Celiac Disease Research Sheds Light on Future of Autoimmunity

Written by: Hailey Motooka, Bonnie Feldman, DDS, MBA, Ellen M. Martin

Celiac disease is an autoimmune disorder that causes damage to the small intestine when gluten is ingested. When a celiac patient eats gluten – a protein in wheat, rye, and barley – it triggers an imperfectly understood abnormal immune response that damages the villi of the small intestine, inhibiting nutrient absorption. Absorption is important because it’s the body’s way of converting digested food into useable energy. In addition to malnutrition, celiac disease can cause long-term ill effects like anemia, fatigue, and infertility. More consequences include neurological disorders, the development of other autoimmune conditions, and more. Learn more about the symptoms, diagnosis, and treatment here.

Beyond Celiac

Overall, about 3 million people in the US suffer from celiac disease, which is largely under- or misdiagnosed. For this reason, Alice Bast founded Beyond Celiac in 2003, a non-profit that unites with patients and partners to drive diagnosis, advance research and accelerate the discovery of new treatments and a cure. On October 10, 2018, Beyond Celiac hosted their second annual research symposium to discuss the very latest in celiac disease research.

The symposium hosted a highly esteemed group of panelists including:

• Ciaran Kelly, MD– Professor of Medicine at Harvard Medical School and Director of Gastroenterology Training at Beth Israel Deaconess Medical Center. In 2004 he founded the Celiac Center at BIDMC. He also founded the Celiac Research Program at Harvard Medical School in 2013. Dr. Kelly has engaged in patient care and research in celiac disease for more than 20 years.
• Maureen M. Leonard, MD, MMSc– Clinical Director of the Center for Celiac Research and Treatment at MassGeneral Hospital for Children (MGHfC) and an Instructor of Pediatrics at Harvard Medical School (HMS).
• Stephen D. Miller, PhD– Judy E. Gugenheim Research Professor of Microbiology-Immunology and Director of the Interdepartmental Immunobiology Center at Northwestern University Feinberg School of Medicine.

Panelists began by answering questions from moderator Marie Robert, MD, Chief Scientific Officer for Beyond Celiac and Professor of Pathology and Medicine at Yale University School of Medicine. They later addressed questions from members of the audience. Here’s a summary of what the experts had to say.

Robert kicked off the symposium right away by asking perhaps the most pressing question on everyone’s mind:

Is any real progress being made in clinical research trials for celiac disease?

The answer is yes. Ten years ago, research for celiac disease was mainly observational and epidemiological. Whereas now, there’s a significant amount of progress in interventional research. In fact, within the next few months an agent called Larazotide acetate will become the first drug for celiac disease to enter into the final phase III part of clinical trials.

Though there seems to be promising progress in developing a drug for celiac disease, a few challenges remain.

1. Money. Clinical researchers are finding it difficult to obtain funding for celiac disease research from the National Institutes of Health.
2. Finding patients to enroll in clinical research projects. This can be due to a variety of reasons such as inefficient patient recruiting, lack of interest in research participation, and an inability to meet study qualifications.

One of the main reasons as to why patients are hesitant to participate in clinical studies is due to the fact that many studies often require patients to take part in gluten tests.

Is a gluten challenge a necessary part of clinical phase ll celiac research?

Not all studies related to celiac disease require participants to consume gluten. Several studies that are further along in the drug pipeline do not use a gluten challenge whatsoever. The gluten challenge is most often used in early phase trials, providing a well controlled experiment in which researchers can measure the outcome of giving gluten to someone on the gluten-free diet.

The challenge is useful for initial proof of concept studies to determine whether a treatment is likely to work. However as research moves forward, researchers are more likely to include study participants who continue to have symptoms even on the gluten-free diet. This allows scientists to determine if a drug or treatment under study affects those symptoms. In some studies, researchers want to see if a particular agent is capable of tricking the immune system into not responding to gluten by inducing regulatory cells specific to gluten, quieting down the normal immune response (of patients with celiac disease).

Patients worry about gluten challenges due to physical, symptomatic reasons or due to the fact that many people have been told for years to avoid gluten by following a strict diet. To turn this rule on its head and purposefully consume gluten can be quite a culture shock.

How does the body’s immune response to gluten affect the brain?

Celiac disease is often associated with neurological problems such as headaches and seizures, as well as psychiatric disorders such as anxiety and depression. So far, researchers have developed three theories in an attempt to explain this correlation:

1. Opioid Excess — Gluten, when digested, breaks down into a particular peptide that resembles opioids that target and bind to receptors in the brain causing symptoms of celiac.
2. Intestinal Permeability– During inflammatory processes there is an increase in intestinal permeability and many inflammatory cells in the area are able to travel to other parts including the brain.
3. Microbiome — People with anxiety and depression may have a different microbiome than that of healthy individuals, suggesting that having a particular microbiome, or particular microbial members that produce metabolites are signalling to the brain causing symptoms.

How is the gut/intestinal microbiome involved in celiac disease?

The microbiome is the collection of organisms that live in or on our body — bacteria, virus, fungi, with each part of body containing a unique microbial community. It is known to contribute to the development of the immune system. It also helps us derive energy from food, produce vitamins, and protects us from pathogens. The microbiome is first established during gestation or the delivery process. It then develops over the first two years after birth in a chaotic scramble of bacteria trying to find their place within the microbial community.

Patients with celiac disease contain a microbiome with reduced microbial species diversity compared to the microbiomes’ of healthy control individuals. The question is, is this difference in microbiome composition due to celiac disease? Or does the change in microbiome contribute to the development of the disease?

For this reason, more substantial understanding of the microbiome during the development process may provide further insight into the optimal time to intervene with either food or environmental triggers, and steer an individual towards health. A curated collection of research on this topic can be found here.

What implications does celiac disease research have for other autoimmune diseases?

Most autoimmune diseases are multifactorial, meaning that they can be caused by numerous genetic, behavioral, and environmental factors. It’s often most difficult to determine the environmental factor for a certain autoimmune disease but for celiac disease, the most important environmental factor, gluten,  is known. A lot of steps in the pathogenesis (how disease begins) of celiac disease are very well understood, as opposed to a majority of autoimmune diseases where this remains uncertain.

That being said, there is still much to be learned about why certain individuals are initially prone to developing the disease itself. The continuous expansion of research and the ability to dissect the underlying mechanisms that lead to symptoms of autoimmune diseases allow researchers to continue to build upon the foundations of autoimmunity. Eventually, this understanding of autoimmune diseases will soon be applied to future treatments.

The replay of the full symposium as well as a summary of the proceedings are available at Beyond Celiac.