Saturday, January 09, 2010

Gluten: Does coeliac disease require an infection?

OK, time to post again. This one is a bit of a stand alone for those of us with food phobias which include gluten.

A zymogram is a very interesting tool, one I had never heard of until I received the pdf of this article via a friend in Scandinavia. It's from the same research group as discussed in this post. It's just a letter rather than a full research paper as the study is small, but possibly very important.

Anyway, a zymogram is an electrophoresis technique where an electric field is used to move a charged protein through a gel. It's used for hunting enzymes and what is special about the gel is that it contains the substrate for the enzyme you are hunting. If you bind gliadin in to the gel you can go hunting gliadinases in the gut contents of a human who does or does not have coeliac disease. Use your electric field to separate out the proteins and in the location where a hole gets burned in your gel, that's where a gliadinase is active. You can then work at characterising the gliadinase.

Here is a zymogram. The two ladders on the left are from normal people, there are no white bars. The next ladders have faint white bands where the gliadinases have eaten in to the gel. These are untreated coeliacs. The last lane, lane 5, has that massive burn out at 33kDa. This is a fully treated coeliac with no symptoms yet who has plenty of gliadinase in their gut.




Proline is an amino acid with a bent back. It's side chain is attached to it's amino group, putting a rigid bend in to a protein's structure. Apart from putting the essential tight twists in to collagen, proline also puts kinks in to gliadin. Lots of kinks. The sorts of kinks which stop gliadin fitting in to normal mammalian protein digesting enzymes. Particularly difficult to deal with are pairs of adjacent prolines. In fact there are only a handful of mammalian enzymes known which can act at this point. None of them fit the size/charge of the gliadinase found by Bernardo et al in their zymograms, at least one of which can do this. They think the enzyme is of bacterial origin. They only find it in the gut contents of people with coeliac disease.

It doesn't matter if you have active or diet controlled coeliac disease, the enzyme, and presumably the bacterium producing it is (pretty well) always and only present in coeliacs. So is coeliac disease an infection? Or are people with coeliac disease exquisitely good hosts for the gliadinase producing bacteria which do not establish in normal people?

This is fascinating. It's probably not the enzyme itself which is the trigger for coeliac disease (as pullulonase is for IBS) because it is detectable in controlled coeliacs as well as those with active disease. When there is no gliadin present to promote production of the enzyme it has to have other uses beyond splitting double prolines in gluten and it simply goes in to production overdrive when gliadin arrives. This seems likley.

If it's not the bacterium or the protease which trigger coeliac the other logical explanation is that the gliadinase is particularly good at producing immunogenic peptides from gliadin. This might be to do with the ability to split paired prolines, not something pancreatic lipase or brush border peptidases can do.

At the moment the only information available is observational. An intervention trial would eliminate the bacterium and its enzyme, check this on a zymogram, then re challenge with gliadin. We are probably years away from being able to try this but, if it turns out that this is a cure for coeliac disease, just think of the implications...

A genetic coeliac could eat real artisan breads, drink pints of Nelson's Revenge, freely eat pizza until having to buy a longer belt, develop hypothyroidism, get a wheelchair for gluten ataxia or multiple sclerosis... In fact all of the gifts of direct gluten consumption and toxicity (which probably don't need enzymic digestion to be received) could be shared by people who might have had to avoid gluten for digestive reasons! Share and share alike. We all need wheat.

Oh, except those of us who have contracted food phobias through dabbling in the scientific literature!

Hee hee, makes me think of "Three Men in a Boat" with pubmed substituting for the British Museum.

Peter

35 comments:

pyker said...

Well that's just great, now I've got Housemaid's Knee. I better get over to Dr. Ayers' site to see how I can cool that off.

Matt Stone said...

Thanks Peter. We're exploring this issue at great length at Infection-Cortisol at Yahoo from the bias that most health problems stem from infection, at least in part, including Celiac's. It's hosted by The Potbelly Syndrome author Russ Farris:

http://health.groups.yahoo.com/group/infection-cortisol/

Your input would be greatly appreciated there.

Roj said...

That's fascinating Peter, for me as a coeliac. That said, if anyone did cure me, I can't see me and gluten ever being best buddies. Too much water under that bridge ;-)

Stan (Heretic) said...

Hi Peter,

I don't understand how do gliadinase producing bacteria know that they are supposed to live in the gut of coeliac patients only, but not in non-coeliac?

If that is a symbiosis then it must have taken a long (evolutionary) time to develop.

Would that not indicate that coeliac disease may be some protective adaptation (against what?) just like sickle-cell anemia is protecting against malaria, rather than being a purely destructive mutation?

Regards,
Stan

poonja said...

I use approx 3grams of proline per day with pauling/rath protocol. Any reason to stop using the proline?

VersatileDeft said...

It's pretty funny that should show up right after I emailed you about something along these lines, Peter. haha. This is Chris.

Its funny how bread can be considered the staff of life... yet so many of us [Celiacs] kindly reject it. XD

But a cure would be nice for just cross contamination...

PJ said...

This is really very interesting. I don't even know what it means yet, or might, except that I find ANY insight into gluten-reaction a good thing and moving forward.

I notice however that as I am merely 'intolerant' (gluten like having pasta or bread gives me asthma) and some friends are actual celiac even if not officially diagnosed (just having something from the same dish or pan as previous gluten-foods will either make them in agony for awhile in acute pain, or make them miserable in more long-suffering sort of effects for a week), that due to "degree of visible, experiential damage" they are a lot less prone to screw up and eat gluten than I am, obviously.

I have sometimes thought that for my own good it'd be better if it had such a horrible digestive effect that I was brought to the same pain they are; they are fanatic, as a result of "getting gluten'd" as they put it, to avoid even accidental cross contamination, while I eat lowcarb whole foods but sometimes go on dontgiveadamn binges where I actually eat a former loved food like bread or pasta.

In the end I'm sure I am paying the price "on the inside" but given I was already fat to begin with, and aside from this apparent stupidity don't suffer any other major diseases that are visible, then so far it's harder for me to put in place the sufficient level of panic-based self-discipline they've got. (They didn't have it to begin with, but pain is a powerful motivator!)

So I think that finding what allows people to eat gluten without having digestive discomfort, while that would be wonderful for celiacs' ability to not get gluten'd all the damn time from the most unlikely sources, it might also allow more people, as you note, to keep happily eating grain (=crap) foods and getting all the longer-term and larger-scale health complications from that. You're right about that.

mary said...

speaking of food phobias: the japanese consume a great deal of unfermented soy products (like tofu and soymilk). do you consider the japanese a 'disease-prone' society? if so, why do they have the longest average life span?

gn said...

(apologizing for sort of hijacking the thread)
re japan and soy sproducts:
difficult to infere how much is a "great deal", but i guess it's not more than is consumed by non-japanese who eats a lot of processed food with added soy or its derivatives
re japanese longevity:
i've read somewhere that if adjusted for mortality from firearms and car accidents average lifespan in the usa it would be not that much lower than in japan;
i live in japan and have a neighbor who is 83 but looks not older than 70, and is very active both physically and mentally, so i asked him what was his secret of longevity; he answered that he was eating almost no meat but a lot of fish and organic vegs which he grows himself, but he said that he was thinking that the most important thing was that he and his generation in genereal had endured a lot of hardships during war and afterwards, and he was not exposed to all that crap they put in food nowadays

old people in japan (those who, by dying old, make the statistics of longevity) are those who are the "strong ones", who successfully lived through quite difficult times when they had to experience food scarcity (aside from direct war casualities, there was a great del of natural selection), it is rather doubtful if younger generation will live that long

Elizabeth said...

Hi Peter,

As it is a food-phobia topic today, can I please ask you to refresh what it is you do to your dairy to make it better for you. I remember you ferment it? Is that the cream? Is that to reduce the casein protein - would this help me do you think with casein difficulties?

Thanks for any feedback
Elizabeth

Heike said...

An interesting post, thanks Peter! I avoid grains myself (in particular in the mornings), and it does me good.

It still brings me back to my comment of a few days ago. Around 95% or more of Europeans consume what you and I would consider VAST amounts of grain, without being stunted in their growth or suffering from MS en masse. Life expetancy keeps rising, too.

Also, the two or so comments on the Japanese diet. My gran also lived to nearly 90 and looked fit & healthy. Only for her, lots of potatoes & flour based foods, not a veg in sight.

Eating grains is doubtless prevalent. I think it is possible that different people(s) process gluten in different ways.

It seems to be true though that virtually everybody wants to have a lie-down after eating pasta for lunch!

Thanks for the good work!

donny said...

Wouldn't it make sense for the lion's share of adaptation to symbiosis to be made by the shorter-lived bacteria? Species that killed the host wouldn't make it. We haven't had much time to adapt to sugar and corn oil and soy, but to our gut bacteria, it's been ages, and we're caught in the cross-fire. The speed with which the host could adapt wouldn't have to enter the picture. I guess studies where obese rodents are seeded with gut bacteria from lean rodents fit into this idea.
Maybe the right probiotics could help minimize the effects of accidental trace gluten ingestion?

Robert McLeod said...

Peter,

There are four hypotheses for how autoimmune diseases manifest (molecular mimicry, cryptic antigens, superantigens, and bystander activation). All, more or less, do require infections to actually induct an autoimmune condition.

However, I have been wondering if food allergens may be able to act as superantigens. Consider the MHC molecule. Let's say something binds on the outside, reconfigurating the protein and now suddenly a MHC that previously would not bind to 'self' proteins now does bind to one.

Elizabeth said...

Sorry- pestering again on topic of autoimmune. Are casein problems leaky gut then? Is that what is really going on- had 200ml 45% fat cream this morning in the coffee. To see what the reaction would be - and nothing else all day and will wait to see tomorrow what the level of pain is. Had a streaming nose immediately and after the sore dry eyes. Now for the joint pain. Perhaps the really high fat cream will prove to be more tolerable for occasional forays into the unknown of dairy consumption.

I do find it addicitve and it doesn't make me feel great afterwards but hey.. I still adore whipped cream, how sad is that - what we do to have our favourite things. Intersestingly it did not effect my blood glucose readings much - stayed from 4, down to 3.7 back to 4.5 now which is 9 hours later.

Thanks,

caphuff said...

"all of the gifts of direct gluten consumption and toxicity (which probably don't need enzymic digestion to be received)"

So I guess this would be an exception to the rule against looking gift horses in the teeth, eh? :)

Peter said...

Hi Pyker, Hee hee, it will be menthol. Interestingly I've seen some amazing case reports in the mainstream using menthol application for treating suicidal grade neuropathic pain (from chemotherapy) with marked effect. Apart from free radical effects there are also menthol receptors in the nervous system! Plants would hardly develop pharmaceuticals without reason.

Matt, some interesting papers discussed there. I guess you are well aware of Dr Ravnskov's infection hypothesis of atherosclerosis?

Roj, yes, as a mild intolerant that's the way I would see it.

Stan, coeliac disease is associated with a number of specific HLA subtypes, used for many things as part of the immune system. It would be very interesting to find the bug, characterise its surface proteins and look whether specific HLA subtypes of the host are particularly ineffective at getting rid of the bug. I suspect the bug is ubiquitous (so if you "cured" coeliac it would only last until the next encounter) and there might be something special about the immune system of genetic coeliacs. The adaption may be favoured in mild form as a protection against iron overload.

http://www.ncbi.nlm.nih.gov/pubmed/15929194

Treating the chronic anaemia of coeliac allows haemochromatosis to be unmasked when the gut is healed. You than start to ask whether haemochromatosis was selected against in HGs and is allowed to persist by mild coelaic when the extreme form makes you a non survivor as per sickle cell anaemia. But of course high iron intake was probably common in pre agriculture times but might not give liver problems in the absence of agricultural omega 6 PUFA. So coeliac might protect against the effects of PUFA on a "normal" human iron intake. Getting a bit convoluted here! But yes, ultimately there could be a recent onset advantage to tolerating mild coeliac.

Peter

Peter said...

Poonja, Not that I can see. How are you getting on with Rath/Pauling? I have some time for this hypothesis (as pharmacology goes) but Dr Davis suggests it doesn't work for elevated Lp(a) per se, but I don't think he has mentioned it's effect on CAC score progression/regression. Have you had any numbers/scores to assess effectiveness?

Chris, yes, perhaps, but I doubt many people who are made gluten tolerant would really stick to the coeliac diet. It's the pain which saves you.

PJ, this is exactly how I see the world. I do wonder how well any normal people find it to comply with a gluten free diet. My problems are so minor that I consider Pubmed to be a major protective influence, comparable in effectiveness to surrogates for information, like gut pain. The really unfortunate people are on omeprazole for life and their Dr pooh poohs coleiac. A half hearted elimination will do nothing other than convince you that gluten is not the problem and you were born with an omeprazole deficiency.

Mary, I wasn't aware that the Japanese ate much soy, I'd not call 8g/d a lot really...

http://www.ncbi.nlm.nih.gov/pubmed/9446845
http://jn.nutrition.org/cgi/content/full/128/2/209/T1

gn, yes, I've heard similar discussions. Actually a long life span and good health is a trait of the Hiroshima survivors which has been attributed to the per-acute selection pressure at the time of the blast and merely acutely during the firestorm which followed, then during the weeks before any medical aid arrived. Only the fittest and luckiest survived. So much has changed in Japan, but currently some things still seem better than in the West (from the view of someone who has never been there!). I remember a documentary about Japan which claimed they had more MRI scanners per head than anywhere else at the time. If the scan said you had a terminal illness they tended not to operate/chemo for the sake of it. Probably this decreases medically induced deaths! And that reminds me of doctors' strikes, there have been several, death rates drop!

Elizabeth, I used to ferment my cream but 6 months in very cramped and then cold conditions stopped me. Now that we have a superb kitchen and effective heating I might re start but when I look back critically I can't see a huge change in anything from stopping. I used to do this:

http://high-fat-nutrition.blogspot.com/2008/01/easiyo.html

Casein can undoubtedly open tight junctions in the gut. Once it has done that a host of triggers is available for stiff joints. I guess if you really want to know if it is casein you could work down from ghee through butter to double cream. Yogurt would have to be another experiment.

Peter

Peter said...

Heike, the most important thing I can see about longevity seems to be insulin sensitivity. If you can eat a diet of potatoes and maintain reasonable levels of glycaemia with reasonable levels of insulin you are probably on to a (genetic) winner. Others might get there accidentally by having a second rate tolerance of carbohydrate (probably fructose) and yet get to old age by accidentally avoiding carbohydrate. At the moment I just see most degenerative diseases improving with carb restriction. I'd rather hope that this might extend life, or healthy life anyway. Of course a very carb based diet might well be low in protein and so in cystein too, the other longevity hypothesis.

Donny, I never got to extend this post the Gottschall's diet, the possible roll of probiotics in IBD, how they might be correcting a bacterial problem... This then eventually allows you to eat gluten and all the fun that that brings. If the SCD worked for me, I'd be loathe to go back to traditional eating, but many people seem able, and relieved, to do this.

Rob, Over the years I treated a number of dogs with very severe skin disease usinga meat and bone meal diet. When it worked it worked really well and I always assumed it was eliminating gluten and gut damage. But I ALWAYS would give a secondarily infected skin at least two weeks of broad spectrum antibiotics, as well as the diet change. You have to ask if you were treating the skin or the gut with the abs. But still the diet change was needed as antibiotics alone had always been tried before, so perhaps the diet was a trigger too. The problem clinically is that you deal with such small numbers of patients and so few have co operative owners...

Plenty of plant proteins are sticky/lectin/lectin-like. Believable.

Caphuff, I guess this depends on what you are going to do with the horse.....!

Peter

gunther gatherer said...

Hi Peter,

"a long life span and good health is a trait of the Hiroshima survivors which has been attributed to the per-acute selection pressure at the time of the blast and merely acutely during the firestorm which followed, then during the weeks before any medical aid arrived"

Could it also be due to hormesis from the radiation exposure itself? I'm not suggesting this is good for you, but it may be an aspect along with what you pose above.

This brings me to an outlying factor in health that's caught my attention recently: that of lack of hormesis, ie. no challenge to cells in one's lifestyle. I've been experimenting with eating certain "inflammatory" foods such as nightshades, with interesting results.

I was wondering how you felt about hormesis in general, since you don't discuss it much on the blog,. I agree with you that vegetables aren't optimal human food, but they may serve a purpose when intermittently SEPARATELY eaten from real food and ONLY for hormetic purposes. The idea is to invoke the same cell-protection effects as fasting or exercise.

Here are some fascinating studies:

http://www.ncbi.nlm.nih.gov/pubmed/17913594?dopt=Abstract

http://www.nature.com/ejcn/journal/v61/n2/abs/1602507a.html

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6X1H-4PJM9F8-1&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=4a6944b9a488089a3e5e00c9b919eef9

http://www.ncbi.nlm.nih.gov/pubmed/18648607?dopt=Abstract

http://www.ncbi.nlm.nih.gov/pubmed/18543123?dopt=Abstract

Cheers, G

gunther gatherer said...

Please let me add that the above ingestion of phytotoxins is considered only in the context of a healthy gut! (I.e. don't be using grains, or any other neolithic gut-shredding items for this. The idea is not to permanently inflame the gut, but to temporarily raise the body's sympathetic nervous system and acute immune response...)

Manne said...

What you briefly mentioned about pullulanase and IBS made me very interested.

Can't find much more detail about it online though, do you have more informationabout that?

Robert McLeod said...

On the topic of induction of autoimmune diseases by viruses and bacteria,

Samarkos (2005), "The role of infections in the pathogenesis of autoimmune diseases."

Nigel Kinbrum BSc(Hons)Eng said...

All this talk of infection & autoimmune disease makes me think....hypovitaminosis D!

Ken said...

A new Germ Theory. "Consider a disease with a fitness cost of one percent -- that is, a disease that takes a toll on survival or reproduction such that people who have it end up with one percent fewer offspring, on average, than the general population. That small amount adds up. If you have an inherited disease with a one percent fitness cost, in the next generation there will be 99 percent of the original number in the gene pool. Eventually the number of people with the disease will dwindle to close to zero -- or, more precisely, to the rate produced by random genetic mutations: about one in 50,000 to one in 100,000 {..]

The most fitness-antagonistic diseases must be infectious, not genetic, Ewald and Cochran reason, because otherwise their frequency would have sunk to the level of random mutations. The exceptions would be either diseases that could be the effect of some new environmental factor (radiation or smoking, for example), or genetic diseases that balance their fitness cost with a benefit. Sickle-cell anemia is one example of the latter."

Nigel Kinbrum, take a look at this please.

caphuff said...

My (non-scientific) executive summary: gluten is plant venom, the adverse effects of which may include (among other things) coeliac.

But the coeliac who has gut-problems alleviated (by removal of a bacterial infection, say)ought not to assume he has found the gluten anti-venom.

Tim TerlegÄrd said...

Now that you're talking life span. I heard some time ago about a theory that age is decided by the length of telomeres. Was that theory valid? If age is about the telomeres, how does insulin influence telomeres?

blogblog said...

Mary said:
"speaking of food phobias: the japanese consume a great deal of unfermented soy products (like tofu and soymilk). do you consider the japanese a 'disease-prone' society? if so, why do they have the longest average life span?"

Nothing could vbe further from the truth. The Japanese consume almost no unfermented soy- tofu and soy sauce are fermented. The total soy consumption in Japan is also quite low.

Mrs. Ed said...

Have you ever read "Management of Celiac's Disease" by Sidney V. Haas (published 1951)? Before it was discovered that Celiacs had a gluten issue he argued that it was a bacteria that was changing what was eaten into something damaging. He was very ahead of his time, he would even be more so today.

blogblog said...

I am sure that the lack of gut parasites in modern western populations is a major contributor to autoimmune and inflammatory diseases.

I clearly observed the anti-inflammatory role of gut parasites about two years ago. My cat had just used the litter tray and I noticed a wriggling tapeworm segment in his stool. I wormed him later that day. A few days later he developed hay fever for the first time despite being 18 years old. He hadn't suffered any obvious problems at all when he had the tape worm.

blogblog said...

Peter,
the hemochromatosis/celiac idea is interesting. I had borderline anemia for years due to Crohn's despite eating a huge amount of red meat.

There is also some evidence that regular blood donations are cardioprotective for men.

blogblog said...

My GP refused to prescribe corticosteroids for my IBD. He said that any underlying infection would be masked potentially making the problem much worse.

O Primitivo said...

Despite of this, they insist wheat is very healthy: "Britons May Be Avoiding Wheat Unnecessarily, UK" - http://www.medicalnewstoday.com/articles/176895.php

Peter said...

Blogblog, that sounds remarkably sensible.

O P, yes, and saturated fat causes heart disease! Dr Heather Mackenzie and Dr Carina Venter seem to have about as much information about the innate immune system as Catherine Collins RD does on Dr Briffa's site, down in the comments. None.

How do these people get in to positions to destroy people's lives?

Peter

Melinda said...

Oh la la

.... said...

Bacteria are not only harmful to humans, too many industries depend in part or entirely of bacterial action. Lots of important chemicals such as ethyl alcohol, acetic acid, butyl alcohol and acetone are produced by specific bacteria. Bacteria are also used for curing snuff, tanning leather, rubber, cotton, etc.. The bacteria (Lactobacillus often) along with yeast and molds have been used for thousands of years for the preparation of fermented foods such as cheese, butter, pickles, soy sauce, sauerkraut, vinegar, wine and yogurt.