Anti-Inflammatory Diet

All health care starts with diet. My recommendations for a healthy diet are here:
Anti-Inflammatory Diet and Lifestyle.
There are over 190 articles on diet, inflammation and disease on this blog
(find topics using search [upper left] or index [lower right]), and
more articles by Prof. Ayers on Suite101 .

Thursday, January 9, 2014

Transglutaminase, Gluten, Celiac, Inflammation, Autoimmunity

The point of this post is that the intestines produce an enzyme, transglutaminase (TG) that normally protects the gut from toxic plant proteins, such as grain gluten, but modern food processing and antibiotics corrupt digestion of gluten to produce intestinal inflammation and a series of related autoimmune diseases including celiac, thyroiditis, diabetes, baldness and atherosclerosis. 

Transglutaminase Links Proteins Enzymatically
Transglutaminase is a ubiquitous enzyme produced in the intestines, thyroid, heart, skin, hair follicles, etc.  This enzyme attaches to a protein (TG + ProA ~~> TG-ProA) via amino groups extending from some of the protein's amino acids, e.g. lysine or glutamine, and then the enzyme replaces itself by another protein leaving the two proteins crosslinked (TG-ProA + ProB ~~> TG + ProA-ProB).  Another alternative reaction is to leave the original glutamine without its amino group to yield glutamic acid residues.

Linking Proteins Makes Connective Tissue Tough
Transglutaminase is useful to crosslink the proteins in connective tissue.  Proteins in basement membranes form a matrix by binding to the heparan sulfate sidechains of another basement protein, perlecan.  The heparin-binding domains consist of basic amino acids that TG can react with to crosslink the proteins.

Linking Pathogen Proteins
Transglutaminase is also produced to crosslink the DNA/heparin/matrix polysaccharide-binding domains of pathogenic bacteria leading to aggregation, localization and death of the bacteria.  Inflammation resulting from activation of the inflammatory transcription factor, NFkB, stimulates production of TG.

Gluten is a Plant's Way of Saying "Don't Eat Me!"
Gliadin is a protein component of gluten that contains long stretches of glutamine residues, i.e. it is a polyglutamine protein similar to the protein that causes Huntington's disease.  Gliadin is an advantage as a storage protein for grain, because it is aggregated by the TG that protects the lining of the intestines of herbivores, such as humans, makes the animal sick and thereby discourages eating the grain.  Aggregation of gliadin/gluten inhibits digestion of the grain protein and can leave TG bound to gliadin.  Conversion of the polyglutamine stretches to polyglutamic acid stretches that are negatively charged, produces proteins that will bind to the positively charged heparan sulfates that circulate along the surface of intestinal cells leading to damage and inflammation.

Basic Triplet Leads to Antibody Production
Transglutaminase is also transported into cells, because it contains a region with a triplet of basic amino acids (...EPKQKRKLVA...).  This internalization probably contributes to enhanced presentation of TG to the immune system for subsequent antibody production.

Transglutaminase is Inflammatory
Transglutaminase interaction on the surface of cells also activates, NFkB, the transcription factor responsible for inflammation. Thus, TG turns on inflammation and part of inflammation is the activation of the innate immune system that includes production of TG.  This circular activation may produce autoinflammation that is associated with various forms of inflammatory bowel diseases.

Gluten Sensitivity is Normally Controlled By Gut Flora
Gluten sensitivity expressed by most people, is the intestinal response to the toxicity of gluten as it interacts with TG and causes inflammation.  This inflammation will also result in immune presentation of both gliadin and TG, and production of antibodies to both. Antibody production will normally be controlled by regulatory T cells of the immune system, unless spreading inflammation in the gut and/or antibiotics destabilizes the gut flora and compromises regulatory T cell development in the intestines.  

Anti-Glutaminase Antibodies Attack the Gut
Celiac results from uncontrolled production of antibodies to gliadin and TG with attack by the immune system on the aggregated gliadin/TG on the surface of the intestinal epithelium.  Celiac flare ups in response to eating even small quantities of gluten lead to further inflammation of the gut and further disruption and simplification of gut flora.

Celiac Leads to Thyroiditis and Much More
Transglutaminase is also produced by the thyroid and celiac will develop into a more generalized autoimmune disease that results in Hashimoto's thyroiditis.   TG production in the skin can result in skin rashes and may contribute to rosacea.  The base of hair follicles contains TG involved in hair production, and may contribute to some forms of hair loss.  Another substantial worry about the sequelae of celiac and gluten intolerance is the presence of TG in coronary arteries.

Antibiotics are Part of the Gluten Problem
Celiac and gluten sensitivity seem to be increasing with modern processing of grains and increased use of antibiotics.  Wheat has been gradually changed by traditional breeding, but genetic engineering has not yet been developed for wheat.  So, at least in this case, GM wheat cannot be part of the problem.  Many recent studies show that antibiotics profoundly and permanently alter gut flora.  As a result, the immune system, which is dependent on gut flora diversity is compromised, and various forms of autoimmunity and allergies develop.

Super Fine Flour Damages Gut Flora
Germ and bran are removed from all wheat before it is ground.  This is true even for whole grain flours, which have some of the germ and bran added back after milling.  Modern milling may be part of the gluten problem, because the flour is ground so fine that the grains of starch are broken.  Broken starch grains are digested by pancreatic amylases in the upper intestines, whereas some of the starch from intact grains is digested by gut flora in the colon.  Thus, modern wheat flour fails to feed gut flora like soluble fiber to produce short chain fatty acids, e.g. proprionic acid that supports Treg development; modern superfine flour supports autoimmune diseases and allergies.

Cultural Practices Make Gluten Safe
Wheat has been bred to produce bread as fast as possible from superfine flour.  This rapid bread production eliminates the exposure of gluten to enzymes from both germinating wheat seed and fermenting bacteria, which are part of traditional bread making.  Coarsely milled, traditional flour responds to soaking in water by activating enzymes that partially digest gluten, since gluten is a storage form of amino acids destined for the seedling.  Sour dough starter, a mixture of bacteria that can ferment the starch and gluten into short chain fatty acids and bubbles of carbon dioxide, has been used traditionally to provide leavening and flavor to bread.  Both flour and bacterial enzymes modify the structure of gluten to render it less toxic to the intestines.  Cultural traditions insured that gluten would be systematically detoxified by enzymes during hydration and fermentation of dough prior to baking.  Modern processing leaves wheat gluten in bread unmodified and toxic.

Prevention and Cure:  Eliminate or Detoxify Wheat and Add Bacteria
Preventing and curing diseases associated with gluten and transglutaminase is simple.  Eliminating wheat would do the trick.  Unfortunately, wheat is the mainstay in many parts of the world.  Fortunately, gluten intolerance is not uniformly observed where wheat is eaten.  This indicates that there are potentially safe ways to eat wheat and bread.  I gained insight into how to eat wheat safely from two books that were recently published:  Cooked by Michael Pollan and Artisan Bread in Five Minutes a Day by Jeff Hertzberg, MD and Zoë François.

Michael Pollan has recently become interested in gut flora and his book revealed how he built up a healthy gut flora eating homemade fermented food and compromised his work with antibiotics.  The major breakthrough that I made by reading Cooked was based on his experiments in baking whole wheat bread.  He hydrated the flour first and then used sour dough starter for lengthy fermentation.  This was the same process that I had used to make great loaves of bread (photo above) using Jeff Hertzberg’s directions in Artizan Bread in Five Minutes a Day.

The answer to gluten intolerance and most autoimmune diseases amounts to eliminating wheat or treating wheat in a safe, traditional process that inactivates the toxic properties of gluten; and maintaining a healthy gut flora (probiotics are not enough) with hundreds of different species of bacteria that promote the development of the suppressive immune system mediated by regulatory T cells:

Safe Traditional Bread 

  • Remove bran and discard as toxic insoluble fiber.
  • Grind wheat to retain starch grain structure.
  • Soak flour to hydrate and activate wheat enzymes to start digestion/detox of gluten.
  • Ferment dough with bacteria (sour dough starter) to continue digestion/detox of gluten.
  • Bake.

Develop Healthy Gut Flora and Suppressive Immune System

  • Avoid antibiotics that kill bacteria.
  • Avoid hygiene practices, e.g. antibacterial soaps, bleaching surfaces, closing toilet covers, etc. that eliminate sources of healthy bacteria.
  • Kiss your loved ones and pets, and encourage everyone to garden/play in the soil (an excellent source of thousands of different species of bacteria.)
  • Recruit healthy gut bacteria by eating a variety of homemade fermented vegetables. My most highly recommended source is my friends at:
  • Remember that cooked or pasteurized foods do not contain useful bacteria.
  • Remember that dairy probiotic bacteria cannot live in the human gut and can only provide a temporary help to the immune system.
  • Limit the variety of foods that are consumed and gradually change with the seasons to avoid rapid changes in nutrients to which gut flora cannot adapt.  Food intolerances indicate maladapted gut flora.
  • Constipation indicates dysfunctional gut flora and a compromised immune system.


Tucker Goodrich said...

Great post.

The only thing I think you're missing here is the difference in the gluten proteins in different members of the wheat family.

The most toxic varieties of gluten come from Tausch's goatgrass, which was crossed with einkorn (safe for some celiacs, the wheat from the Bible) to make triticum wheat, then again to make the modern dwarf wheat.

Goatgrass seeds are quite toxic to animals, and reliably give them pretty nasty intestinal distress. 75% of the seeds pass undigested through their victims' guts, making the evolutionary advantage of the protein clear: what a great way to spread your seeds: hijack a cow's gut.

"Mapping of gluten T-cell epitopes in the bread wheat ancestors: Implications for celiac disease"

As these more toxic proteins have become incorporated in the food supply, celiac incidence has risen.

Dwarf wheat was hybridized by Nobel-prize winner Norman Borlaug.

I have inquired on the ancestral consumption of goatgrass: apparently no-one eats it. The name is a message...

Dr. Art Ayers said...

Thanks for the thoughtful comments.

I understand your points, but I don't think that the goatgrass contribution is any more of a problem than T-cell epitopes. I don't think that it is a quantitative problem with higher copy numbers of goatwheat gliadin in dwarf wheat. I don't even think that the toxicity of goatwheat is due to its gliadin. It is simply a non-domesticated grain that has not been selected for palatability and hence has lots of other toxic plant chemicals.

I persist in thinking that the problem is damaged gut flora and a compromised immune system, which are the basis for most of our modern diseases.

T-cell epitopes are irrelevant, because they just represent the peptides presented and do not reflect why gliadin and transglutaminase are presented in the first place. It could be that the critical change in wheat is the presence of a new basic triplet and that would be interesting.

Marybeth said...

If you were to buy one book on making your own fermented food, what would it be? Thanks

Anonymous said...

Can you make safer bread with flour from the store? Like spelt or stoneground flour? Or would you have to buy wheatberries and some kind of contraption to grind it yourself?

Anonymous said...

So, from the above analysis, would you say that beer is a safe grain product to drink?

Dr. Art Ayers said...

The book that I recommend for home recipes for fermented vegetables is a new book by our friends on a family farm in Oregon:

Fermented Vegetables: From Arugula Kimchi to Zucchini Curry, a Complete Guide to Fermenting More Than 80 Herbs and Vegetables
By Kirsten Shockey, Christopher Shockey

(Available for preorder om Amazon)

Dr. Art Ayers said...

I think that even starting with commercial flour and following the instructions in Artisan Bread, which includes lengthy fermentation in the fridge, you can bake safer bread.

My current thought is that hydration and bacterial fermentation are more important than the grain. It may be hard to get past the super fine milling problems, if those are predominant.

Thanks for your questions.

Dr. Art Ayers said...

The mention of beer brewing is insightful. I think that celiacs have problems with some grain beers, because of their gluten content. So, the brewing process may not remove the antigenicity of the gluten. My suggestions on changing wheat processing may be only a little better, but most beer processes ferment using carefully controlled yeast cultures. Yeast and bacterial enzymes are very different and I expect their impact on gluten proteins is also different. Gluten proteins with different modifications will interact differently with immune cells and determine if antibodies against gluten will be produced and if gluten will bind to intestinal cells and trigger immune cell attacks.

Beer warrants more thought.

Matt said...

Great post.

I know you recommend a low starch diet when dealing with inflammation but what are your thoughts on resistant starch?

There's much talk on the web about the benefits of resistant starch. The benefits are touted as selectively feeding good bacteria with the production of SCFAs like butyrate. Would you recommend resistant starch to persons with an inflamed gut?

Another major source of constipation in the modern diet is a lack of iodine. Iodine will increase intestinal transit time via thyroid hormone. I apply two drops of Lugol's iodine to my skin daily. It's very easily absorbed.

Marybeth said...

And in the meantime? :)

Anonymous said...

Hi Art,
I am also interested in your thoughts on resistant starch, particularly unmodified potato starch which is apparently 80% resistant starch.

What is the effect of feeding the bugs that you have? Is there an altering of populations to benefit colon health or might I be feeding bad bugs?

I was experiencing chronic constipation and the Bob's Red Mill Unmodified Potato Starch (4 TB/ day, cold and taken with water) seems to have had a major benefit after a couple of weeks. Still need to see if I realize a lowering of blood sugar readings as others have reported.

The profanity guy at is all over it.


Dr. Art Ayers said...

Resistant starch
I don't think that resistant starch is magical. The only consideration is whether the starch is converted by pancreatic amylase into glucose in the small intestines and goes into the blood stream, or reaches the colon and is converted by gut flora into short chain fatty acids that feed the colon and gut flora as soluble fiber.

If some forms of starch are slipped into the gut without disturbing their coiled structure, they can make it to the colon. If they are melted into gravy first, they can be digested by amylase and spike blood sugar.

It seems easier to me to just eat other forms of soluble fiber, such as pectin in fruit or inulin in vegetables or meat polysaccharides, e.g. chondroitin sulfate.

With all forms of soluble fiber, it is of utmost importance for the gut flora to adapt. Gut flora rapidly create new species of bacteria by exchanging DNA/genes, but if the genes that code for the bacterial enzymes needed to digest a new polysaccharide are not there, the polysaccharide just acts as a laxative. Incompatible soluble fiber and gut flora are called food intolerances/allergies. New genes/new bacteria are needed and are not present in dairy probiotics (except in the case of lactose intolerance.). Antibiotics lead to food intolerances.

Dr. Art Ayers said...

I love your persistence, but remember that I am retired.:)
Try some of the recipes on my fermentista friend's web site:
Or start with the recipe in Michael Pollan's book or the sources he recommends, including Wild Fermentation by Sandor Katz.

Anonymous said...

On destructive methods and motives of "resarchers".

Thank you Art Ayers for your intellect and honesty. You have helped me and mine greatly.

AlmondD'oh said...

Very interesting and informative post. Thank you.

Jack C said...

Dr. Ayers,

You state the constipation indicates dysfunctional gut flora and a compromised immune system.

I eat a lot of raw milk aged cheese which will cause constipation unless I supplement with magnesium. The ratio of calcium to magnesium of cheese is about 26 to 1 compared to the "recommended" calcium magnesium balance of between 2 to 1 and 4 to 1. It seems to me that the constipation that results from my cheese consumption is the result of magnesium deficiency, not dysfunctional gut flora.

Anonymous said...

Agreed that resistant starch is not magical but you may still find it interesting.

Here is a link to a post where you can find lots of links to research articles and ample speculation.

Best regards

Matt said...

Hi Art

If you have some spare time read this post on resistant starch.

"In this study, they took human fecal matter and applied RS to it and watched what happened. The results were astounding--within minutes, it was colonized by butyrate producing microbes in ways they had never imagined. Certain species formed rosette like structures and biofilms around the RS granules."

Coach said...


I'm thirding the resistant starch point. I've been in gut distress since about 6 years old (I'm 43). Somewhere about 23-24yo I found the low-carb anabolic diet by Dr. DiPisquale. Later dropped the weekend cycles. Essentially, I have been eating your low-inflammation diet since, but have always had infrequent-frequent loose bowels / diarrhea. No pain, just unhappy bowels. Veggies never worked for me, I guess.

Enter RS - I had read about the benefits and decided to try. Very first day, nice bowel movement - and every day since (3 months in).

Also, I'm no longer dairy intolerant; sleep has improved exponentially; mood is much better; overall feeling of wellness - I feel so much better, physically and mentally.

This all from a few pennies per day of RS via potato starch (which has now increased in price).

Thoughts? Why couldn't I get this from veggies?

Thanks, Art.


Anonymous said...

Dr. Ayers,

First off, thank you for your advice. I have adopted your diet in the last few years, and
have seen great benefits.

I just found this blog about MSG being a cause of inflammation, etc.

Katherine Reid, Ph.D - in biochemistry.

Her daughter was sick....

Thank you again.

Dr. Art Ayers said...

Resistant Starch,
I think that it is great that people find the soluble fiber to fit their existing gut flora and the resulting health benefits are substantial. For some people resistant starch is a panacea. For people with different gut flora RS is ho hum.

The fact that RS is just common starch glucans with an odd coiling may mean that more people have gut flora bacteria that can digest it. Other soluble fiber polysaccharides, such as the sulfates forms in kelp, are more exotic and bacteria with the requisite digestive enzymes may be harder to encounter, unless a family member has them.

Lifelong vegans may not have gut flora that can digest meat soluble fiber, GAGs and the reverse would be true for strict carnivores.

We need to devote more time to deliberately introducing new bacteria into our guts.

If you are checking out a new health book and it doesn't have "gut flora" in the index, don't buy it.

Dr. Art Ayers said...

Anon on glutamate,
I am essentially ignorant of glutamate and autism. Thanks for bringing it to my attention.

Anonymous said...

If a person with strong digestion and no cavities kisses a person who has poor digestion and candida or some other bad bacteria plus a mouthful of cavities -- couldn't the healthy person be negatively impacted by the other person's bad bacteria?

Also, how can being sprayed by a toilet flush in a hospital where c-difficile and other baddies are rampant be a good thing??

Steve said...

Dr ayers, what type of flour are you using to make your bread?

Kay Dee said...

Artisan Bread in Five Minutes a Day" Instructions "are clear and highly functional but:
1 - they use Commercial Yeast and not Sourdough – Homemade Sourdough have a rich bacterial community, but Commercial Yeast?
2 - they ferment Dough in the Fridge – does low temperature inhibit fermentation?
Does really this method detox gluten?

Thanks for sharing your Science D. Ayers
Kay Dee

Dr. Art Ayers said...

on bad germs...
I have stopped believing in bad germs and pathogens and lean more toward sickness being a deficiency. The deficiency, however, is not usually a missing nutrient. As you might guess, I think that the predisposed, presick body is deficient in the right .......gut flora.

The fun aspect of these thoughts is that health is dominant. (Remember that I am a molecular biologist and that means that alleles that code for an active, functional enzyme are dominant in genetic terms.). That means that sickness is recessive, so intimate kissing between sick and we'll yields two well people. Lactose tolerance is contagious. Food tolerances are contagious, but gluten intolerance is a dominant exception, because it is not actually a food intolerance. (That would be like saying that "vitamin" D is a vitamin, when it is actually a steroid hormone.)

So... In most cases we get sick because we have compromised systems, because we have compromised gut flora, because we have compromised diets, because we have processed foods, because we have subsidized crops,
because we have politicians, because we want to make lots of money, because we are human.
We get sick because we are human. The germs didn't do it and there is no point in trying to make ourselves feel safer using antibiotics and antibacterial soaps.

Healthcare systems feed politicians, but home grown fermented veggies feed people. Viva la fermentista!

Healthcare is/in a crock.

Thanks for the questions and comments.

Dr. Art Ayers said...

Kay Dee,
Obviously, obviously, maybe.
The book is for the general public and like all recipes, they can be adjusted for personal use.

Chemical reactions are always temperature based and the rule of thumb is that every decrease in temp of ten degree decreases the reaction rate by half. Lowering the temp by 30 degrees should make the reaction about one eighth as fast. That means that fermentation will just keep poking along in the fridge.

Unfortunately, trying to stop the gluten intolerance and obesity epidemics isn't very easy, because there isn't an obvious way of making money on reversing processes that were designed to make money. No one is doing research on safe bread or repairing gut flora using reduced hygiene and fermented veggies. What are the dietary recommendations to reduce the impact of flu?

My hints on how to reduce the impact of gluten make sense, more sense than the bread industry, but neither system has been tested. All we know is the commercial bread industry has problems.

Thanks for your questions and comments.

kay Dee said...

D. Ayers your hints make tremendously sense - your vision is brilliant, is a "cosmic" vision, from micro to complexity…
In the last articles you pointed out the "antioxidants" question… I think your evaluation on antioxidants ("they are just plant defense chemicals") is changed: but the header of your blog yet suggests "plant antioxidants" - can you deeply explain this crucial point?

Always thanks
Kay Dee

Anonymous said...

Dr. Ayers, have been reading and learning from your posts for a some time now. Your insights have already helped me in many ways.

My question is about Sarcoidosis.

Specifically, do you have any suggestions or speculations beyond your normal AI diet and lifestyle that might be helpful (or potentially curative) for sarcoid in particular?

Thanks for your time and all the great posts.

Hale Sumner

Dr. Art Ayers said...

Sarcoidosis is an autoimmune disease and that means that the primary problem is not in the organs that provide the symptoms, but rather in the defect in your immune system. This is hopeful, because it means that you should be able to reverse the course of the disease by repairing your immune system.

There is a lot of recent research showing that Tregs are deficient in autoimmune diseases and since Tregs develop in the lining of the gut, that means that repairing the defect is just a matter of fixing the gut and gut flora. In most cases, this type of disease is preceded by an antibiotic treatment that permanently damaged the gut flora and immune system. I have written several posts on repairing gut flora with diet (soluble fiber) plus, plus, plus (emphasis on plus) new bacteria typically in the form of fermented veggies. It may be as simple as making and eating your own fermented veggies for a couple of months or perhaps getting a quick fix with a fecal transplant.

You would also be expected to be deficient in vit.D and are probably not taking enough fish oil.

Let me know what happens.

Debbie said...

Hi Dr. Ayers,

I've been reading through posts on your blog concerning constipation, autoimmunity, thyroid and healing the gut. I have a few questions.

Is there a significant difference between homemade fermented vegetables and traditionally made but store bought? I've been buying them: beets, carrots, sauerkraut.

I've also been supplementing with potato starch in a kefir drink (homemade kefir - just starting that) and Vitamin C a few times/day.

Constipation is MUCH improved - I'm almost worried, as I'm unused to anything approaching normal bowel movements.

Should I assume I'm on the mend and continue what I've been doing, or can I do more? I have low T3 and have had eczema, hair loss, obesity (normal weight now) - all these are connected, I realize.

About the playing in dirt: I live in a large city; people walk their dogs in our building's front garden. Is this dirt okay to stick my fingers in and possibly imbibe?

Thanks so much for this blog. I don't understand most of it, but I get the main ideas!

One more question, regarding supplementing with Vitamin D: do we know that raising blood levels corresponds with better health? Are there studies?

Thank you!

Debbie said...

I'm sorry, one more question: I've been gluten/grain free for a long time, but haven't considered "cross reactive" foods, such as coffee and chocolate, which I do eat. Do you have an opinion on that?


Debbie said...

I'm sorry, one more question: I've been gluten/grain free for a long time, but haven't considered "cross reactive" foods, such as coffee and chocolate, which I do eat. Do you have an opinion on that?