Sunday, February 27, 2011

Depression and a Leaky Gut

First off, please go by and read That Paleo Guy's account of being in the middle of the latest Christchurch earthquake.  Fortunately he and his loved ones and cat are all okay.  You can also follow his twitter feed here.  I've never been at the epicenter of disaster, and I don't know that I would have acquitted myself quite so well.  I mean, once when I was in college our power was taken out by a storm, and since we lived in a crappy part of town (cheap apartment for college), it took about two weeks to get it fixed, and we congratulated ourselves on the campfire we improvised on the back porch to roast marshmallows by.  But no ground shifted.  I don't think anyone died, though quite a few trees were taken out, and there was some flooding.  Other than that, well, I've seen plenty of death and destruction in the ER and ICU, but those are more or less controlled settings.  Anyway, I hope Jamie's life is back to some sort of normalcy soon.

But for a bit of literary grounding, let's visit John Steinbeck's greatest work, East of Eden.

"But the Hebrew word, the word timshel—‘Thou mayest’— that gives a choice. It might be the most important word in the world. That says the way is open. That throws it right back on a man. For if ‘Thou mayest’—it is also true that ‘Thou mayest not."

I need a song.  Something quiet.  How about Satie's Gymnopedies No. 1? (right click in new tab)

Back to Evolutionary Psychiatry.  During the research for the Wheat and Serious Mental Illness post, I came across this intriguing paper by none other than Michael Maes, the cranky Belgian researcher who has churned out so many fascinating papers on depression and inflammation

Maes and crew took 51 subjects, 23 controls and 28 outpatients with Major Depressive Disorder from the outpatient clinic.  Everyone with substance abuse, anyone on medication, and anyone with chronic fatigue or other autoimmune diseases were excluded.

The basic premise of the experiment was that activation of the inflammatory response system plays a role in the pathology of major depressive disorder.  Our guts are chock full of gram negative bacteria, who have lots of a lipopolysaccharide (LPS) on their little bacterial cell membranes.  If one finds LPS in the bloodstream, that means those naughty bacteria are somehow squeezing through the so-called tight junctions of our intestinal tract - a leaky gut.  That would be bad.  And, not surprisingly, LPS found in the bloodstream ("systemic LPS") results in rapid increases in TNFalpha levels, which might remain elevated for as long as 10 months.  Brain microglia (immune cells in the brain) launch into action to fight the invasion and send out more inflammatory cytokines.  LPS in the system results in elevations of all those cytokines associated with major depressive disorder - TNFalpha, IL-6, IL1beta.  In animal studies, LPS administration results in an appearance of symptoms of poor appetite, psychomotor retardation (meaning lack of normal fidgeting movement, characteristic of depression), malaise, and loss of interest.  These symptoms are very similar to the clinical symptoms of depressive disorders. Increased LPS also seems to induce the catabolism of tryptophan (meaning more tryptophan, the amino acid precursor of serotonin, is chewed up and not used to make serotonin.)

So Maes checked antibodies (IgA and IgM - basically, gut antibodies and freshly minted antibodies) to LPS of 6 different enterobacteria.  Turns out that IgM and/or IgA were significantly elevated against most of the enterobacteria in the subjects with major depressive disorder.

In short, people with major depressive disorders were busy mounting an immune response to bacteria which never should be in the inner sanctum of the body in the first place - bacteria that live in the gut, and ought to stay in the gut.  Symptoms of irritable bowel, fatigue, and "a subjective feeling of infection" were most likely to be associated with a large immune response. 

Maes goes on to describe some interesting characteristics of the leaky gut - he contends that an inflammatory response itself actually worsens the leaky gut, that the activation of interferon gamma and IL-6 help the gram negative bacteria use the lipid rafts to get through the gut lining into the bloodstream.  That is interesting, as inflammatory response is increased in response to stress.  So stressful life events might in themselves increase the permeability of the gut.  (Jamie, do some yoga!).  Other things that induce lipopolysaccharide translocation - alcoholism, infections such as AIDS, inflammatory bowel disease (like ulcerative colitis or crohn's), and autoimmune disorders.

Maes ends his paper by optimistically suggesting that people with major depressive disorder be checked for the presence of leaky guts via measurements of IgM and IgA against LPS, and that those with leaky guts should be treated with a "leaky gut diet." (1) (the reference indicates one can write the Maes researchers to get the details of the diet - which I have done this evening!).

So - once again - don't have a leaky gut!  As Robb Wolf would say, keep your poo where it belongs.


  1. where did you see the email link? I would like this as well.

  2. Email was on the full text of the LPS and depression paper - but when I emailed it it bounced. Maybe Ill look at his website more closely...

  3. I would like to know what the Maes researchers respond regarding a diet for a "leaky gut!"

  4. P.S. After studying comparative physiology, nutrition, endocrinology, toxicology, pathology, energetics and ecophysiology, at both the undergrad and post-graduate levels (and continuing as a research assistant in these fields for several years thereafte), as well as studying, practicing and clinically applying the most holistic system of medicine in the World for more than a decade now, I am convinced beyond any doubt that there exists NO system of knowledge on Earth with a deeper understanding of the body-mind and the root causes of (as well as what is needed to fully heal) dis-ease than Ayurveda.

  5. The LPS issue maybe why we see elevated HS CRP in patients. Emily have you ever considered ordering this and vitamin D levels on patients who are seriously depressed? I think its entirely reasonable and you may find an observational finding that is publishable. I am doing the same with metabolic bone disease for the last three yrs and the results so far have been astounding. Only 6 patients have had normal labs when I screened them with exams and MRI studies as I worked up their spine issues. Its changed the way I do things now. The LPS angle for me is interesting to say the least.

    1. Hi John
      Embarrassed to say I have never written on a blog site so am unsure if this will reach you. Am quite interested in your metabolic bode disease and LPS experience. Can you email me at Thank you

  6. Hi there! Been reading a good while, and chewing over much of the interesting material you post here. I am slowly being convinced I should probably do some sort of paleo-ish diet. So I'd be very interested to see what this diet your surly Belgian is suggesting as well.

  7. Great article. Off to share it. I know when both starches and sugars are taken out of the diet a more stable mood is felt by many people I know personally (completely anecdotal). I wonder if it's just/mostly the wheat that causes or exacerbates the mood disorders. Thank you for writing this in an easily understood way.

    One small pinchy point though, HIV is the infection, AIDS is the syndrome.

  8. According to me nobody can stop the person getting into depression once if he lose his loved ones....correct me if am wrong

  9. Hyperpermeability of the gut (leaky gut!) is fast becoming the bad guy in relation to many conditions. The paper by Laura de Magistris and colleagues on gut permeability in autism is so far one of the most interesting in that it reported that permeability "decreased" as a function of implementing a gluten (and casein) free diet. Does this mean that gluten (wheat et al) functionally alter permeability? Or does it mean that gluten-free diet alters the gut bacterial populations which then has a knock-on effect (similar to the process in pseudomembranous colitis and clostridia)?

  10. He is cranky:
    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”, a symptom complex which could not be detected by the first author, a skilled psychiatrist.
    I like that :-)

    Well, the case he describes sure sounds like some sort of infectious attack on body (and mind), that the body takes care given the right treatment and nutrition - and maybe getting rid of the worst nutritional toxins.

    I get the feeling that his treatment with antioxidants and "TJ-healer" (L-glutamine, gamma oryzanol, zinc, etc.) errs on the broad side, that he includes rather one too much than too little. But better an antioxidant too much than including an antipsychotic ...

    BTW, I'm sick from all those self-styled "skeptics" basically saying "It's all in your head" - this is an idealistic, non-materialistic position, that should have been buried over 200 years ago. These "skeptics" are as dangerous ulcerous bulges (to use a expression from Paracelsus) as many of those esoteric quacks they fight. "Conventional medicine" has done diddly squat to help people with CFS, fibro and so on (and even fights against evidence based research), instead they label those people as hypochondriacs and insane. And instead of questioning the conventional medicine, they attack those who try to figure it all out (and might not have an answer to every question).

  11. Maes describes the "leaky gut diet" as "consisting of milk allergic, gluten-free and low-carb diet. The latter sometimes should be combined with an exclusion diet, based on the elimination of dietary allergens.",%20leaky%20gut%20in%20CFS.pdf

  12. Once the gut becomes hypothetically permeable to LPS, is there any hypothesis on how one would make it not so with diet, etc?

  13. Wow! The limits of professional etiquette are rather shredded here! Still, it must be very frustrating dealing with idiots on the battlefields of CFS. Great link.


  14. John - I check vitamin D all the time but *rarely* do I see levels of 25 (OH) D3 above 25. I would say 50% are 22 or less. I haven't checked LPS - and they checked specific antibodies to specific LPS from different bacteria - a little less easy to get from Quest labs, but seems like a no-brainer for a big study, and then tests thereafter.

    Megan - yup, I was quoting the paper there but you are quite correct

    signsof - I am somewhat loosey goosey with the terms on my blog in the service of folksiness (I'd be harsh if one of my students did the same thing in a clinical write-up) - "depression" is a state of being sad. depressive disorders are particular syndromes characterized by symptom complexes and associated with certain inflammatory and sleep changes. If we lose a loved one, of course we will be depressed (part of being human), but we may not develop a depressive disorder.

    Paul - excellent question! Zonulin is a promising mechanism but not a hole in one.

    Jen - thanks for the link!

    Tony, Peter - when I first looked at his webpage, he had a somewhat virulent take-down of a very preeminent depression researcher who had ignored Maes' work in a recent review of depression and inflammation studies. So yes, he is cranky! On the other hand, his papers are amazing. He hammers out plausible biologic mechanisms at every step from gut to hippocampus with explanations for every symptom of depressive disorders. It's really quite compelling. I imagine he must get sick of the Freudian hand-wavers. I'm rather fond of Freud in a historical sense, but I'm not a big believer of depression as "anger turned inward" and all that jazz.

    Spice doc - the autistic kids had less-leaky guts to the mannitol/lactulose tests with gluten-free, casein free diets.

  15. One more thought: I find the use of N-acetylcysteine by Michael Maes interesting and I think there is more to it. Wikipedia has an interesting list of its wonders. I have no idea how an researcher comes up with the idea to investigate if "NAC may help prevent noise-induced hearing loss", but the list of underinvestigated problems includes things like pancreas protection, treatment of OCD and autism. And NAC seems to be helpful in schizophrenia, bipolar disorder and depression, the classic three (or did I miss one?). My wild guess: there is something metabolically going wrong and NAC fills up what's missing (as does Q10, IMHO).

    @signsof: No one disputes that an traumatic episode can lead to depression, PTSD and Darwin knows what. Yet, without being an expert, from my point of view in many cases (and even when there is a traumatic trigger) the underlying reasons for depression are nutritional, probably combined with a genetic disposition, that lead to an chronic inflammatory response of the body, affecting the mind. (And my pet theory, that the balance of Omega-3/Omega-6 based neurotransmitters are out of whack)

    Address the trauma with therapy, address the inflammation with proper nutrition (Primal/Paleo/etc.). Use antipsychotic, antidepressive or what ever pharmaceuticals only as a means of intervention, if necessary.

    @Emily: AFAIK, Freud stole all the good stuff from Pierre Janet anyway. From what I read Janet's concepts of dissociation and the subconsious are more to the point than Freuds watered down version and connect to a evolutionary view of shamanism, IMHO. Both Janet and Freud brought great progress, but clinging to a "mind only" view of psychological problems is no longer tenable.

  16. Tony - I have to say Tylenol is never my pain killer du journey after reading how it completely depletes glutamate. Paul Jaminet is a big fan of NAC - my only experience with it is working with people after Tylenol OD (as you likely know NAC will save the liver and person a horrific death if given soon enough and in the correct quantities) - and the one notable thing about NAC was the foul, foul smell.

  17. Oh, and psychiatrists have a certain conceit as the last shamans of medicine - we dress a little different, know one can explain exactly what it is we do, and our meetings are secretive. As mental illness is little understood it is best shipped out of the village to be soaked up by the shaman and cleansed, as it were.

  18. A timely review on the potential effect of zonulin on intestinal barrier function:
    Agreed not a 'hole in one' (but perhaps a good shot onto the putting green)

  19. oops - not glutamate. glutathione. Js - love Clair de lune.

  20. and "no one" Good Lord. I was a bit sleep deprived yesterday. I should get my commenting privs revoked sometimes.

  21. @Paul Whiteley. Thank you for posting that! Alesio Fasano is brilliant. I have a friend that has access to full text and sent it to me but I see now that it's actually free. After dinner reading this evening.

  22. Isn't Tylenol (aka Paracetamol) N-acetyl-para-aminophenol (APAP)? And isn't Maes advising N-acetylcysteine (NAC, known as N-acetyl-L-cysteine or Acetylcysteine), as does Paul Jaminet? Haven't check it if it's true, but Paul writes that N-acetylcysteine precursor to glutathione.

    Be glad, at least "know one" and "no one" are pronounced the same, I somtimes mix up "who" and "how"... :-)

  23. Here's the quote from wikipedia on the cleaning up of tylenol liver berserkage:

    "Intravenous acetylcysteine is indicated for the treatment of paracetamol (acetaminophen) overdose. When paracetamol is taken in large quantities, a minor metabolite called N-acetyl-p-benzoquinone imine (NAPQI) accumulates within the body. It is normally conjugated by glutathione, but when taken in excess, the body's glutathione reserves are not sufficient to inactivate the toxic NAPQI. This metabolite is then free to react with key hepatic enzymes, therefore damaging hepatocytes. This may lead to severe liver damage and even death by fulminant liver failure.

    For this indication, acetylcysteine acts to augment the glutathione reserves in the body and, together with glutathione, directly bind to toxic metabolites. These actions serve to protect hepatocytes in the liver from NAPQI toxicity."

  24. Both Paul Jaminet and Michael Maes think acetylcysteine is useful, I didn't see a reference to paracetamol overdose - or did I miss something? Sorry, English is not my mothers tongue and I might have misunderstood (and I'm a bit dense the last couple of days, maybe just a flu...)


    Thought I let you know, while we were in the direction of Maes and CFS. I just found one more reason to make sure one has adequate sunshine exposure and/or Vitamin D3 intake:

    Recent evidence suggests that Vitamin D deficiency/insufficiency plays a role in the development of hyperparathyroidism

    Of those patients who do present with symptoms, they are commonly associated with the effects of an increased level of calcium. Since calcium is involved in trans-synaptic communication in the nervous system, high blood calcium levels have a direct effect on the nervous system. Thus, most of the symptoms of parathyroid disease are "neurological" in origin. Common manifestations of hyperparathyroidism include weakness and fatigue, depression, bone pain, muscle soreness (myalgias), decreased appetite, feelings of nausea and vomiting, constipation, polyuria, polydipsia, cognitive impairment, kidney stones and osteoporosis.

    (And some of those symptoms sound suspiciously close to CFS/Fibromyalgia)


    BTW, I can recommend the Gnossienne Nr. 1 from Satie, they sometimes play it on Radio Paradise, my radio station of choice.

  25. Hey there. Slightly off-topic question: Are you familiar with Julia Ross and her "Mood Cure?" She advocates a paleo-ish diet and makes connections to depressive disorders and all sorts of deficiencies, gut disbiosis, etc, like what you look at. But her method hinges on megadoses ofparticular amino acids for particular types of what she terms "false moods." What do you think of that? I am aware of problems with tryptophan because of how you mention it is food for some bad bacteria. But in general, would you advocate trying amino acid supplements to help the brain make feel-good chemicals?


  26. I probably won't get a response to this, as this post is old, but just the same: how do you convince your doctor to test you and see if you have a "leaky gut"? I'm Canadian and doctors here only do tests if they think there is a good reason - you can't really pay for them yourself, and our healthcare system frowns on weird tests :-) Also, half the world now seems to be allergic to wheat, sensitive to wheat or celiac. I actually ordered a home test for celiac disease and I don't have it (yay). And I don't seem to have any negative reactions of wheat or any other grains, as least not as far as I can tell. But perhaps all my symptoms of depression and anxiety are caused by a leaky gut?? And wheat is inherently evil and I should stop eating it right now? I have NO idea. It just seems that these days if you have the slightest bit of anything wrong (a rash, some IBS, a bit of anxiety) everyone immediately says "stop eating wheat! no more dairy! horrible red meat or horrible PUFAs!" depending on their dietary bent. What to do?

  27. The link, labelled 1, is dead I'm afraid. Interesting read, however.

    1. There is a copy here it seems


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