Study authors have affiliations with ImmunogenX and Biomedal/Glutenostics

Gluten Free Watchdog has no affiliation with either Biomedal/Glutenostics or ImmunogenX.

The study, “Determination of gluten consumption in celiac disease patients on a gluten-free diet” was recently published in the American Journal of Clinical Nutrition. In the opinion of Gluten Free Watchdog this is one of the more significant studies published on celiac disease and the gluten-free diet in recent memory. It is the first study that attempts to analytically determine the actual amount of gluten consumed by a sub-group of individuals with celiac disease.

Article Summary

What researchers did: Researchers analyzed prior clinical data to determine how much gluten is accidentally consumed while on a gluten-free diet. They conducted a meta-analysis on data from studies involving measurements of gluten in stool and urine and trials for the investigational drug latiglutenase.

What researchers found: Mean daily consumption for adult participants on a gluten-free diet were determined to be 244 mg (stool analysis), 363 mg (urine analysis) and >228 mg (ALV003-1221 trial analysis). According to the study, “There is a general consistency in these analyses and the potentially higher value for the latter case may reflect that this trial enrolled a more symptomatic CD population.”

Keep in mind that in the US, it is recommended that folks with celiac disease consume no more than 10 mg of gluten per day. This is approximately equivalent to 17 one ounce servings of labeled gluten-free food containing just under 20 parts per million of gluten.

What researchers concluded: Many individuals following a gluten-free diet regularly consume sufficient gluten to trigger symptoms and perpetuate intestinal histologic damage.

Note from Francisco Leon (one of the study authors): Not all recurrent symptoms while on a GFD are due to gluten. Many cases are due to other co-morbidities (bacterial overgrowth, pancreatic enzyme deficiency… and even true refractory celiac disease) or dietary causes (low fiber intake, for example, see recent article https://www.ncbi.nlm.nih.gov/pubmed/29505551 – these patients are not the patients we studied, these have healed mucosa yet persistent symptoms).

Assessing gluten consumption is a first step in the evaluation of recurring symptoms by patients and clinicians. If there is clearly no gluten consumption yet symptoms persist, more invasive exploration is warranted to identify the cause of the symptoms.

The full study is available at https://academic.oup.com/ajcn/article/107/2/201/4911450

Bottom line :

If you have been diagnosed with celiac disease and continue to have persistent symptoms, it is the recommendation of Gluten Free Watchdog that you speak with your dietitian or physician about stool testing using Glutenostics Gluten Detective at-home stool test. Gluten Free Watchdog recommends using the stool test (versus the urine test) as it reportedly has a lower limit of detection of approximately 50 milligrams gluten as compared to the urine test with a lower limit of detection of 500 milligrams gluten. While these tests are available to consumers it is best to use them under medical supervision. Please see our previous post on the Gluten Detective stool and urine tests for more information https://www.glutenfreewatchdog.org/news/gluten-detective-consumer-test-kits-for-detecting-gluten-in-stool-and-urine/

Q&A with Study Authors

Gluten Free Watchdog reached out to Francisco Leon, one of the study authors and the co-founder of Glutenostics and Jack Syage, corresponding author and CEO and co-founder of ImmunogenX. What follows is a Q&A with Dr. Leon and Dr. Syage.

What is the main strength of the study?

FL: The medical community has known for a long time that patients with celiac disease are frequently exposed to gluten. In most studies, 30 to 50% of patients on a gluten-free diet have intestinal mucosal atrophy, and these patients heal completely if monitored closely. This proves they were getting contaminated. The article’s strength is that it quantifies the amount, and that is extremely valuable not just for patients but also for companies developing medications. Now we know how much gluten we need to counteract.

What is the main weakness of the study?

FL: The calculation is indirect. It’s a meta-analysis and relies on a mathematical model. Directly measuring gluten in food, stool and urine will give us more direct information. Such a study is currently underway.

JS: On the whole it should be realized, and I hope we make this clear in the paper, that there are many assumptions and approximations in determining consumed gluten so this can only be considered a semi-quantitative analysis at best. It is the best we can do with the available data. I think the model is sound and hopefully new data can be generated with this model in mind to refine the analysis.

In one of the studies used in the meta-analysis about 30 to 40 % of participants were classified as having moderate to severe symptoms (based on various criteria including frequency of diarrhea, constipation, etc.). Do you believe this percentage in generalizable to the entire population of folks with celiac disease?

FL: Yes, I believe the percent of 30-40 is extrapolable to the general population based on all of the studies available to us.

JS: In the Alvine/AbbVie ALV003-1221 trial about 2000 patients were screened and about 30-40% had moderate to severe symptoms as measured by a CD-specific symptom patient reported outcome questionnaire. These patients were further screened for histologic damage that reduced this number to about 25% of the screened patients entering into the trial.

Were the participants with high levels of gluten in their stool and urine considered non-compliant with the gluten-free diet?

FL: Yes, by definition, these patients are eating gluten (in small amounts), so they are not compliant, but they are not necessarily “cheaters”. It’s contamination for the most part.

JS: Keep in mind if an average non-gluten-free diet is say 15 g then 99% success at compliance is still 150 mg of gluten sneaking in, an amount considered unsafe.

Had the participants who were considered non-compliant received counseling services from a dietitian on the gluten-free diet?

FL: This is the worst part; most of these patients were followed at some of the best centers in the US and abroad, so it’s likely many of them had received counseling.

Do we know how much gluten is consumed by folks with celiac disease reporting mild symptoms?

FL: Celimmune looked at gluten in stool in celiac patients with no or mild symptoms in our NRCD-001 study, using a different definition. About 20 % of the patients in this study had mucosal atrophy, and of those we detected gluten in 20 % only – suggesting they were eating gluten only occasionally, but enough to trigger atrophy. We did not get a precise quantification, only positive/negative.

Members of the Gluten Free Watchdog community asked the following two questions due to interest in transparency.

Were patients advised during the study enrollment period that researchers had various relationships with the manufacturers of the drug and test kits prior to enrollment?

FL: Patients were of course informed of the sponsorship by Biomedal and Alvine of the respective original studies. The meta-analysis study is retrospective, and patients had consented to let researchers use their data in future celiac research by the sponsors and their collaborators. Then Immunogenx bought Alvine and Biomedal partnered with Glutenostics (companies which did not exist at the time of the original studies).

How might the interpretation of the data by study authors be influenced by relationships with these companies and the desire to illustrate the importance of monitoring stool and urine for gluten and the importance of developing drug treatment for celiac disease?

FL: Of course, there is bias in everything we do, but ImmunogenX (who drove the study) would in any case be interested in finding as low a contamination as possible (to claim their drug will be able to treat) so the bias -had it existed- may have been to minimize the amount of gluten – and yet we found a lot. Certainly Biomedal and Glutenostics are interested in showing there is contamination, but that’s well known already.

JS: In our minds there were two motivating factors behind this study: (i) how much gluten is being consumed on a gluten-free diet so we know how to design our real-world trials to provide doses that are sufficient to protect against these unintended exposures and (ii) in gluten challenge trials are the gluten intakes representative of real-world intrusions so that if these trials are successful one is confident it will have real therapeutic value. This is an interest of the FDA as well.

Thank you to Francisco Leon and Jack Syage!

Personal note from Tricia Thompson, Founder of Gluten Free Watchdog: Admittedly, this study has shaken me up a bit. If the gluten levels reported in this meta-analysis are reasonably accurate and can be corroborated by additional studies, this raises so many questions–in my mind at least. I need time to digest it all but some of the questions rattling around in my brain include:

How does this analysis change my opinion about drug therapy for celiac disease?

What does this analysis say about how folks with celiac disease are being counseled to follow the gluten-free diet? How can we do better?

What might this analysis mean about the foods folks with celiac disease are eating?

What might this analysis say about the levels of cross contact in naturally gluten-free foods, such as grains and legumes?

What might this analysis say about foods that are the trickiest to test for gluten? Are we not detecting gluten when it is present?

What might this analysis say about gluten levels in food—might levels be higher than gluten test results indicate?

What can we do to make eating outside of the home less likely to result in cross contact with gluten?

We will continue to watch for future studies. In the meantime, please adhere to the gluten-free diet to the best of your ability.