Prospective CRISPR research

[Lotte18]

Hi all, 

I'm just wondering if anyone knows whether Theresa Flores of Stanford University has been able to fund her research proposal to use CRISPR technology to directly alter our celiac genetic DNA coding?  I know there's been a lot published on using CRISPR to alter wheat so it's "less" aggravating.  But no one seems to indicate that wheat would then have to be grown in a vacuum.  My understanding is that wheat can self cross pollinate/contaminate if it's grown downwind from other strains of wheat.  Go ahead and correct me if I'm wrong.  

Anyway, what I'd really like to know is, what's up with research to directly alter celiac DNA coding?  Is Flores the only person out there proposing this?  Has the NIH funded a CRISPR study for us?  

Many thanks, Charlotte

[Aretaeus Cappadocia]

4 hours ago, Lotte18 said:

Hi all, 

I'm just wondering if anyone knows whether Theresa Flores of Stanford University has been able to fund her research proposal to use CRISPR technology to directly alter our celiac genetic DNA coding?  I know there's been a lot published on using CRISPR to alter wheat so it's "less" aggravating.  But no one seems to indicate that wheat would then have to be grown in a vacuum.  My understanding is that wheat can self cross pollinate/contaminate if it's grown downwind from other strains of wheat.  Go ahead and correct me if I'm wrong.  

Anyway, what I'd really like to know is, what's up with research to directly alter celiac DNA coding?  Is Flores the only person out there proposing this?  Has the NIH funded a CRISPR study for us?  

Many thanks, Charlotte

I saw your post and it made me curious so I did a little online research.

While I could not find "Theresa Flores" or any human celiac CRISPR studies, I found 2 articles that are perhaps relevant to your questions:

1. "T cell receptor precision editing of regulatory T cells for celiac disease" Mar 2025  (https://www.science.org/doi/10.1126/scitranslmed.adr8941).

"Cell Therapy for Celiac Disease. The cover image shows CD4+ T cells (green) engineered to express a gluten-specific T cell receptor (TCR) in the duodenal mucosa and Peyer’s Patch of a mouse that received an oral administration of gluten. B cells are shown in red, dendritic cells in white, and nuclei in blue. Currently, the only approach to manage celiac disease is a strict and costly gluten-free diet, highlighting the unmet need for therapeutics. Porret et al. opted for a cell therapy approach by engineering regulatory T cells (Tregs) to express a gluten-specific TCR. They found that these engineered Tregs could suppress conventional gluten-reactive CD4+ T cells in vitro and in vivo after exposure to gluten. These data suggest that engineered Tregs already in the clinic for other disease indications may offer a cell therapy for celiac disease."

In other words, in a mouse model of celiac, researchers were able to demonstrate creation of genetically modified cells that block a key step in the celiac pathway. This shows some promise for making it into human trials.

2. "CRISPR Clinical Trials: A 2025 Update" Jul 2025 (https://innovativegenomics.org/news/crispr-clinical-trials-2025/) This review did not mention any human CRISPR studies related to celiac disease. 

[Lotte18]

Hi Aretaeus,

Thanks for posting these articles.  The second of the two relates to my query.  Last week there was a podcast by the Washington Post with the director of the NIH and CDC.  Both institutions are now headed by one guy, Dr. Bhattacharya.  He claims that research funding for rare diseases has NOT been cut.  The question still remains, how do we get Celiac on their radar when of course we are competing for dollars with all kinds of other diseases?  Are people in our community interested in a CRISPR cure?  

It seems to me CRISPR works at odds with big pharma because it actually IS a cure.  You wouldn't have to take a drug to suppress T cell inflammation for the rest of your life.  CRISPR is supposed to permanently rewrite your DNA.  I assume we would really need the NIH to fund that research, not rely drug companies.  Dr. Dounda, the brilliant microbiologist, who won the Nobel for her research, making CRISPR possible, thinks that the hefty price will diminish as treatment migrates from bone marrow transplant to infusion therapy.  

Because Stanford University started studying celiac and CD8 cells a few years ago, I was curious to see if any progress had been reported.  What I found was a proposal to create a CRISPR platform for celiac by Theresa Flores.  I haven't found anything that states whether or not she got funding.  If anyone at Celiac.com has seen something, please let me know before I start composing a letter to Dr. Bhattacharya.  Not that one little voice in the wilderness is going to move the needle.  If others would also like to write to him, or help compose a joint letter, that would be great.  

[Scott Adams]

This is a great topic, so thank you @Lotte18 for bringing it up, and it is a Celiac.com article-worthy topic for sure.

CRISPR research related to celiac disease is still in very early stages, and most current work is focused on understanding the immune pathways involved rather than directly editing human DNA to prevent the disease. To date, there is no widely reported clinical research program funded by the NIH or other major agencies that aims to use CRISPR to alter the genes associated with celiac disease in people. One reason is that celiac disease is not caused by a single gene that could easily be edited—rather, it involves several genetic risk factors (especially HLA-DQ2 and HLA-DQ8) plus environmental triggers like gluten exposure. Because those genes also play important roles in the immune system, altering them could have unintended consequences. Most research right now is focused on therapies that block the immune reaction to gluten, improve gluten digestion, or prevent intestinal damage. As for wheat, you are correct that wheat can cross-pollinate under some conditions, but it is primarily self-pollinating, which is why researchers exploring gene-edited wheat are working on varieties that reduce immunogenic gluten proteins rather than eliminating cross-pollination entirely.

[Lotte18]

Hi Scott, Thanks so much for all this great info!  You mentioned the HLAs do more in the immune system.  I know little about that.  Is there research that explains what those other roles are?  

I hope Flores gets her funding because whatever the upshot, we'll at least have more information.

As to the wheat...when I first heard about it, I thought, "Oh great!"  But wouldn't it have to rely on newly built gluten free storage silos, gluten free transport trucks, etc.  And then there's still the potential for cross contamination once it gets to a restaurant kitchen.  Is it that much more advantageous than the wheat that has gluten extracted from it?  

 

[Scott Adams]

The HLA-DQ2 and HLA-DQ8 genes are part of the immune system’s antigen-presentation system—they help immune cells recognize and respond to foreign proteins like bacteria or viruses. In people with celiac disease, those same molecules happen to bind certain gluten fragments very effectively and present them to T-cells, which can trigger the autoimmune reaction in the small intestine. There’s quite a bit of immunology research on how these HLAs function generally, and much of the current celiac research focuses on interrupting that specific gluten-presentation pathway rather than altering the genes themselves.

Regarding the wheat issue, you’re right that supply chain separation would still matter. Even if gene-edited wheat produced fewer or less immunogenic gluten proteins, it would still need careful handling to avoid mixing with conventional wheat. The main advantage researchers are exploring is reducing the specific gluten peptides that trigger celiac immune reactions, which could potentially make wheat safer at the biological level. But even if such wheat proves helpful, it probably wouldn’t eliminate the need for gluten-free production controls or kitchen cross-contamination precautions.

[Lotte18]

Hi Scott, thanks so much for explaining this.  Sorry to keep pestering you--I have that mindset where every answer leads to another question, lol.  What I don't understand is, what is the difference between celiac HLAs and everyone else's?  I get that ours trigger a T-cell response.  But what is that special something that ours possess that makes them want to?  There must be some identifiable difference about the cell itself.  No?   Or maybe there is another force at work?  Another influencer leaning on the HLAs to misbehave?  Something that has yet to be identified?

[Aretaeus Cappadocia]

1 hour ago, Lotte18 said:

Hi Scott, thanks so much for explaining this.  Sorry to keep pestering you--I have that mindset where every answer leads to another question, lol.  What I don't understand is, what is the difference between celiac HLAs and everyone else's?  I get that ours trigger a T-cell response.  But what is that special something that ours possess that makes them want to?  There must be some identifiable difference about the cell itself.  No?   Or maybe there is another force at work?  Another influencer leaning on the HLAs to misbehave?  Something that has yet to be identified?

HLA molecules are like locks, waiting to be unlocked with their specific key. The "keys" are little molecular signatures that typically derive from infectious/parasitic agents, but sometimes there are cases of "friendly fire" where the system is set off by something benign or even useful to us. So, the HLA molecule collection is a line of defense in our immune system. Our genetic code makes a huge, but not unlimited, number of these locks. Each person has a slightly different set of locks that they got from their parents. When the HLA molecule meets the specific key (could be a piece of a virus or a piece of gliaden/gluten, for example), it tells the immune system that there is an invasion and it's time to go on the attack. About a third of us contain one of the 2 known HLA locks that recognize gluten. If you don't have one of those specific HLA molecules you almost certainly can't get celiac. However, if you have the celiac HLA molecule, you have about a 5-10% chance of developing celiac. Why does it happen to some of us but not others? That's complicated, but an important part of it is simply physical separation: the gluten is in your gut and the HLA molecule is in tissue, nearby the digestive tract, but separate. It the gluten is able to penetrate the barrier, lock and key meet, the immune system declares war, and celiac develops.

[Lotte18]

I'm really grateful that you're so good at explaining this stuff!  Does this research about "portals" that aren't really portals, apply to your locks and keys analogy? https://www.rockefeller.edu/news/39142-this-tiny-cellular-portal-could-open-vast-possibilities-for-medicine/

[Aretaeus Cappadocia]

On 3/14/2026 at 7:43 AM, Lotte18 said:

I'm really grateful that you're so good at explaining this stuff!  Does this research about "portals" that aren't really portals, apply to your locks and keys analogy? https://www.rockefeller.edu/news/39142-this-tiny-cellular-portal-could-open-vast-possibilities-for-medicine/

Not really. The "locks" sit on the outside of the cell while waiting to meet their key. This part of the process does not involve the nuclear pore complex.

[Lotte18]

Got it.  Thanks Aretaeus.  

[knitty kitty]

Human Leukocyte Antigen genes are coded for in our DNA.  They act like street signs on cells so the body knows that they are "Self".   Tissue typing in organ transplantation looks for donors with "Self" street signs similar to the recipient's in order to prevent rejection of the transplanted organ.  

The HLA DQ genes code for immune cells.  Some immune cells are encoded to recognize certain protein strings when that protein string attaches to the receptor on its cell membrane.  Originally, these protein strings were found in the cell walls of harmful viruses and bacteria.  

I like to think of these immune cells as patrolling police with orders to "be on the lookout for armed and dangerous suspects matching your cell membrane receptor description".  

However, segments of these dangerous protein strings are also found in the carbohydrate storage protein Gluten.  During digestion, Gluten segments bind with Tissue Transglutaminase, an enzyme that builds and repairs structural components of our "Self" cell membranes in our bodies.  

This Gluten-Transglutenaminase globule fits into the receptors on the patrolling police immune cells and sets off an alarm.  Mother immune cells begin producing antibodies (anti-tissue Transglutaminase antibodies ie, tTg antibodies) against the Transglutaminase-Gluten globule.  

Unfortunately, we have tissue Transglutaminase in the structure of all our cell membranes.  The antibodies attack healthy cells in our digestive tract, damaging them, causing them to signal to nearby cells "I'm sick, get away from me so you don't catch it!".  Spaces appear between cells.  The tight junction between cells is lost.  Gastrointestinal permeability is compromised.  This allows for other Transglutaminase-gluten globules to leave the intestinal tract, enter the blood stream, and travel to other organs and cause problems there. 

All the while, more police immune cells are alerted along the way with more mother cells producing more antibodies.  Sort of ends up looking like a "Smokey and the Bandit" movie in my mind, but with more than one "Bandit" driving around.  

So, people with a genetic predisposition (they have HLA DQ genes known to code for Celiac Disease) can go for years without developing Celiac Disease.  There needs to be a trigger that turns the genes on.  Triggers can be physical stressors like having an infection (like the flu or the common cold), or an injury, or an emotional stressor (like losing a loved one or abuse).  

There's some scientific proof that Thiamine insufficiency triggers autoimmune diseases.  During times of illness and emotional stress, the body requires additional Thiamine to provide the energy for the increased metabolic demand that comes with physical and emotional trauma or stresses.  Athletes have higher metabolic demands.   People who work outside in sunshine have higher metabolic demands, too.  This is because light (sunlight or indoor lighting) breaks thiamine down, denatures it, so that it cannot be used.  People who drink alcohol need more thiamine because alcohol will cleave thiamine in half making it useless.  People who eat a diet high in carbohydrates have a higher metabolic demand for thiamine and the other B vitamins needed to turn food into energy.  

Mitochondria are involved in producing energy, ATP, from Thiamine Vitamin B 1.  When there is a thiamine deficiency inside a cell, the mitochondria can no longer make energy ATP.  This is relayed to the DNA.  On the DNA, a switch is thrown to signal there's no thiamine, and another switch is turned on.  This is the switch that turns on the DQ autoimmune genes coded for in that DNA.  Whatever autoimmune genes are on your DNA start turning on. 

Thiamine Vitamin B 1 is needed to turn food into energy for the body along with the seven other B vitamins and minerals. Thiamine and magnesium make life sustaining enzymes.  Thiamine does stuff by itself, too, like regulate the immune response, and prevent mast cells from degranulating histamine. Thiamine influences which bacteria grow in our microbiome.  Thiamine deficiency allows Small Intestinal Bacterial Overgrowth (SIBO).  Immune responses and inflammatory cytokines are higher in thiamine deficiency.  

Thiamine cannot be stored long (18 days).  Thiamine insufficiency or deficiency can occur within three days if stores are depleted due to high metabolic demand and depleted stored thiamine.   

The majority of people with Diabetes have been shown to be deficient in Thiamine.  People with obesity who plan gastric bypass surgery have been found to have insufficient thiamine.  People Hashimoto's (autoimmune thyroid problems) have been found to improve with thiamine supplementation.  People with autoimmune arthritis have been shown to improve with thiamine supplementation.  People with MS have been shown to improve with thiamine supplementation.   

Blood tests are not reliable measures of thiamine level.  The brain controls the amount of thiamine in the blood stream.  The brain will order tissues and organs to release their stored thiamine into the blood stream in order to keep a constant supply going to the brain, heart, and lungs.  So, there can be organs with depleted thiamine stores, while blood levels stay constant.  This results in a localized deficiency within the organ or tissue.  

The best way to tell if there's a deficiency is to take thiamine hydrochloride for several weeks and look for health improvements.  Higher amounts of thiamine are needed to correct thiamine insufficiency or deficiency.  This helps replenish thiamine stores inside cells and tissues as well as meet increased metabolic demands.  

Processed foods containing wheat are required to have vitamins added to them to replace the ones lost with the removal of the germ and bran.  Food manufacturers use Thiamine Mononitrate, a cheap, shelf-stable form of thiamine that is not easily absorbed nor utilized by the body.  

A diet high in ultra processed foods, high in sugar and simple carbohydrates requires additional thiamine to turn the carbs into energy for the body.  Excess carbohydrates and low thiamine encourages SIBO.  For every 1000 kcal of carbohydrates the body needs an additional 500 mg of Thiamine.  The RDA is based on the minimum amount required to prevent disease.  This was set in the 1940's, when people ate very differently.  

Early symptoms of thiamine insufficiency include depression, anxiety, impulsivity, and changes in mood and cognitive function, digestive problems, nausea, abdominal pain, diarrhea, constipation, fatigue, muscle cramps, high blood pressure, tachycardia, blurry vision, insomnia or other sleep disturbances.  All so easily overlooked or attributed to daily stresses.  

 

Edited March 15 by knitty kitty
Typo correction

[Lotte18]

On 3/13/2026 at 12:25 PM, Aretaeus Cappadocia said:

About a third of us contain one of the 2 known HLA locks that recognize gluten. If you don't have one of those specific HLA molecules you almost certainly can't get celiac

All of this is discussed in Flores' research proposal.  Unfortunately, the document is too large for me to upload here.  

Thank you Knitty Kitty for the info on Thiamine.  I've always tested at "normal" levels for the B vits.  But as you say, blood testing may not be a reliable way to measure for it.  I will be more vigilant about maintaining it.

[Lotte18]

Here is a page from Flores' paper...

Researchers at Feng Zhang laboratory, created gRNA sequences that specifically alter the HLA-DQA1 gene in humans. The CRISPR gRNA is used to target a gene with the technique WT SPCas9 (single-guide RNA)- guided S. pyogenes). Another method used for transcribing the HLA-DQA1 gene in humans is the CRISPR/Cas9 Synergistic Activation Mediators (SAM) complex, CRISPR SAM specific (Feng Zhang Laboratory, 2023).

By using this CRISPR technology, we can bioengineer the variants at the gene locus to wild-type phenotype, and that could potentially result in alleviation of Celiac Disease. By correcting the variants at the specific loci (HLA- DQ2.5 or HLA-DQ8), we can minimize the resulting cascade of immunological effects.

Apheresis is a medical procedure that extracts specific blood components, such as plasma or platelets, by separating them from whole blood and returning the remaining components to circulation. It utilizes centrifugal force on anticoagulated blood and is an efficient method for collecting mononuclear cells (MNCs) required for chimeric antigen receptor (CAR)-T cell culture. CAR-T cell therapy has the potential to transform the treatment of hematologic malignancies (Fesnak, 2016). A similar therapeutic approach could be applied to autoimmune diseases by targeting autoreactive T cells that become abnormally activated and attack self-cells. By leveraging apheresis to isolate these dysregulated T cells, followed by engineered interventions, it may be possible to alleviate the autoimmune response and mitigate the disease, ultimately promoting systemic recovery.

[knitty kitty]

Mother cells that produce antibodies live for about two years.  If you can go those two years without getting the same mother cells triggered, the body may return to remission.  But nutritional deficiencies must be corrected as well.  

[Lotte18]

1 hour ago, knitty kitty said:

the body may return to remission.

I'm sorry, I only understand remission as it relates to cancer.  

Anyway, I'll do my best to keep my cells happy and untriggered.

 

[knitty kitty]

Google say:

"Remission is the reduction, abatement, or disappearance of the signs and symptoms of a disease, particularly cancer or chronic illnesses."

So, you have the right idea...

[Aretaeus Cappadocia]

2 hours ago, Lotte18 said:

Here is a page from Flores' paper...

Researchers at Feng Zhang laboratory, created gRNA sequences that specifically alter the HLA-DQA1 gene in humans. The CRISPR gRNA is used to target a gene with the technique WT SPCas9 (single-guide RNA)- guided S. pyogenes). Another method used for transcribing the HLA-DQA1 gene in humans is the CRISPR/Cas9 Synergistic Activation Mediators (SAM) complex, CRISPR SAM specific (Feng Zhang Laboratory, 2023).

By using this CRISPR technology, we can bioengineer the variants at the gene locus to wild-type phenotype, and that could potentially result in alleviation of Celiac Disease. By correcting the variants at the specific loci (HLA- DQ2.5 or HLA-DQ8), we can minimize the resulting cascade of immunological effects.

Apheresis is a medical procedure that extracts specific blood components, such as plasma or platelets, by separating them from whole blood and returning the remaining components to circulation. It utilizes centrifugal force on anticoagulated blood and is an efficient method for collecting mononuclear cells (MNCs) required for chimeric antigen receptor (CAR)-T cell culture. CAR-T cell therapy has the potential to transform the treatment of hematologic malignancies (Fesnak, 2016). A similar therapeutic approach could be applied to autoimmune diseases by targeting autoreactive T cells that become abnormally activated and attack self-cells. By leveraging apheresis to isolate these dysregulated T cells, followed by engineered interventions, it may be possible to alleviate the autoimmune response and mitigate the disease, ultimately promoting systemic recovery.

@Lotte18, thank you for providing this page from the research proposal. Some comments, if I may (apologies for what you already know):

They start by saying that previous research has shown that it's possible to modify the HLA-DQA1 gene and have that new version expressed "in humans" (not sure if they mean intact humans or just cells in culture). This is a standard form of scientific communication where you explain what is already known as it relates to what you want to do next.

The HLA-DQA1 gene encodes 1/2 of a series of "locks" from my earlier metaphor. Two of the types of locks that can be made by variants of this gene are called DQ2.5 and DQ8 (either of which will confer susceptibility to celiac). DQ2.5, DQ8, and other DQ's are referred to as "heterodimers" - "dimer" means made up of exactly 2 pieces and "hetero" means that the pieces are not identical to one another (identical parts would be homodimer). HLA-DQA1 genes each make a protein that becomes one of the two parts of a series of heterodimers. Different forms of HLA-DQA1 are called "variants" or "alleles". 

Next they say that they propose to use the same technology in attempt to minimize/cure celiac. The idea is reasonable science and before considering all of the caveats it certainly has merit as something to consider. As a side note, I would challenge some of their language. DQ2.5 and not-2.5 are both "variants" or "alleles" - one is not "wildtype" nor the other "mutant". Their proposal is to "modify", not "correct" the gene. This might sound picky but I have a background in genetics and this is jarring to me.

The last paragraph outlines more of the roadmap for their proposal using relatively mundane steps (apheresis) and relatively advanced steps (CAR-T). There is a logic to their approach but there are severe caveats. CAR-T is kind of a nuclear option. It has shown many miracle cures in certain kinds of cancer and it is being studied for some kinds of life-threatening autoimmune disease. It also has devastating side effects. If tomorrow someone offered me a fully validated CAR-T procedure for celiac along the lines of this proposal, based on my understanding of the risks I would turn them down. Separately, I would also have concerns about the "off target" risk of the CRISPR part of the procedure.

In addition to funding issues, there may be significant ethical issues that would challenge their proposal. Human clinical trial proposals go through extensive review before they are approved and one of the significant considerations is whether the risks to the patient are warranted (relative to the benefit). If a procedure has really horrible side effects but it is the only available option for a dying patient, the review board is likely to approve. However, if there is a much less harmful treatment option that delivers enough of a benefit, then there is a higher chance that the trial would not be approved. For celiacs, the availability and relative effectiveness of gluten-free diet will raise the bar for trying risky therapies in the clinic.

Science and medicine constantly progress, so it's entirely possible that someday there will be a safe and effective genetic "cure" for celiac. However not anytime soon and I believe it would only come after these CAR-T procedures have become routine in the treatment of a long list of other diseases.

In a world of unlimited funding for scientific research I would definitely fund this proposal. In the world of tight competition for research funding that we live in I would need to know a lot more about their proposal and the greater context of how it fits in with other research before I would give them money at this time (not that anyone is asking me).

[Lotte18]

Hi Aretaeus,  Thanks for your candor!  Sorry I didn't send the whole paper because she does discuss heterodimers and alleles, etc.  Her paper is online if you'd like to read it.  

I don't have a background in genetics, but I did watch my mother's celiac health struggle deteriorate into a deadly cancer.  Between then and my diagnosis 40 years later, the research on autoimmune disease just stagnated.  Heart attack, stroke, diabetes.  That's where the money was.  But you already know that.    

I'm sure plenty of people will take issue with me but, I don't buy this idea that if you just eat the gluten free diet, etc, all will be well.  There ARE people who eat gluten free and still die from this disease.  I can't forget watching an online conference with top celiac researchers from the UK who were urgently advocating for solutions because they had patients with refractive celiac who were dying.  Some people need treatment more urgently than others.  

I don't expect Flores to hit a home run her first time at bat.  I see this as a starting point.  As you know, it took many years for AIDS patients to get the complex cocktail of treatment that's available today.  It was messy and fraught with failure in the beginning.   And with the stigma that was attached to it, their funding battle was much more difficult than our funding competition.  I guess I feel much more optimistic about today's research capabilities than you do.  With AI modeling outside the body, we should be able to "see" mistakes and make corrections a great deal faster than we did in past years.  It seems China is willing to make a start.  I have no idea what their ethical gate posts are but I'm terribly interested in their work.  Who knows?  Maybe they'll get there first.  Maybe, even in my lifetime!

 

 

[Lotte18]

23 hours ago, knitty kitty said:

"Remission is the reduction, abatement, or disappearance of the signs and symptoms of a disease, particularly cancer or chronic illnesses."

 

I just wouldn't use the term remission.  Some people might think that after a gluten free, symptom free, 2 years, they get their pre-celiac life back and return to eating gluten.  Just a thought.

[Aretaeus Cappadocia]

Hi Lotte,

Just to clarify one point:  I understand that there is refractory celiac where gluten free diet does not abate the disease, and I'm sure there are also cases where someone thinks they are eating gluten free but there is something they missed. Gluten free diet is not a 100% guaranteed cure. However, gluten free diet is a very effective treatment for most celiacs. Our rules say a clinical research plan has to try to avoid giving an intrusive therapy to someone who would benefit from a non-intrusive therapy.

25 years ago I worked at a small company that was bringing a product through the clinic for an autoimmune disease. Back then it was an extremely difficult field to make progress in. Today, with more advanced technology, we have more hope, as you point out. I tend to be gloomy on the outside, but inside I hold out hope. What's more I try to manifest that hope by signing up for clinical trials when they will take me. My age precludes me from participating in some trials and the first one I signed up for they rejected me. I am evaluating 2 other trials now to see if I can /want to participate.

Fingers crossed for the future. My child will be dealing with their celiac long after I am gone.

[Scott Adams]

On 3/14/2026 at 4:56 PM, knitty kitty said:

Human Leukocyte Antigen genes are coded for in our DNA.  They act like street signs on cells so the body knows that they are "Self".   Tissue typing in organ transplantation looks for donors with "Self" street signs similar to the recipient's in order to prevent rejection of the transplanted organ.  

The HLA DQ genes code for immune cells.  Some immune cells are encoded to recognize certain protein strings when that protein string attaches to the receptor on its cell membrane.  Originally, these protein strings were found in the cell walls of harmful viruses and bacteria.  

I like to think of these immune cells as patrolling police with orders to "be on the lookout for armed and dangerous suspects matching your cell membrane receptor description".  

However, segments of these dangerous protein strings are also found in the carbohydrate storage protein Gluten.  During digestion, Gluten segments bind with Tissue Transglutaminase, an enzyme that builds and repairs structural components of our "Self" cell membranes in our bodies.  

This Gluten-Transglutenaminase globule fits into the receptors on the patrolling police immune cells and sets off an alarm.  Mother immune cells begin producing antibodies (anti-tissue Transglutaminase antibodies ie, tTg antibodies) against the Transglutaminase-Gluten globule.  

Unfortunately, we have tissue Transglutaminase in the structure of all our cell membranes.  The antibodies attack healthy cells in our digestive tract, damaging them, causing them to signal to nearby cells "I'm sick, get away from me so you don't catch it!".  Spaces appear between cells.  The tight junction between cells is lost.  Gastrointestinal permeability is compromised.  This allows for other Transglutaminase-gluten globules to leave the intestinal tract, enter the blood stream, and travel to other organs and cause problems there. 

All the while, more police immune cells are alerted along the way with more mother cells producing more antibodies.  Sort of ends up looking like a "Smokey and the Bandit" movie in my mind, but with more than one "Bandit" driving around.  

So, people with a genetic predisposition (they have HLA DQ genes known to code for Celiac Disease) can go for years without developing Celiac Disease.  There needs to be a trigger that turns the genes on.  Triggers can be physical stressors like having an infection (like the flu or the common cold), or an injury, or an emotional stressor (like losing a loved one or abuse).  

There's some scientific proof that Thiamine insufficiency triggers autoimmune diseases.  During times of illness and emotional stress, the body requires additional Thiamine to provide the energy for the increased metabolic demand that comes with physical and emotional trauma or stresses.  Athletes have higher metabolic demands.   People who work outside in sunshine have higher metabolic demands, too.  This is because light (sunlight or indoor lighting) breaks thiamine down, denatures it, so that it cannot be used.  People who drink alcohol need more thiamine because alcohol will cleave thiamine in half making it useless.  People who eat a diet high in carbohydrates have a higher metabolic demand for thiamine and the other B vitamins needed to turn food into energy.  

Mitochondria are involved in producing energy, ATP, from Thiamine Vitamin B 1.  When there is a thiamine deficiency inside a cell, the mitochondria can no longer make energy ATP.  This is relayed to the DNA.  On the DNA, a switch is thrown to signal there's no thiamine, and another switch is turned on.  This is the switch that turns on the DQ autoimmune genes coded for in that DNA.  Whatever autoimmune genes are on your DNA start turning on. 

Thiamine Vitamin B 1 is needed to turn food into energy for the body along with the seven other B vitamins and minerals. Thiamine and magnesium make life sustaining enzymes.  Thiamine does stuff by itself, too, like regulate the immune response, and prevent mast cells from degranulating histamine. Thiamine influences which bacteria grow in our microbiome.  Thiamine deficiency allows Small Intestinal Bacterial Overgrowth (SIBO).  Immune responses and inflammatory cytokines are higher in thiamine deficiency.  

Thiamine cannot be stored long (18 days).  Thiamine insufficiency or deficiency can occur within three days if stores are depleted due to high metabolic demand and depleted stored thiamine.   

The majority of people with Diabetes have been shown to be deficient in Thiamine.  People with obesity who plan gastric bypass surgery have been found to have insufficient thiamine.  People Hashimoto's (autoimmune thyroid problems) have been found to improve with thiamine supplementation.  People with autoimmune arthritis have been shown to improve with thiamine supplementation.  People with MS have been shown to improve with thiamine supplementation.   

Blood tests are not reliable measures of thiamine level.  The brain controls the amount of thiamine in the blood stream.  The brain will order tissues and organs to release their stored thiamine into the blood stream in order to keep a constant supply going to the brain, heart, and lungs.  So, there can be organs with depleted thiamine stores, while blood levels stay constant.  This results in a localized deficiency within the organ or tissue.  

The best way to tell if there's a deficiency is to take thiamine hydrochloride for several weeks and look for health improvements.  Higher amounts of thiamine are needed to correct thiamine insufficiency or deficiency.  This helps replenish thiamine stores inside cells and tissues as well as meet increased metabolic demands.  

Processed foods containing wheat are required to have vitamins added to them to replace the ones lost with the removal of the germ and bran.  Food manufacturers use Thiamine Mononitrate, a cheap, shelf-stable form of thiamine that is not easily absorbed nor utilized by the body.  

A diet high in ultra processed foods, high in sugar and simple carbohydrates requires additional thiamine to turn the carbs into energy for the body.  Excess carbohydrates and low thiamine encourages SIBO.  For every 1000 kcal of carbohydrates the body needs an additional 500 mg of Thiamine.  The RDA is based on the minimum amount required to prevent disease.  This was set in the 1940's, when people ate very differently.  

Early symptoms of thiamine insufficiency include depression, anxiety, impulsivity, and changes in mood and cognitive function, digestive problems, nausea, abdominal pain, diarrhea, constipation, fatigue, muscle cramps, high blood pressure, tachycardia, blurry vision, insomnia or other sleep disturbances.  All so easily overlooked or attributed to daily stresses.  

 

The description of HLA genes as helping the immune system distinguish “self” from foreign proteins is broadly correct, and in celiac disease the HLA-DQ2 or HLA-DQ8 molecules present gluten peptides to immune cells after tissue transglutaminase modifies them, which triggers the autoimmune response. However, several parts of the explanation are oversimplified or inaccurate. HLA-DQ genes do not “code for immune cells”; they code for antigen-presenting proteins on certain immune cells. Also, while infections or stress can sometimes precede the onset of celiac disease, there is currently no strong scientific evidence that thiamine deficiency activates HLA-DQ genes or triggers celiac disease or other autoimmune disorders. Thiamine is important for metabolism, but the idea that low thiamine “switches on” autoimmune genes or that high-dose thiamine can treat multiple autoimmune diseases is not supported by mainstream research.

5 minutes ago, Aretaeus Cappadocia said:

Hi Lotte,

Just to clarify one point:  I understand that there is refractory celiac where gluten free diet does not abate the disease, and I'm sure there are also cases where someone thinks they are eating gluten free but there is something they missed. Gluten free diet is not a 100% guaranteed cure. However, gluten free diet is a very effective treatment for most celiacs. Our rules say a clinical research plan has to try to avoid giving an intrusive therapy to someone who would benefit from a non-intrusive therapy.

25 years ago I worked at a small company that was bringing a product through the clinic for an autoimmune disease. Back then it was an extremely difficult field to make progress in. Today, with more advanced technology, we have more hope, as you point out. I tend to be gloomy on the outside, but inside I hold out hope. What's more I try to manifest that hope by signing up for clinical trials when they will take me. My age precludes me from participating in some trials and the first one I signed up for they rejected me. I am evaluating 2 other trials now to see if I can /want to participate.

Fingers crossed for the future. My child will be dealing with their celiac long after I am gone.

I agree with this--the most common issue with not recovering on a gluten-free diet is regular, low-level gluten exposure, usually from eating outside your home, or not fully understanding where hidden gluten can lurk in foods, medications, etc.

[Lotte18]

4 hours ago, Aretaeus Cappadocia said:

I am evaluating 2 other trials now to see if I can /want to participate.

That's great.  Now I'm curious as to which trials you're thinking about being in.  And I'm doubly hopeful your child will have a celiac free future!!  

[Aretaeus Cappadocia]

I volunteered for a total of 3 this year (that's all I found). All rejected me, but one only rejected me because I don't live near a study center for the trial, so maybe if they open new trial centers they'll contact me.

https://celiac.org/icureceliac/participate-in-research/

- AVALON is a Phase 1 clinical trial assessing VTP-1000. Phase I trial for a drug to reduce celiac disease symptoms from accidental gluten exposure by promoting tolerance to gluten

- Forte Biosciences Celiac Disease Study (FB102-301). Phase II trial for a drug to treat symptoms and intestinal damage when gluten is ingested

https://clinicaltrials.stanford.edu/trials/p/NCT04524221.html

- PTG-100 for Patients With Celiac Disease. Phase I trial for a dye to be used with diagnostic endoscopy without requiring a gluten challenge

As a side note to the moderators ( @Scott Adams ), "Clinical Trial Tracking" would be a good Forum topic for this site (maybe I'm just using the wrong search terms).

[knitty kitty]

Sorry if I Readers' Digest condensed and oversimplified the explanation again.  

Thiamine deficiency causes hypoxia.  Hypoxia-Inducible Factor 1α binds to thiamine transporter SLC19A3 and activates it to increase thiamine uptake.  HIF-1α signaling also triggers the release of inflammatory cytokines and inflammatory cells proliferation.  HIF-1a affects genes in the nucleus, entering through micro-pores.  Hypoxia and high levels of HIF-1a are found in many autoimmune diseases and cancer.

"HIF-1α shows its functions through translocating into the nucleus, dimerizing with HIF-1β and binding to hypoxia-responsive elements of the HIF-1α target genes. Recent data have also suggested that HIF-1α plays a role in maintaining intestinal epithelial barrier functions [37,38]. Accumulating evidence has also shown that HIF-1 α plays an essential role in cells via interaction with the NF-kB p65 pathway in the pathogenesis of inflammation [17]. In addition, previous research has further reported that HIF-1α expression is increased in the duodenal tissue of celiac disease patients [19,39]. It has been pointed out that activated HIF-1α is involved in celiac disease pathogenesis."

References are here: