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Helminths & ME

Discussion in 'The Gut: De Meirleir & Maes; H2S; Leaky Gut' started by JenB, Nov 11, 2014.

  1. JenB

    JenB

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    Previous discussions on PR re: the use of helminthic therapy in ME patients have usually ended with the observation that helminths (intestinal parasites like whipworm, hookworm) shift the host immune system to a more Th2 response and therefore would not be appropriate for the management of ME, a Th2 dominant condition.

    I've been puzzling over this for a few days and have come to the conclusion it is way, way, way more complicated than a simple case of Th1 v. Th2. I am presenting some of the pieces of what I've learned in the hopes that others here might help me make sense of this. I find studies on immunological markers even harder to wade into as a layperson than other areas of research and so @Jonathan Edwards please forgive me for any violence I do to the science!

    Helminths are godsends for some autoimmune patients

    First there have been both some remarkable anecdotal reports as well as tantalizing preliminary research on helminth infection arresting, diminishing and sometimes even effecting full remission in a wide array of autoimmune diseases.

    The preliminary studies in multiple sclerosis have been especially encouraging, including one study showing fewer new lesions in helminth-infected MS patients and a convergence with the control group (i.e., resumption of disease progression) after deworming.

    Here is a bibliography of helminth studies in humans and animals: http://wormswell.com/science-research/ (I noticed at least one study on celiac disease and hookworm showing a null result wasn't on here so as always, exercise caution when relying on information someone else has aggregated for you, this post included!)

    Many of the diseases in which helminths have been experimentally and anecdotally effective are "Th1 dominant," which supports the paradigm that since helminths induce a Th2 pattern, they are "good" for Th1 diseases.

    Helminth/Th2 paradox

    The paradox of course is that epidemiologically, there is an inverse correlation between helminth infection and incidence of both Th1/Th2 autoimmune diseases as well as allergic disorders. Despite the Th2 polarization, helminthic infections protect against allergy. Might they also, then, protect against ME?

    Helminths increase regulatory T-cells

    One of the primary mechanisms through which helminths exert this positive effect is by increasing the production of regulatory T cells, increasing TNF-Beta, and increasing IL-10.

    Regulatory T cells are low or malfunctioning in a number of both "Th1 and Th2 dominant" autoimmune diseases. And so whether you have MS (Th1) or Lupus (Th2), correcting low treg numbers may be helpful, even if in general the helminths elicit a Th2–leaning immune response.

    But we already have a lot of tregs

    However, regulatory T cells have been found to be present in higher than normal numbers in ME patients and are perhaps one of the reasons why we have such low NK function (the treg cells being thought responsible for suppressing NK function).

    We also have increased levels of IL-10 and TNF-Beta. Perhaps the presence of helminths might further suppress NK function and only worsen the dysregulation present in ME patients, even as it might help attenuate it in other diseases.

    Maybe it's about the B cells?

    Helminth infections in MS patients were shown to generate B-cell populations producing high levels of IL-10. IL-10-producing B-cells are called "regulatory B-cells." Bregs are lower in patients with RRMS, especially during flares. However in one mouse study, researchers injected IL-10-negative B-cells from mice with helminths into mice with Experimental Autoimmune Encephalitis (an MS model) and it slowed disease progression, suggesting helminth-altered B-cells may be protective independent of IL-10.

    While we have significantly higher levels of regulatory T cells, ME patients like patients suffering from autoimmune diseases have significant decreases in regulatory B cells.


    Pregnancy: increased tregs, bregs and has other helminth-like effects

    Superficially, hosting a fetus and hosting a helminth seem to share a lot in common! Pregnancy induces a Th2 shift and also increases the number of treg cells and breg cells. A lack of increase treg/breg cells has been associated with spontaneous abortion. It seems the strategies a fetus employs for insuring your body does not reject it are similar to the strategies a hookworm might employ.

    We know that pregnancy can temporarily improve symptoms in women with a variety of autoimmune diseases. However, the one study on pregnancy in CFS showed a pretty even split between improvement (30%), worsening (29%), and no effect on symptoms (41%). Anecdotally, the number of women approve seem to be higher. At least according to a panel held at an OFFERUtah conference in 2011, several practitioners including Bateman and Klimas reported that all or nearly all of the patients whose pregnancies they followed reported an improvement in symptoms, will several gaining full remission.

    Whether the true number of women who experience improvement is 30% or something higher, it still begs the question of whether "Th2 shift = bad for ME" is too mechanistic a story, especially when you include number of women who experience no change in symptoms as well the fractional (but still hard to ignore!) number of women with ME who experience a complete remission.

    Hookworms and NK cells

    Hookworms (a species of helminth) increases the number of tregs (at least in patients with low tregs), which would theoretically inhibit NK function. However in vitro they have been found to secrete a protein that binds selectively to NK cells and induces the NK cells to produce more IFN-gamma and in vivo they attract NK cells to their attachment site and stimulate their activity, perhaps as a strategy to evade the host immune system.

    IFN-gamma has immunoregulatory, antiviral and anti-tumor properties and promotes NK cell activity as well as macrophage activity.

    It also "abundantly" produced by the developing fetus and is decreased in ME patients.

    (That said, results of interferon therapy in ME/CFS have been mixed.)

    What about hosting helminths while pregnant?

    There is very little research on the effects of helminthic therapy on pregnancy. There is a lot of research on the negative effects of helminths in pregnancies where they are endemic because very large parasite burden (much higher than a therapeutic dose) can cause anemia and low birth weight. There are certainly a handful of patients experimenting with inflammatory/autoimmune conditions experimenting with helminth inoculation pre-conception to either try to prevent miscarriage or inflammation-related birth defects in their children. Babies born to women with helminth infections were found to have lower rates of eczema and allergies.

    Helminths and the other trillion+ residents of your gut

    Helminths may also independently alter the composition of gut bacteria. One study in Malaysia showed villagers infected with helminths had greater gut microbiota diversity than those who did not (while this is an observational study and perhaps helminth-infected people eat more soil or something, one might presume that other diet and environmental factors are more or less similar between among people living in the same village).

    I was not able to find any randomized trials on helminths and gut bacterial populations in humans. However, there are studies in animal models. Some helminths increase population of pathogenic bacteria while other helminths increase populations of commensal bacteria.

    One animal study showed helminth infection might decrease intestinal inflammation and increase mucus production. This may explain at least part of the benefit in IBD and ulcerative colitis, especially given the importance in those disease of helminths not just to altering systemic immunity but providing "islands of profound calm" localized around their attachment sites.

    Many helminths, many effects

    Lastly, different species of helminths have different effects on the immune system.

    Here are two helpful overviews of the effects of different species of helminths on the immune system:
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2706953/
    http://www.sciencedirect.com/science/article/pii/S156899721400216X

    It is also helpful to note that different helminths fill different "niches" in the intestine. That is some colonize the small intestine while others colonize the colon. This means that the optimal therapy for someone with ulcerative colitis might differ for someone with Sjorgen's, for example.


    Should ME patients experiment with helminths?

    There is zero research and very little patient anecdote to suggest helminths would be helpful to ME patients, particularly given that many of the modifications helminths make to avoid expulsion by the immune system tend toward an expression pattern that is similar in many respects to the immune dysfunction already present in ME.

    At the same time, most of the research on the effects of helminths on immune dysregulation in humans and animal models have been in diseases like multiple sclerosis. Helminths are a dynamic intervention – they secrete dozens of immunomodulatory chemicals in response to the host environment, so it is uncertain what they would do in a host with a different pattern of immune dysfunction. My guess is that in a host that already has large numbers of regulatory t-cells, for example, a hookworm would not increase the numbers of regulatory t-cells. Why bother? Rather, it would do the minimum necessary to ensure an environment conducive to its own survival. So it is possible that a helminth infection might positively affect your breg status in a way that could be disease-modifying, while leaving your tcells alone.

    The last thing to mention is that there is some evidence that helminth infection might encourage viral reactivation and at least theoretically, inhibit your ability to fight cancer. We should worry about that not only because of our tendency toward viral reactivation but because we have a 4x increased risk of cancer. I've looked and there is not a whole lot of work in this area. The research I have found has not so far found a link between helminth infection and cancer (in fact, certain helminths might reduce your risk of gastric or colon cancer, perhaps by attenuating the damage induced by H. Pylori infection in the case of the former). Moreover, there is no strong evidence that helminths (endemic in many areas with high rates of HIV infection) lead to higher viral loads or more disease progression. In fact, some studies found the opposite. But the results on both are conflicting and the evidence is really not there, either way.

    This lack of consistent evidence supporting theoretically negative effects of helminths on cancer or virus suppression may be due to the fact that while much of the helminth research focuses on Th1 dominant autoimmune diseases and emphasizes importance of helminths' effects on tregs, helminths have multiple and dynamic effects on the immune system which probably depend heavily on the host environment and on host-helminth interactions. Put another way, the immunomodulatory "protocol" a helminth would prescribe for your immune system depends a) on the particulars of your immune response and b) on whatever your immune response signals to the helminth it must do in order to ensure its survival. So we just don't know, for better or worse, what a helminth would do when it meets an ME patient's immune system. But I hope someone decides to study it!

     
    Last edited: Nov 11, 2014
    Cheesus, hixxy, dannybex and 2 others like this.
  2. Dreambirdie

    Dreambirdie work in progress

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    JenB likes this.
  3. alex3619

    alex3619 Senior Member

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    Too much speculation, too many possibilities. I used to have contact with someone who was looking into worms and CFS, and he was finding, I think, roundworms. However in the last ten or so years I don't think his research has advanced much, or maybe it hit a brick wall.

    I don't have much to add except that the research on such parasites is inadequate.
     
  4. JenB

    JenB

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    Yes @alex3619 there definitely needs to be more research on the therapeutic use of helminths, but there have been dozens upon dozens of human and animal studies in diseases that are not ME, in addition to the observational/epidemiological work that prompted those experiments. It's still early, but the combination of research and patient anecdote are pretty compelling, particularly in multiple sclerosis and given the low/minimal risk. Taken together, that's a lot more evidence for helminth therapy than for most of the therapies folks in the ME community try, at least in those diseases that are being researched.

    As for speculative...pretty much anything that can be said about ME is speculative because almost no single finding has ever been replicated! (Except natural killer function and a few more things.) It's a big shame and one of the most frustrating things about the field.

    I am not really sure what you mean by too much speculation, though. It's a literature review that tries to summarize what we know about helminths in autoimmune disease and what we know about how the immune system functions in ME. It was useful for me to write because not only some folks on this board but many scientists have made assumptions about how helminths might function in humans based on a simple Th1/Th2 paradigm. That paradigm predicts an increase in allergies, asthma, eczema, etc. in patients with helminths, as well as increased disease progression in HIV positive patients. We see none of these things in the literature. My main point is that there is no reason to think hookworms couldn't have a beneficial effect on ME patients simply because of the tendency toward Th2 polarization in this disease. Whether or not their effect is positive, negative, or neutral remains to be seen because, as you rightly say, there's no research.
     
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  5. Hip

    Hip Senior Member

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    @JenB
    An interesting question that you ask.

    If you look at Prof Edward's thread here, you see that based on his experience with ME/CFS patients, he suggests that there may be several different subtypes of ME/CFS, some of which are virally triggered, and others which have an autoimmune basis (these may show a positive ANA test).

    I guess the effects of helminth therapy might depend on what subtype of ME/CFS you have. My guess is that for the viral subtype, you may get worse, because of the reduction in Th1 and boost of Th2. But for the autoimmune basis ME/CFS, there may conceivably be improvements in symptoms from helminth therapy.

    I was thinking that helminth therapy might show benefit for postural orthostatic tachycardia syndrome (POTS), since a groundbreaking recent study indicates POTS may be caused by autoantibodies interfering with the receptors on the autonomic nervous system. By boosting tregs with helminth therapy, you might be able to inhibit these autoantibodies, and thus improve POTS systems.

    The trouble with helminth therapy though is the high cost. If you look at this list of helminth therapy suppliers, you see that the price can be as high as $2500. That's a lot of money for a treatment which may have no benefit whatsoever, and may even make you worse.

    One ME/CFS patient on this forum tried helminth therapy (with the Necator americanus species of hookworm), and found his ME/CFS got worse. Details on this thread.

    I don't think there would be much in the way of risks in trying helminth therapy, because you should be able to kill off the worms with agents such as ivermectin if the therapy does not work, or if it makes you worse.


    There is an interesting Wikipedia article about the effects of helminth therapy on the immune system here:

    Effects of parasitic worms on the immune system - Wikipedia

    It's interesting that this article says for types 1 diabetes, some species of worm showed benefits, but other species did not.
     
    Ninan likes this.
  6. alex3619

    alex3619 Senior Member

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    I think this is an area that needs more research but my comment is broader than that. I was at the end of a long day so I gave a terse response, and did not have the energy to elaborate.

    We do not know very much about how many parasites actually operate, from basic biology to medication to eradicate them. Most of the research has been on treating pathological worm infestations that are common in the Western world. Other parasitic and symbiontic biology, including treatment of for example South American and African parasitic worm infections have languished.

    One caveat I want to make though is that while i have investigated this my knowledge is about a decade out of date. This was once a hot topic in ME research but it died away.

    Many worms release all sorts of substances that alter immune function. Its in their interest to dampen the immune response. I do not know any of them are completely benign, but then if you have a severe autoimmune response then a mild parasitic infection that suppresses that might still be a good idea.

    One of the big research issues is that we are really bad at detecting such parasites. It should also not be limited to just gut infestations - some of these wander through the tissues. However from my limited understanding most uses of therapeutic parasites, more of a symbiontic relationship really (or symbiotic for most people, long story) have been oral. Much of the advances in allergy responses, for example, have come from realizing that wider tolerance can come from oral tolerance.

    If an advance is going to come in this area then I suspect it would be serendipitous like it was for Rituximab. At some point helminth therapies might be more widely tested, and some of those will have ME (though in most clinical trials patients with comorbid conditions will be eliminated) and then if it helps some doctor might, just might, notice it.

    @JenB you are right that much of the discussion on ME is speculative. Its particularly problematic though when speculative ME pathophysiology is combined with speculative treatment modalities. I was not going to comment on this thread, which I had seen, till i was tagged. There is not a lot I can say. Now if we had even a small pilot study done, with whatever results emerged we could have a more focused discussion.

    One thing I would like to say is it seems that over time we are focusing more and more on the human biology as an ecology. When things go wrong with pathogens its an ecological issue. Many human pathogens are actually beneficial under one context (eg. staph bacteria) but dangerous or lethal under another. Biological control on disease is one huge area that is massively underfunded.
     
  7. alex3619

    alex3619 Senior Member

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    Many helminthic parasites cannot be adequately controlled by current drugs. Research could only really proceed on the more well understood species for which treatment is very effective. This leaves a huge hole for the many species that are drug resistant but which might be beneficial therapeutic agents.

    One of the issues with the old parasite research in ME was that most ME patients might have some kind of parasitic infection (though this might be more opportunistic rather than causative) but that they resist treatment.

    If i have time I will look up the published research and comment further, most of the information I had was private so I do not want to say too much.
     
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  8. Hip

    Hip Senior Member

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    If that is the case, would think twice before introducing an organism to the body which could not be eradicated. That would concern me.

    Imagine if the helminth therapy started making your ME/CFS worse, but you could not eradicate the helminths. So it would be a good idea to only use helminths that can be eradicated with anti-helminth agents.
     
    Last edited: Nov 12, 2014
  9. Dreambirdie

    Dreambirdie work in progress

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    Helminths are not difficult to eradicate. In fact, you have to be careful to not accidentally do so. Garlic is one food that can kill them.
     
  10. Dreambirdie

    Dreambirdie work in progress

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    This map is certainly interesting...

    1122334-13368327296724055-Iggy-Igette_origin.jpg
     
  11. Hip

    Hip Senior Member

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    @Dreambirdie

    Prof John Stanford believes that Mycobacterium vaccae, which is found in the intestinal flora of Africans but not Westerners, is also a factor that may explain why the prevalence of autoimmune disorders is less in Africa. He has been developing a vaccine containing heat-killed Mycobacterium vaccae as an immunotherapy for autoimmune conditions. See here.
     
  12. Dreambirdie

    Dreambirdie work in progress

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    Thanks. I imagined there had to be more than one reason for the lack of autoimmune disorders in under-developed countries. Probably many reasons.

    The toxic load of chemicals that we all live with in the western world is undoubtedly a big contributor to auto-immune issues.
     
  13. Hip

    Hip Senior Member

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    Yeah, but which ones. Perfluorooctanoic acid (PFOA), used in Teflon, Gor-Tex fabric, pizza delivery boxes, etc, has been linked to autoimmune thyroid disease and ulcerative colitis. PFOA is being phased out by 2015 (no more Teflon frying pans).

    If you overheat a Teflon pan, it can release PFOA, which incidentally can instantly kill pet birds like parrots if they breath it in.
     
  14. alex3619

    alex3619 Senior Member

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    This is counter-factual. Some of them have no known therapeutic agent. The common ones in the Western world can be eradicated, but other species have no known effective therapeutic agent. None of them works. Of course I am a decade out of date as I said, but the reason nobody cared to do more research was that these were pathogens in third world countries, and there was no money in it. So I doubt it has changed much.
     
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  15. alex3619

    alex3619 Senior Member

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    Its not quite that simple. Toxic chemicals have variable effect on people, depending on genetics and health status. Some toxic loads might kill or disable one person and the next will wonder what the fuss is. It all depends on our detox paths - whether or not we can handle that particular chemical at that particular dosage. Different gene variants on those detox paths can make a huge difference.
     
  16. alex3619

    alex3619 Senior Member

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    Using pathogens to treat disease should have been a top priority with us for decades, if for no other reason its a way to get around drug resistance in pathogens. Yet its not easily patentable, so I guess the big pharma money has ignored it. They are in the business of making drugs not using natural living organisms.
     
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  17. barbc56

    barbc56 Senior Member

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    But does it really tell us anything other than there are more autoimmune diseases reported in developed countries. It reminds me of the spurious correlations website.

    This theory focuses on one possible factor for the difference in autoimmune disease prevalence which may or may not be accurate.

    There are so many other things that could explain this phenomenon. Maybe autoimmune disorders are not being diagnosed because of the standard of medical care. I would question if the few medical personnel available are trained to diagnose let alone treat these type of disorders. Wouldn't the focus of health care be on things such as sanitation? Is the reporting the same? How does the fact that life expectancy is lower in non industrialized countries factor into this theory.

    I'm not sure there's a biological plausibility that this theory might be correct. I don't understand what I'm reading as my medical expertise is limited. I guess the question is if it's probable but I don’t think there's enough evidence to say either way nor credible enough to buy something that costs $2500 that might help or might hurt a patient. But that would be un individual decision.

    If it does turn out this theory is correct, it does seem that like the vaccine, a treatment where the ingredients that are therapeutic are extracted would be a safer way to go. But I need to read more about this.

    There's also the yucky part that's hard to get past but I would not be surprised if this is also true of other medications, but we just don't know about it.
     
    Last edited: Jul 23, 2015

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