that the original enterovirus finding might not be reliable?
    He gives more detail in the comments section:
    Sorry my poop joke didn't go down well :). Actually, I thought that was the best bit of the blog, but if others feel the same way as you I will revise as I didn't mean to cause offense - comments appreciated on this.


    Interesting stuff, thank you. I will try to check if the Lipkin study is looking at leaky gut
    Last edited: Jan 14, 2014
  9. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    This interests and excites me. Does it not point to a possible mechanism for autoimmunity? A past infection with an enterovirus producing autoantibodies against mitochondria? The virus could be long gone but the antibodies still attacking the mitos. This definitely fits with my preferred theoretical mechanism(s) of causation and perpetuation.

    It's no problem for me, but if more sensitive souls are adversely affected by all means remove it! :) I believe that some people have indeed ingested the said substance orally. :vomit: I am happy to edit this out if required, but it is a fact, albeit unpalatable. Whoops - I did it again. :D
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  10. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    Affirmative in my case, Captain.

    A full lower bowel makes my legs weak and achy. After a bowel movement, the legs are often dramatically stronger and pain-free. But not always - sometimes they are even weaker after a bowel movement. In the early days I sometimes had significant difficulty standing up after a BM as my legs had turned to jelly. My theory is that as things move along, the gut biota are altered in particular parts of the bowel which affect other parts of the body. pH could be part of it. The vagus nerve could too.

    Also, when I have bloating of the lower abdomen I also have brain fog and sleepiness, which are dispelled when I release the gas! I also get brain fog and sleepiness at other times so there is more than one cause of that, ditto probably the leg problems.
  11. user9876

    user9876 Senior Member

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    The thing I struggle with is putting the different pieces together. With the limited evidence from the rituximab trials it seems like b-cells are involved. But I guess this brings up a question of what anti-bodies are reacting with and what is then affected by the result of this reaction. Could different microbiomes be causing different stuff to be released into the blood that anti-bodies then react to with the result being some structure that blocks something else such as messaging in the body's control system? In which case would the rate of release of the stuff from the gut be determined by say exercise or over excursion in which case going someway to explain PEM. Or does this make no sense?

    Even if this is the case there may be a hideous matching problem making deductions very hard. Could it be that different antibodies match with different stuff from the gut and hence to produce similar structures. If this is the case there may not be unique signatures within the microbiome but it may be a combination of different antibodies when matched with a given microbiome.
  12. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    My thoughts:

    What you say makes a lot of sense.

    Different microbiomes could be involved in determining what gets into the bloodstream, but so could different diets, medicines, supplements, mains water variations, combined with different genotypes.

    (over-)Exertion does indeed increase gut wall permeability, which would presumably increase the rate of entry into the bloodstream of undesirable substances, some of which could be antigenic (is that the right word? I'm a bit foggy today!).

    Yes, it is complex, and some antibodies may well be against important physiological regulators so that further abnormalities will occur, and positive feedback loops could be set up that are very hard to break. @Jonathan Edwards refers to such loops in his thread, in the context of autoantibodies (not necessarily resulting from gut hypermeability).

    It may be hard to know which antibodies/antigens to look for, as you suggest.

    Another approach could be to dampen down immunity generally, for example with corticosteroids, but of course these have adverse effects. If we could find a way to get our own corticosteroids back in balance this may help considerably, but maybe that system is one of those to which we are producing autoantibodies - a vicious cycle.

    Rituximab wipes out all B-cells, I think, which is rather drastic and I don't fancy it.

    Leaky-gut diets appear to be beneficial but different people seem to respond to different variations of this, and it can be a long, frustrating search for the right one.

    Hopefully the current research work will throw up some more clues.
  13. Bob

    Bob

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    @Simon, thanks for your comments and the link. I hadn't seen the info re possible cross-reactivity between enterovirus and mitochondrial enzymes. I hope the IiME researchers will use the same enterovirus test as Dr Chia, otherwise they may miss any cross-reactive mitochondrial proteins, if they end up being relevant.

    Intriguing.
    Last edited: Jan 14, 2014
  14. Bob

    Bob

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    Last edited: Jan 14, 2014
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  15. globalpilot

    globalpilot Senior Member

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    This may help explain why the first time I did the test I tested negative for VP1 but positive for dsRNA. After lengthy oxymatrine treatment, I tested negative for dsRNA but .... positive for VP1.

    The VP1 could be explained by cross reactivity, but then why didn't it test positive in teh first test ? And why did my small bowel sample test negative ? I would think the mitochondrial enzymes would always be stained.
  16. Simon

    Simon

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    The problem is that those enterovirus results from John Chia may be false positives, detecting human mitochondrial proteins (which will be in the gut wall in abundance) rather than enteroviruses. So the goal would be to use a different test - without cross-reactivity to human proteins - to validate the original findings.

    Invest in ME have confirmed that they are doing biopsies but are not looking for viruses in the biopsy samples, only in the gut, so it does look like this won't answer the enterovirus question.
    See above - I think this doesn't link to autoantibody findings. And am glad you didn't find my material unplatable...
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  17. Bob

    Bob

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    I was thinking along these lines... Whatever Dr Chia is detecting, if it is detected at a different rate between ME patients and controls (I'm not very familiar with his studies), then it could be significant. So if he is detecting mitochondrial enzymes at a different rate between patients and controls then it would/could be significant. Dr Chia could potentially have serendipitously discovered a significant research finding relating to mitochondria, in his search for enteroviruses. But cross-reactivity doesn't prove an absence of enteroviruses, so perhaps he's finding enteroviruses.

    Unless I've misunderstood something?

    Thanks Simon.
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  18. Simon

    Simon

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    That would be a hell of a find. Differences between controls and mecfs patients are commonplace in research (witness XMRV) so if the test isn't reliable (it's not clear: as you say, he may really have found enteroviruses) then it's more likely to be a dead end than an important new discovery. But I salute your optimism :)

    Meant to reply to this earlier.
    Metabalomics is another " 'omics ", allowing unsexy metabolism to join the hot new fields of genomics: it refers to looking at the whole metabolism (or at least big chunks of it) as opposed to focusing on single pathways, in the same way genomics looks at the whole set of genetic material as opposed to individual genes. (Unfair jibe, metabolism is taking off, precisely because of such approaces.)

    In fact, looking at the metabolism of the whole microbiome, made up of many different organisms, is metametabolomics similar to metagenomics looking at all the genomes of the microbiome together. Community metabolomics is a less confusing way of saying metametabalomics. Sorry, probably more info than you wanted.
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  19. snowathlete

    snowathlete

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    Great article @Simon, thank you.

    I used to think there was little wrong with my gut but then a stool test showed my gut bacteria was way off normal and another test showed I had a bunch of food intolerances that seem to be as a result of a leaky gut. Then I got ulcerative colitis. So my opinion on the gut has also changed quite a lot in recent years. Can't wait for those stool-pills to become more mainstream.
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  20. Bob

    Bob

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    Perhaps it isn't quite such a wild theory as it may appear.
    In terms of a cause of ME, for some time I've been thinking about the possibility of a virus attacking the mitochondria, or of an auto-immune issue that affects the mitochondria.
    We've also seen that too much acid is produced in the tissue of ME patients (Newton) which open up the possibility of the mitochondria (or associated mechanisms) being faulty.
    It wouldn't surprise me if mitochondria play a central role in the disease, in which case it wouldn't surprise me if ME patients had abnormal levels of certain mitochondrial enzymes in their tissues.
    Yes, it would be a bit of a coincidence if Dr Chia had detected increased levels of mitochondria enzymes accidentally, when looking for enteroviruses, but it doesn't seem impossible or implausible.

    Perhaps I'm desperately clutching at straws, but the cross-reactivity does seem to fit with the idea of faulty mitochondrial function.

    @MeSci's auto-immune hypothesis seems plausible to me as well, and intriguing.
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