House CallDec/Jan 2014 Issue

Allergies Q & A - Celiac Disease, Microbiome, & More

Leading celiac expert Dr. Stefano Guandalini discusses the latest news about celiac disease and gluten

Photo courtesy of University of Chicago Celiac Disease Center

Photo courtesy of University of Chicago Celiac Disease Center

In September, the world’s leading celiac investigators presented new research into the causes and treatment of celiac disease at the 15th International Celiac Disease Symposium in Chicago. Much of the conversation centered around how the microorganisms and bacteria in our intestinal tracts (called the microbiome) shape our immune systems, possibly influencing the development of celiac disease. Almost every organ in the body is affected by the presence of bacteria in the gut, presenters said.

Researchers also discussed new diagnostic tests, new information about the genes responsible for celiac, whether intestinal biopsy is necessary for celiac diagnosis and changes in the clinical spectrum of celiac symptoms.

There was continued talk about non-celiac gluten sensitivity, calling the condition into question. It’s possible that those with non-celiac gluten sensitivity who remove gluten from their diet are responding to the removal of FODMAPs*—foods containing short-chain carbohydrates that include gluten, lactose and fructose—or sensitivity to amylase trypsin inhibitors (ATIs), a protein in wheat that naturally protects the plant against pests and may trigger innate immunity in some people who ingest it.

Researchers are studying how to prevent celiac disease. A panel of experts discussed new treatments on the horizon, medications designed to be adjuncts to the gluten-free diet.

As the symposium ended, Living Without sat down with co-chair Dr. Stefano Guandalini, founder and medical director of The University of Chicago Celiac Disease Center.

Living Without Congratulations on the symposium. There are so many new studies and new approaches for understanding and treating celiac disease.

Dr. Guandalini It is an exciting time for celiac disease and gluten-related disorders. We have new information on predisposing factors for the disease. We have new information in terms of prevalence. We are on the verge of having new information on possible ways of preventing celiac disease, and we certainly will have new information on alternative treatments. Right now, the only treatment available is the adherence to a gluten-free diet for life. Chances are in the near future, there will be more options available.

There’s a lot of discussion about the microbiome. What is the role of the microbiome and intestinal bacteria in the development of celiac disease?

This is an evolving field, like everything in science, so the state-of-art research that we’re discussing today might be different six months from now. Our bodies are a combination of cells and genes from the human species and from the much larger population of bacteria that we harbor. These bacteria interact with our immune system and are actually influencing the way the immune system develops.

If you are lucky enough to be born by a normal vaginal delivery and you inherit most of your microbiome at birth from your mother, then that puts you already in a good starting position. If you are breast-fed, that contributes to the healthy development of your microbiome. The good bacteria that you harbor interact with the immune system in the gut and make it an ideal environment to tolerate the foreign antigens from food. We have a very finely tuned immune system in the gut that discerns these foreign proteins and is able to not mount an allergic or immune response. Most of this modulation comes from the microbiota that establishes itself during the first few months of life.

We are beginning to see the possibility of using specific live bacteria to restore a population of beneficial microbes. I’m talking about probiotics. We are not there yet—but some preliminary data are beginning to emerge that might be promising. Once we understand the very dynamic and complex world of the microbiome and its interaction with the human immune system, then we might be better positioned to say which probiotics, which strains, which dosage and under which circumstances we should use them in genetically predisposed individuals to thwart the development of celiac disease.

The genes HLA-DQ2 and HLA-DQ8 are responsible for celiac disease. Researchers are also finding more genes that might be associated with the condition. How does this affect diagnosis and treatment?

Genetic predisposition remains the largest contributor to the risk of getting celiac disease. We have heard data at this symposium, which are actually quite surprising—even for those of us who have been working in this field for many years. For instance, in a multi-center European study on infant feeding practices and the development of celiac disease, the preliminary data show that if you are homozygous for DQ2 (if you have two copies of the HLA-DQ2 gene, inherited both from your mother and your father) and especially if you are female, 14 percent of you will develop celiac by the age of 3. And presumably, a much larger percentage will develop celiac in subsequent years. So you can see the genetics of this condition exert a major, major role.

At least 40 other genes have been identified to play a role, although a minor role, in the genetic predisposition to celiac disease. Once we have a full genetic mapping of all the genes that lead to the predisposition of celiac disease, we can determine the individuals (like those with a double dose of HLA-DQ2) who would benefit from an active intervention in terms of preventing celiac disease with probiotics or proper infant feeding practices.

Is there any information that’s out now on treatment of celiac disease with probiotics?

There is a lot that is known on possible choice of proper probiotics for a number of gastrointestinal conditions. When it comes to celiac disease, the research is still in its infancy. So we only have preliminary data, not enough to speculate on treatment with probiotics. One study presented at this conference looked at bifidobacteria. But I want to say clearly at this point in time this is too premature. Even when we say bifidobacteria, we allude to such a number of different strains within the genus bifidobacterium that it’s hard to pinpoint exactly the one or the combination of strains that would be most effective.

Researchers said that amylase-trypsin inhibitors (ATIs), a natural pest-resistant protein in wheat, can trigger innate immune responses. Do ATIs play a role in non-celiac gluten sensitivity?

This is mostly the result of the work of Dr. Detlef Schuppan from Germany, who is also a professor of medicine at Harvard Medical School. They have identified this protein in wheat as responsible for some inflammation in animal species and in biopsies of celiac patients. This seems to be a protein theoretically responsible for some of the side effects that people who eat gluten but don’t have celiac disease say they experience. So the trigger might not be gluten at all.

What does the latest research say about non-celiac gluten sensitivity?

The definition of non-celiac gluten sensitivity has actually been brought into question during this meeting by a very rigorous investigation conducted by an Australian group. We had Dr. Evan Newnham here presenting data showing—quite convincingly, I must say—that many of the individuals that researchers had shown to be gluten sensitive, not celiac, responded not so much to the elimination of gluten but to the elimination of a number of carbohydrates that go collectively under the name of FODMAP. The acronym stands for fermentable, oligo-, di-, mono-saccharides and polyols. Basically it’s a number of difficult-to-digest sugars that are present in wheat, garlic, onions, some fruit, milk and so forth, whose presence may be responsible for most of the irritable bowel syndrome-like symptoms that these patients have. Hence eliminating these foods is actually the reason they feel better. It is not gluten at all.

So are we saying that non-celiac gluten sensitivity, whose existence we have finally accepted for the last couple of years, does not exist anymore? I don’t know. It’s a moving target. If you examine the bulk of data in the literature on this issue, which is growing almost every day, it’s fair to say that some individuals who do not have celiac might truly benefit from the elimination of gluten. But perhaps a good portion of those who report improvement are individuals who would benefit from the elimination of FODMAPs* or perhaps from the elimination of ATIs—and really not gluten. Certainly in terms of irritable bowel syndrome, I would say a good portion of patients would benefit from the elimination of FODMAPs alone. This is quite well proven at this point in time.

There’s been discussion here about the changing presentation of celiac disease. Have you seen this change?

Oh yes. We have documented in our Celiac Disease Center and in collaboration with other centers in Europe that, in the span of the last 30 years or so, there has been an ongoing shift in age of presenting symptoms and in the kinds of symptoms in those who are symptomatic.

The age of presentation is shifting upward. It used to be a disease of the toddler. The type of symptoms seems also to be changing. In the past, we mostly saw gastrointestinal presentations—that was the paradigm of the definition of celiac disease. Due to a combination of a better understanding of celiac disease—as not just a disease limited to the gut but expanding to the rest of the body—and due possibly also to objective changes in the way people with celiac disease are reacting to gluten, the gastrointestinal presentations are declining and the non-intestinal manifestations are increasing. I’m talking about anemia, osteoporosis, short stature, dental enamel defects, liver issues, arthritis and infertility. All of these non-intestinal manifestations are definitely on the rise.

Due to the wide application of screening techniques that now are available, mostly the tTG blood test, when we started checking for celiac disease in individuals who were healthy but belonged to groups at risk, we learned that the majority of celiac patients are asymptomatic or at least almost asymptomatic. They don’t have symptoms severe enough to make them go to the doctor and seek a physician’s help; they might think it is normal to have minor problems. But some of them are completely asymptomatic. Together they constitute the majority—the submerged part of the celiac iceberg.

What is the future of treating celiac disease? Will we see a pill? A vaccine?

There are several different approaches, as adjuncts to the gluten-free diet. They could actually be complementary to each other. I see that, at some point, you might want to use them at the same time. Why not think of using a pill that would detoxify gluten in the stomach before it reaches the small intestine, along with a pill that would increase the tightness of your intestine in order to prevent any possible remaining traces of gluten from entering?

There is an enzyme, AN-PEP, that will be marketed in the next couple of months, based on findings by Dr. Frits Koning from The Netherlands. It will be sold as a food supplement, thereby not needing to go though the FDA radar. The product seems to have reliable evidence in a number of in vitro and in vivo studies to be effective in detoxifying gluten before it hits the gut, to an extent at least.

The other pills, ALV003 and Larazotide Acetate, which will have a drug status, will have to go through more rigorous trials before being marketed. But I am confident. I know how serious the research behind them is and how efficacious these products will be. So I’m confident these will come to fruition, as well.

And then there is this very ambitious goal of a vaccine, Nexvax2, that Dr. Bob Anderson reported on. We are collaborating with him in several phases of the experimentation. This will be a way of desensitizing somebody who already has celiac disease, much like what you do with environmental allergies, to bring the immune system to actually tolerate gluten, restoring the tolerance that was lost in the first place when somebody converted from tolerance to celiac.

This is a very ambitious goal. I know that Bob Anderson is very optimistic that it will come to fruition very soon, meaning two to three years. It might take longer. But I think the day is not too far off that we will see the possibility of curing celiac disease. It’s our most ambitious, ultimate goal.

Dr. Stefano Guandalini is founder and medical director of The University of Chicago Celiac Disease Program. He serves as professor of pediatrics at The University of Chicago and is chief of Pediatric Gastroenterology, Hepatology and Nutrition at The University of Chicago’s Children’s Hospital. He was co-chair of the 15th International Celiac Disease Symposium.

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