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My take on leaky gut, autoimmunity, ME/CFS and other autoimmune diseases

Blog entry posted by MeSci, Feb 3, 2014.

This theory may be modified as any additional info comes to my attention and as I relocate info that fits in somewhere! Please note that I don't claim this as MY theory. It's a collection of pieces of info from scientific research and hypotheses, plus info provided by other people, some of whom have produced documents which refer to much of the same research and posit largely the same processes.

The processes described here almost-certainly do not apply to all ME/CFS sufferers. As Stephen Holgate has detailed here, 'ME/CFS/CFIDS' is probably a collection of symptoms with different causes and requiring different treatments.

Whilst I focus on leaky gut and autoimmunity/autoantibodies, the theory is not inconsistent with many other research findings relating to viruses, cytokines, nutritional status, etc. I'm just focusing mainly on a theorised bigger picture rather than more specific components of the pathological process, partly for the sake of simplicity and partly to illustrate a treatment protocol that doesn't need to rely on doctors and a lot of lab tests (although they could help).

I've put this together in something of a hurry (my usual state!) so I welcome constructive comments. If there is anything I have got wrong, or if you can add useful info and/or links to relevant studies, please post them here. I am only interested in info/links related to human studies, as findings from non-human animals only have an average of about 50% concordance with findings from humans. I am also only interested in scientific papers and pages/documents that are well-referenced.

I will try to reply to all comments where needed, and incorporate useful changes as and when I have time, but can't promise!

I don't have all the answers, so I hope that others can help to answer any questions on topics where I lack the required knowledge.

Please adhere to the Phoenix Rising rules of not giving people diagnoses or direct health advice. It's OK to say things like “this helped me” or “this may help you”, or “this site/study/doctor says so-and-so” or “there is a theory that...”, etc. It is not acceptable to say “you have xy illness” or “you should take yx.”

Feel free to tell me off if I inadvertently transgress! (It can be easy to get carried away by one's enthusiasm.)

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The Theory

Firstly there are genetic predispositions.

Secondly there is one or more stressors. Likely candidates include:

  • Infection
  • Vaccination
  • Prolonged psychological stress
  • Over-exertion
  • Physical injury, especially to the head or spinal cord
  • Toxic chemicals

Such stressors can increase the permeability of biological barriers, commonly the gut, but also/alternatively the blood-brain barrier.

Chronic stress is also thought by some researchers to reduce cortisol secretion (often seen in ME), although this appears to be controversial. Cortisol reduces some aspects of immune activity and inflammation, so low levels might allow such processes to become pathological.

Genetic aspects

Some genetic variations (single-nucleotide polymorphisms, or SNPs) appear to be more common in ME sufferers than in the general population. These may include SNPs that increase inflammation and oxidative stress, and impair our ability to break down and remove toxins. (Valentijn is perhaps our expert on this!)

I'm not sure where dietary sensitivities fit in with regard to causation, but I would guess that there is a genetic predisposition, which could be exacerbated by other stressors such as those above. Perhaps they are triggered by the increased permeability of the gut wall ('leaky gut').

Alternatively an SNP could increase the risk of developing dietary sensitivities, which in turn may lead to leaky gut, similarly perhaps to the development of coeliac disease.

Excessive intestinal permeability ('leaky gut)

One feature that seems to be very common, if not ubiquitous, in leaky gut is gut dysbiosis (an imbalance of gut microorganisms). This can have a range of causes such as inappropriate diet, excessive acidity or alkalinity, or antibiotics. Taking the wrong type of probiotic appears to be another potential cause.

Gut dysbiosis may take the form of d-lactic acidosis or small intestinal bacterial overgrowth (SIBO).

There is a paper about d-lactic acidosis and ME/CFS here

Even overexertion can cause leaky gut. A paper describing how exertion can increase intestinal permeability can be read here.

and here is a paper citing the high prevalence of 'irritable bowel syndrome' (IBS) in ME/CFS.

A 'syndrome' is a collection of symptoms and signs of a condition, so IBS could include a range of gut conditions with a range of causes. It is likely to include 'leaky gut', although it appears that not all people with leaky gut have symptoms of intestinal problems.

This paper describes increased intestinal permeability in 39% of subjects with diarrhoeal IBS and cites other research with similar findings.

Connections between leaky gut and autoimmunity

A causal link between leaky gut and autoimmunity, using coeliac disease and Type 1 diabetes as examples, is proposed in the 2009-10 paper

'Tight Junctions, Intestinal Permeability, and Autoimmunity Celiac Disease and Type 1 Diabetes Paradigms' which can be read here.

It seems likely to me that the same mechanisms could lead to a wide range of autoimmune conditions, depending on what substances enter the blood via a compromised gut wall (or perhaps enter the brain/central nervous system via a compromised blood-brain barrier).

A theory I currently favour involves 'molecular mimicry' in which antibodies produced to attack pathogens mistake the body's own cells for the pathogens due to similarities between them, notably due to similar – perhaps even identical – antigens on their surfaces. Thus the body starts attacking itself, and continues to do so long after the triggering pathogens have gone.

The multiple physiological abnormalities, and the changes in presentation over time, could be due to different antigens entering the blood and triggering the production of different autoantibodies.

It is theoretically possible that such processes could account – at least partly - for the variation over time of ME/CFS symptoms that is frequently reported, although the relative consistency of some temporal variations seen in many sufferers (e.g. initial nausea/vomiting and weight loss which is later replaced by excessive appetite and weight gain) suggests that such variations over time may have a different basis.

Autoantibodies could include some to hormones in the hypothalamic-pituitary-adrenal (HPA) axis; e.g. see this paper, and consequently reduce cortisol secretion. What is unclear to me is how such autoantibodies could disrupt the diurnal pattern of cortisol secretion rather than just reduce cortisol secretion overall. Both of these cortisol abnormalities have been reported in ME. Perhaps this is related to the homeostatic delays/'overshoots' that appear to occur in ME/CFS.

Homeostasis is described here.

One endogenous protein to which a percentage of ME patients have been found to have a higher prevalence than healthy controls of the presence of antibodies – Heat-shock protein 60 (HSP60) - is discussed here.

HSP60 has a wide range of functions, including a role in mitochondrial function, so this one antibody type may cause a wide range of abnormalities. It is also found in bacteria, prompting the researchers to postulate that bacterial infection could lead sufferers to produce antibodies that then attack their own mitochondria.

It may be significant that, in evolutionary terms, mitochondria have a bacterial origin. They evolved from being symbiotic bacteria to being an intrinsic part of their host species, although they still possess their own distinct DNA.

Cross-reactivity has also been found between mitochondrial proteins and a viral protein. A lab-produced antibody used to detect enterovirus capsid protein (VP1) has been found to cross-react with two mitochondrial proteins:

http://www.ncbi.nlm.nih.gov/pubmed/23335350

I should say at this point that scientist Professor Jonathan Edwards, whose views I respect, does not favour the 'molecular mimicry' theory of autoimmunity except for a few diseases. You can read his views about HSP60 in this thread (search the thread for 'HSP60' and his name as member).

In the same thread he describes the randomness of antibody generation here and here.

Professor Edwards also gives some views on molecular mimicry in other posts in the same thread.

Whatever the cause of the autoimmunity, we appear to have a range of autoantibodies, which could at least partly explain why ME/CFS has such a wide range of symptoms and biochemical abnormalities.

Perpetuation of autoimmune processes

There may be a number of ways in which autoimmunity can be perpetuated in the case of ME/CFS.

1. Once mitochondrial function is impaired, e.g. by autoantibodies, perhaps to HSP60, even a small amount of exertion will push the mitochondria into anaerobic energy production, which generates and uses lactate/lactic acid. This can lead to high blood lactate levels (hyperlactaemia) which in turn could feed back to the gut, causing it to become over-acidic and perpetuating leaky gut. (NB there may be some sufferers who have the opposite pH problem of too little acidity in their guts, so this particular process may be irrelevant to them.)

In my own case at least, my perception is that over-exertion leads to hyperlactaemia which in turn leads to osmotic diuresis, with resultant electrolyte deficiency. I have not been tested for lactate levels, but am 99% sure that I experience osmotic diuresis as part of my post-exertional malaise (PEM), as I suffer polyuria which is not relieved by desmopressin, and have also suffered from severe hyponatraemia (low blood sodium).

This paper shows how acidosis can be associated with excretion of sodium and potassium (see especially page 6), although I don't know if it only applies to d-lactic acidosis. For example:
What I haven't been able to get my foggy head around is whether hyperlactaemia arising from overproduction of lactate (e.g. in muscles due to our impaired energy/ATP production) can actually exacerbate acidosis via the above mechanism, whether d- or l-lactate is the initial product. I think I understand that production of d-lactate in the gut instead of l-lactate can cause acidosis as in the above quoted section.

My levels of other electrolytes have not been rigorously tested, but symptoms during my worst period of illness (dental damage, and a fracture from a minor fall) strongly suggested to me that I was also losing bone minerals and, since I began supplementing with these, my bones and teeth appear greatly improved.

NB UK doctors tend to rely on plasma/serum testing, which can overestimate levels and miss deficiencies. Red blood cell levels are said to be more accurate.

Electrolyte deficiency likely produces symptoms directly, but a deficiency in some electrolytes may also contribute to leaky gut.

Here's the link again to the paper cited above which demonstrates that exertion can lead to leaky gut, which could therefore perpetuate autoimmunity as described above.

2. It appears that autoimmunity may also be self-perpetuating via one or more pathogenic 'loops', also known as positive feedback (which in biology is often not the benign process that the name may suggest!). Jonathan Edwards discusses such processes in this thread – search the thread for 'loop'.

Of course, any of the initial triggers can also keep the autoimmune process active.

Treatments

Treatments based on this and similar hypotheses consist broadly of a leaky-gut diet and supplements. Careful pacing of activity, incorporating rest whenever the need is perceived, is probably an essential part of any treatment programme for ME/CFS. Some regimes will include appropriate antibiotics, probiotics or prebiotics ('resistant starch' is a type of the latter).

Members discuss various leaky-gut regimes in this Phoenix Rising forum and elsewhere.

Whilst the diets and supplements recommended vary according to theorist and patient, one almost-universal recommendation is to eliminate gluten from the diet. As a high proportion of ME/CFS sufferers appear to have diarrhoeal IBS, this seems worth doing even if it only fixes the IBS as described here.

To heal a leaky gut it is also deemed necessary to eliminate other foods to which an individual is sensitive. Elimination may be piecemeal or may start with a very basic, simple diet consisting only of foods generally regarded as 'safe', followed by reintroduction of other foods to assess whether or not these are tolerated.

Other treatments recommended by some include enemas, colonic irrigation and faecal transplant.

How could healing the gut cure autoimmune disease?

A big question, and answers are still theoretical. The paper linked to above (here is the link again) which postulates how leaky gut (increased intestinal permeability) could cause autoimmune disease, states encouragingly in its concluding remarks:

In other words, the triggering of autoimmunity may stop when the gut is healed.

This may take months or years, while autoantibodies stop being produced. I theorise an analogy with vaccination, with autoantibody production being analogous to the beneficial antibody production triggered by a vaccination. Vaccinations often require boosters as the levels of antibodies decrease over time.

Similarly, if gut healing prevents more autoimmune activity from being initiated, one can hope that autoantibody levels will die down over time.

The presence of a pathological, self-perpetuating loop of autoimmunity (as referred to above) is likely to be harder to combat.

Evidence for the efficacy of leaky-gut treatment in ME/CFS

The evidence is not as strong as one might wish for, consisting of small studies which are not well-controlled, plus a substantial body of anecdotes (unless someone can point me to stronger evidence, which would please me greatly!). This paucity of strong evidence could just be the result of difficulty getting funding for such research. But here are links to two papers which report improvement – even remission – of ME/CFS from a leaky-gut regime.

1. Neuro Endocrinol Lett. 2007 Dec;28(6):739-44.

Normalization of the increased translocation of endotoxin from gram negative enterobacteria (leaky gut) is accompanied by a remission of chronic fatigue syndrome.

Maes M, Coucke F, Leunis JC.

http://www.ncbi.nlm.nih.gov/pubmed/18063928

2. Neuro Endocrinol Lett. 2008 Dec;29(6):902-10.

Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria.

Maes M, Leunis JC.

http://integrativehealthconnection....1/Leaky-gut-in-CFS-treatment-of-leaky-gut.pdf

There is a discrepancy between the theoretical basis for these papers and that for the d-lactic acidosis paper cited above – here is the link again.

The d-lactic acidosis paper reports excessive quantities of gram-positive gut bacteria, whereas the two papers by Maes et al refer to excessive gram-negative bacteria. Perhaps one theory is wrong, or perhaps the different types of dysbiosis identify two ME/CFS subgroups.

Impediments to successful self-treatment

Apart from the common problem of unaffordability of supplements for people whose financial situations have plummeted due to the illness(es), doctors will often be unwilling to carry out tests requested by patients to facilitate their self-treatment. So they may be unable to identify food intolerances, gut pH, nutritional deficiencies, etc.

The self-treatment tends to have to rely largely on trial and error and anecdotal reports from other sufferers.

Ideally we would be able to monitor our progress with the aid of medical tests. For example, if we deteriorate at some stage, we would have a better chance of identifying the reason(s) and taking corrective action. Perhaps a temporary deterioration is part of the recovery process, or perhaps it indicates that we are doing something wrong. Either way, it may mean that we have to change our diets and/or supplements, maybe adjust dosages, etc. But most of us probably have to make do with guesswork, until clinical practice catches up with scientific evidence.

Anecdotal results

Members can read a summary of my own results in my profile. Improvements are not continuous, and I have setbacks from time to time, for which I try to identify and rectify the causes. The trend is undoubtedly positive, but I have no idea how long it might be before sustained remission is achieved, if ever.

Other positive (and sadly not-so-positive) results are cited by others in the leaky gut forum and elsewhere.

POSSIBLY-VERY-IMPORTANT EDIT 18TH JUNE 2014

This relates to the puzzle of sodium (and other mineral) loss in urine, and the polyuria that doesn't respond to desmopressin. It may also be a way to prevent - or at least reduce - PEM.

Some of the points have already been mentioned on PR, and in the past few days, following a few bad nights and apparent mineral depletion yet again, I have been picking up clues here and there and gradually getting my foggy brain to make sense of them.

I will summarise them first, then just paste my notes as I don't have time to whittle them down into a concise and coherent form.

I'll do it in a new blogpost. What shall I call it?

Inflammatory cytokines and mineral loss in urine, I think. I'll edit this again if I change my mind!

EDIT 30TH JULY 2014

I don't know if I have already said this, but:

Having been thinking, foggy-brained, about my current experiment with natural antiinflammatories to try reduce polyuria with mineral loss after exertion, looked again at the exertion-leaky gut paper, wondering whether the inflammatory cytokines I am trying to reduce are involved in causing leaky gut.

And it says:

and:

and:

So, if these three quotes are correct, and my foggy brain is comprehending them correctly, cytokines-leaky gut can represent a pathological loop. Leaky gut can increase inflammatory cytokines, and inflammatory cytokines can cause/exacerbate leaky gut, and exertion can lead to this loop occurring in ME.

So if circumstances won't allow us to rest, the next best thing may be to take antiinflammatories to reduce the inflammatory cytokines and break one of our vicious cycles, or at least weaken it.

So:
  • Leaky-gut diet and supplements
  • Pacing
  • Rest
  • Antiinflammatories
= remission?

See what an optimist I am? :D

Now just have to try to get the antiinflammatories right...have ordered some more Source Naturals Turmeric Extract which is 95% Curcumin plus bromelain and a branded form of piperine called BioPerine. Then I can up my dosage to 2 a day and see how it goes.
Bob, Sidereal, Mij and 5 others like this.
MeSci

About the Author

Hopeful leaky-gut healing enthusiast!
  1. MeSci
    Good pun, @ahmo!
  2. ahmo
    Thank you so much for digesting this info and writing it up so clearly and concisely.
    MeSci likes this.
  3. Christopher
    Do you have a million dollars by any chance?
  4. Beyond
    @Christopher Undoubtely chronic infection is a major cause of leaky gut in ME/CFS. Personally I think I have no infection but just in case let´s load with natural antibiotics!
  5. Christopher
    http://www.ncbi.nlm.nih.gov/pubmed/17720995

    the majority of all CD4+ T lymphocytes are lost during acute HIV infection, with mucosal compartments being most severely affected. The frequency of infection is very high in gut CD4+ T cells, and depletion of these cells persists into the chronic phase of infection. Infection is associated with increased gut permeability, with microbial translocation being evidenced by increased circulating lipopolysaccharide (LPS) levels. Plasma LPS levels correlate with systemic immune activation, which drives chronic HIV infection.