Saturday, March 5, 2011

Leaky Gut and Chronic Fatigue Syndrome

Jen linked another Maes leaky gut paper from the comments in the Depression and a Leaky Gut post.  This paper is a case report of a 13 y/o girl with chronic fatigue syndrome.  In January 2005, the girl had a sore throat.  Thereafter she began to have progressive weakness, increasing fatigue, unrestorative sleep, abdominal bloating, headaches, a 22 pound weight loss, and poor concentration to the point where the girl was in a wheelchair and no longer able to study for school.  From the beginning, after nothing too obvious was found by the internal medicine doctor, the patient's parents were urged to take the girl to a psychiatrist.  Instead, the parents took her to a specialist in chronic fatigue syndrome, who checked a number of inflammatory markers, finding many highly positive.  In addition, the girl had high levels of circulating antibodies to the lipopolysaccharide on the outside of some gram negative gut bacteria - suggesting a "leaky gut."

The girl was treated with antibiotics, but steadily worsened, until she was admitted to the hospital to normalize her nutrition.  Then she was sent to neurology where they checked her muscle fibers, finding some abnormalities, but nothing major.  The senior neurologist felt the patient had a symptom of a psychogenic "conversion" disorder, "la belle indifference."  If the girl exhibited this symptom, she would have been oddly unconcerned about her impaired condition.  The term "conversion disorder" is a Freudian one, meaning that anxiety symptoms are being converted into physical symptoms.  Classically, "la belle indifference" is described in cases of hysterical blindness, where someone can't see and doesn't seem too bothered by the fact.

Problem is, people with chronic fatigue often have a depressed affect, so their emotional responses are muted.  They are suffering a great deal, and certainly feel that suffering, but the face and voice might not quite show it.  However, the content of the discussion is telling.  And Maes (a psychiatrist) was angry with the neurologist who diagnosed la belle indifference.  Maes says he detected no sign of unconcern - instead he saw "a young lady who was very ill and suffered from her illness and not being able to go to school and meet with her friends."

Maes continued the work-up and started her on a whole slew of nutritional supplements and the "leaky gut diet."  The corresponding author email bounces, but this paper (after several teases) gives up the following information about the diet:  "consisting of milk allergic, gluten-free and low carb diet." (Thank you, Jen). 

The nutritional supplements had some basis in thought (not surprising, from Maes, who seems to account for everything except for relying on experience from evidence-based medicine - but you can't turn your back on a 13 y/o girl in a wheelchair if you think you can get her to walk out of it.)  First off, the girl's labs showed signs of an increased immune response in some respects, and decreased immune response in others.  They were consistent with lab findings of other people with symptoms of chronic fatigue syndrome, though there are no official lab findings for CFS.  Maes is quite specific, however, in noting each of the innumerable abnormalities she had, and how they link to issues with disparate parts of the gut, nervous, and immune systems. 

He surmises that the activation of immune cytokines and autoimmunity is related to the increased transfer of the bacterial lipopolysaccharide (LPS) across the gut.  He thinks there is a trigger factor, such as exhaustion, emotional stress, or an infection (perhaps the sore throat in this girl's case - she was also found to have a mycoplasma infection, which was treated), that will cause the inflammatory system to fire up.  Some elements of this system seem to help LPS cross over from the gut into the bloodstream.  Then the immune system mounts a response against the LPS - resulting in further inflammation and the acceleration of the symptoms of CFS.  Once again, Maes is exceedingly specific, defining a large cast of immune characters and the responses. 

So, the supplements - L-carnitine, CoQ10, lipoic acid, and taurine (one might recognize these as some of the compounds that are suggested to help mitochondria run more efficiently - and several of them are absent in entirely plant-based diets.)  In order to deleak (sounds better than plug up, I think) the gut, the girl was given L-glutamine, gamma oryzanol, zinc, "etc" along with the gluten-free, casein free, lactose free low carb diet.  

On top of these supplements, the girl was given IVIg infusions (gamma-globulin, to clean up inflammation.  This stuff is prohibitively expensive.  I've seen it used with good effect in the very rare, but completely disabling likely autoimmune condition called "stiff man syndrome."  Ironically that case was referred to me for suspicion of conversion disorder.  It is also used in immune deficiencies and Guillain-Barre and Kawasaki's disease.)   The girl got daily infusions (which I find incredible - these treatments are maybe $3000-$10,000 a pop? Each treatment consists of the pooled IgG antibodies from thousands of blood donors. I don't know for sure, but I've seen those kinds of figures thrown around) for a month, then the more typical dose every two weeks thereafter. 

For the first 6 months of treatment, the girl showed no clinical improvement, though Maes tracked her immune response to LPS, and it was dropping and dropping.    At her visit 10 months into treatment, however, she walked into the consultation room, and said she could read books again, had started swimming lessons, and her sleep was much improved.  LPS response slowly improved, and eventually she was able to return to school, and her abdominal bloating went away.  After about a year, she was pretty much back to herself, and the IVIg treatments were stopped, though her leaky gut diet and supplements were continued.   At two years into treatment, she remained well. 

In the discussion, Maes really lets loose.  The only way in which it could be described as civil is that there was no swearing. 
Although these [CFS] diagnostic criteria are now well-established, many specialists... still miss and dismiss this diagnosis.  They rather conclude that patients with this medical disorder suffer - in accordance with Freud's non-scientific theories - from "conversion symptoms with a strong psychogenic component." ...It is common practice... that those patients... are referred to a psychiatrist to undergo the mainstream treatment for that condition, i.e. psychodynamic therapies.  This means that patients with severe medical disorders are being treated as having a mental illness with "a nonsense treatment" that does not treat anything.

He goes on to rail against a prevailing political wind in Europe, where the National Health Services can evidently dismiss those patients who are considered hypochondriacs, thus avoiding the cost of treating these difficult conditions.

Well.  A recent study did come out showing that graded exercise and cognitive behavioral therapy are helpful for chronic fatigue.  I wonder if the possible reduction in stress response from the light exercise and CBT help the condition.  It is still poorly understood (though Maes seems to feel he has a handle on it).  Nor is there the kind of evidence we need for Maes' enormous intervention to recommend his treatment as standard therapy.  Somehow he was able to get the IVIg and convinced the family to keep going though 6 months of no clinical improvement (though the labs were hopeful).  And, as I said before, Maes couldn't turn his back on a 13 y/o girl confined to a wheelchair when he was certain he could help her.  In general, chronic fatigue has a relapsing and remitting course, but Maes has his biomarkers to show the steady biological improvement.  All the papers on the first page of google I found linking chronic fatigue to leaky gut are by Maes.  There are other studies of LPS and chronic fatigue, most via exposing cell cultures to LPS to stimulate cytokine production.

The mechanisms seem plausible, and the case study is compelling.  We need more data.  And you might not be surprised that I don't see much harm in trying a "leaky gut" diet - why not?  I don't know about all the supplements and any long-term effects.  I do of course advocate a nutrient rich whole foods "paleo" diet with plenty of animal protein and fat goodness - which would replace some of those supplements, though perhaps not in the amounts prescribed (which weren't listed in the paper). So, you see, once again, just by going "paleo," we are seemingly a lot of the way to Maes' elaborate reduction of leaky gut and systemic oxidative stress and inflammation.  Thus our overarching theory still seems good, that many of our modern diseases are a result of the modern diet and lifestyle that our paleolithic bodies simply aren't designed for.  Interesting.

* In full disclosure I am the author of a book, Feeling Better: A 6-Week Mind-Body Program to Ease Your Chronic Symptoms, which is based on some research I have participated in with Dr. Arthur Barsky, my co-author.  He is a world expert on somatization disorders, and due to my affiliation, I am often referred "conversion disorder" cases for consultation.  Sometimes the conversions are very classic - these almost always get better with time and things like physical therapy.  When the patient doesn't get better with a conversion diagnosis and a bit of time, or if the symptoms aren't particularly classic, I tend to suspect some unknown serious medical illness.  Often these unknowns are eventually diagnosed. 


  1. My 16 yo son has suffered with IBS every day since he was seven. He has been thru the pediatric GI department at CMH in KC. All labs/EGD/colonoscopy were neg. Only med that helps is oxycodone. He could easily have been the fourth patient in Peter's post about Heroin, IBS and Kurt Cobain. Only difference is he always has gradations of diarrhea. Pain every day, particularly with eating almost anything. He's 6 ft. tall and weighs maybe 130 lbs. No MD will write for oxy. Thank goodness for resourceful older brother who has skills. Downside is younger son lives with older brother who possesses a cast iron gut and happily eats junk. Diet advice from Dad registers like you-name-it advice from Dad. Now top this tangled sad tale off with younger son getting in a car crash last year that he walked away from with no immediate injuries. Next day he has bilateral leg myalgias which have persisted and worsened over 9 months and don't allow him to stand for more that 5-10 minutes unless drugged. I would take him anywhere in the USA to get him treatment with a Maes kind of healer. I'd even pay to take him to Maes himself if that had a way to happen.

  2. Emily, one of the passages from East of Eden (recalled by your previous post) which keeps coming back to me is the police officer eating "French Fries" (not called that in those day and would have been much healthier in beef tallow). He comments on how he really loves the fried potatoes, but "they really bind me up". Ah, IBS, starch and Steinbeck..... Steinbeck clearly knew more than most MDs about GI function!


  3. Hi Craig,

    Sorry to hear your son's problems. If you could push for starch free paleo for six weeks... But conforming to this sort of intervention is in some ways harder than medical intervention as it is cheap but requires commitment. Sitting still while someone infuses $10,000 in to your arm, with no high, is much easier than not eating bread, if you have the $10,000 of course....... Particularly if you don't see why bread should do this to you but not to your brother. But it does.


  4. Peter - yes, the great writers are the window into the human condition. There are a zillion gems in that book.

    Craig - I'm so sorry your son is struggling so much. There has to be a better way than risking arrest for a felony, however. He might be eligible for suboxone (buprenorphine) treatment for opiate addiction. It's a partial opiate, legal if prescribed by a certified physician, and will have the same constipating properties as oxycodone, and in most cases is much easier to taper off of. One's tolerance doesn't grow and grow to it as it often does to full opiates. It is not ideal, but might help. It would be hard to tell if any diet would help while he was on either - simply because of course he will get diarrhea when the opiates (partial or not) come out of his system.

  5. Chronic Fatigue Syndrome is indeed a much misundersood condition. A recent newspaper report in one of the UK newspapers appeared about the usefulness of using a gluten-free diet with a young woman with CFS / ME. It is only a newspaper report but it raised some interesting questions about 'mechanisms' (underlying coeliac disease or not - probably not). My feeling is that for a proportion of people with CFS, gluten is probably going to be an issue impacting on symptoms - don't ask me the mechanism though, perhaps a study for a brave researcher wishing to take advantage of the recent UK Medical Research Council call for research proposals on CFS?
    One other interesting issue (related to that raised by Dr D in comment 5) is the suggestion that naltrexone might be of some use in CFS. Naltrexone (opiate antagonist) could theoretically act on opioid receptors (perhaps those tied into gluten exorphins?) but also at low dose (LDN) might also have some interesting effects on cytokines??

  6. If the mechanism is similar somehow to autism, that an interesting idea. Even naltrexone is not FDA approved for autism. Craigs son could not go on naltrexone unless he was off all opiates for a couple of weeks, or else risk
    precipitated withdrawal. All of this is very speculative.

  7. Peter mentions bread, but the number of foods containing starch is quite large - so I am wondering if Peter and others think of all starches from grains differently than starches from other plant foods?

    From Wikipedia:
    Starch is the most common carbohydrate in the human diet and is contained in many staple foods. The major sources of starch intake worldwide are the cereals rice, wheat, and maize, and the root vegetables potatoes and cassava.[9] Many other starchy foods are grown, some only in specific climates, including acorns, arrowroot, arracacha, bananas, barley, breadfruit, buckwheat, canna, colacasia, katakuri, kudzu, malanga, millet, oats, oca, polynesian arrowroot, sago, sorghum, sweet potatoes, rye, taro, chestnuts, water chestnuts and yams, and many kinds of beans, such as favas, lentils, mung beans, peas, and chickpeas.

  8. I'm glad to know about your book, Emily. Somatization disorder is one of the reasons I'm glad I don't have an office-based practice anymore. You know what I mean.

    I've already referred a relative to the online insomnia program you mentioned a month ago. Too soon to tell if it will work.


  9. I think I’ve read that ME patients have higher D-lactic acid levels in the gut. I think higher D-lactic acid level in the serum is associated with muscle soreness and cognitive dysfunction. A low carbohydrate diet is used to treat acute D-lactic acid acidosis following some types of bariatric surgery.

    Perhaps a leaky gut also makes D-lactic acid get into serum and so could explain another connection between ME and leaky gut.

  10. @Nick,

    If you are HLA B27 positive and have klebsiella as a commensal in you gut I would suggest all starch goes completely. Fix your gut, then see what your tolerance level is to paleo starches. Probably no gluten grains ever. There is no deficiency disease associated with starch deficiency, unless you class hunger as one when there is no alternative source of calories... Ah, famine, gift of agriculture!


  11. Hi Steve - it is definitely a lot easier for a psychiatrist to see somatization disorders (we're supposed to be talking about coping and the brain, after all) than the PCP. Actually in some cases I spend a bit of time on the phone giving the PCP some therapy and support!

    Hope the online program is helpful - some of my patients rave about it - others don't want to change habits, as always.

    I sent someone to your book recently who was looking for options for her husband who was newly diagnosed diabetic.

  12. Hi all,

    a few rambled thoughts (sorry, I'm a bit unfocused, have trouble focusing):

    1. I think CFS/ME is chronic Herxheimer (reatction to lipopolysaccharides/LPS).

    2. I think that the NAC-flu (from the link from k1wuk from the other Maes post) is a Herxheimer reaction. I know that NAC causes the EB bodies of chlamydophila pneumoniae (CP) to break up, which fills the blood with LPS.

    3. I know its difficult to culture CP, as it only probagates in a living cells (it steals their ATP). You couldn't grow this bacterium in a petri dish, it's more a semi-virus. Chia reports that viruses settle in tissue and are hard to find in the blood stream.

    I would venture that there are more to the chlamydiaceae family than there are currently known, as they are difficult to find, grow and nobody looks for them. And I think there are more viruses living occultly (XMRV being the newest addition).

    4. Another wild guess: All the problems with the mitochondrial metabolism, oxidative stress and so on are caused by obligate intracellular pathogens.

    5. I would guess that in many diseases you have the following chain: food pathogens, viral pathogens and bacterial pathogens.

    6. The Carb-Flu is more than just the discontinuing of gluten-morphins. It could be the immune system taking care of a bacterial pathogen it couldn't tackle before.

    7. While I think that the "LPS cross the tight junctions and enter the body" is viable, it think it is more likely that we deal with a bacterial pathogen that is living occultly in the body.

    8. I think Maes' leaky gut diet is more than that. I think the diet stops bacterial pathogens and maybe viruses from propagating and lets the body take care of the problem. Maybe interferons would help this along (I know, expensive).

    9. Post-viral fatigue syndrome is more fitting than CFS/ME, but still misses the bacterial pathogen.

    10. Different pathogens could cause the same disease (does it differ for the Herx from which bacteria the LPS comes?). And each pathogen could cause different diseases, depending in which tissue it settles.

    Tony Mach

  13. One more thought: If many problems are caused by obligate intracellular pathogen, its no wonder why those HLAs on chromosome 6 are "associated" with diseases.

  14. @Peter: I'm new to this and was thinking about getting some information about my HLA-type. You seem to know some things about this and I was wondering if you could clear up something for me (&us)?

    1. Am I correct that the technology to sequence the (HLA-)genes is no ready yet (as in far from being commercial available)?

    2. There is the older "serologic HLA-typing", but standard fare here in Germany seems to be the "molecular-biology HLA-typing" for "typing of the genloci: Class I: HLA-A*, -B*, -C* Class II: HLA-DRB1*, -DQB1*, -DPB1*", used for organ transplantation. (hope the translation makes sense)

    Does this catch the individual HLAs? Or only the classes? (I need to study this more thoroughly, like so many areas in biology, but I feel I need to learn *everything* at once to gain an understanding...)

    3. Or does one need to type individual HLAs (like the B27 you mentioned)? From the HLA, the "normal" blood-labs offer only the HLA-B27 and the HLA-B*5701 here.

    4. Have you looked at gene-typing services (like 23andme) and what do you think of it? It seems like a shotgun approach to me, one might catch something but miss a lot... I have a feeling that what they offer might only be valuable if you are lucky and have the "exactly" right mutations on you chromosomes...

  15. Hi Tony,

    HLA molecules are obviously crucial to self/non-self recognition but the work on autoimmunity related to bacterial proteins looks only at very limited numbers of the large numbers of HLA variant genes we carry. Knowing as many of your HLAs as possible seems to be of no use in understanding autoimmunity unless you know which protein is being produced by which bacterium that interacts with a defined HLA to produce an antibody which unfortunately fits normal tissue. HLA B27 recognises a fragment of the enzyme pullulonase, made by klebsiella pneumoniae in response to starch. The antibody produced happens to lock on to a subtype of collagen in your spine and labels it as foreign. The resultant immune attack is called ankylosing spondylitis. Ebringer has located bacterial peptides and associated HLAs/antibodies for ankylosing spondylititis, multiple sclerosis, rheumatoid arthritis and (controversially) BSE.

    Therapy based on manipulating the appropriate microbes seems to work rather well. Prof Ebringer is a great maverick. There are a set of posts labeled HLA B27 over on my blog for some links


    Wow, some awful sentences in this comment but WTH...

  16. Before one even starts to discuss CFS or ME (myalgic encephalomyelitis), one has to ascertain that one is speaking about the same condition.
    There are a number of diagnostic criteria being used. The Oxford criteria, championd by Dr Wessly, who is as psychiatrist only reqiers 6 months of unexplained fatigue, and gives a prevalence of up to 4% of the population. The Canadian criteria and the new ICC criteria 8 specify post-exertional malaise as the main symptom of the disease, and requires a number of other neurological, cognitive and immunological symptoms. The ICC-criteria for ME gives a prevalence of 0.2 - 0.4%, a tenth of the Oxford criteria.
    The theory about sustained stress response goes with the Oxford criteria, but there is little or no evidence to support it. Also, the study showing benefits from graded exercise and cognitive therapy is on patients diagnosed by the Oxford criteria. On the other hand, many patients with ME report a worsening of their condition after having been through these programmes.Many patients and clinicians call for a seperation of the two - CFS and ME.

    There are also many cases where people diagnosed only on the basis of 6 months fatigue have later turned out to have borrelia or atypical MS,depression etc.
    This confusion about diagnosis makes it difficult to understand the reasearch, since you need to know which diagnostic criteria was being used.

    A study in Norway in October 2011 indicates that ME may be an autoimmune disease. Tests at Pacific Fatigue lab using ergospirometry shows that ME patients have a lower anaerobic threshold on day two of testing, as opposed to any other group, regardless of health.

    There is no question that the gut is involved in many cases of ME, and many people develop allergies and sensitivities that they did not have before. Whether this is cause or effect is not known



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