Looking Beyond the Gluten-Free Diet
From the promise of improving digestion to raising energy levels, the last few years saw a tremendous increase in popularity for gluten-free products. In the wake of the gluten-free trend, there has been tremendous research interest in disease associated with gluten intolerance like celiac disease (CD). For the 1% of the population in the world who are impacted by CD, going gluten-free is not a lifestyle choice, but a necessity to avoid permanent gastrointestinal (GI) damage.1 In these patients, a component of the gluten peptide, gliadin, induces an immune reaction, which results in inflammation of the walls of the small intestines and symptoms of abdominal pain, anemia, and weight loss from malnutrition.2 If CD is not treated early with a strictly gluten-free diet, the patient can experience permanent and irreversible GI damage, which is known as refractory celiac disease (RCD). RCD is a rare disorder that severely reduces the quality of life for patients and tends to develop into lymphoma.3 The recent media attention on gluten intolerance and CD has increased the number of early diagnoses to prevent the onset of RCD, and it has encouraged scientific investigations into alternative treatments for RCD other than adhering to a gluten-free diet. Based on recent advances in genetic testing and understanding symbiotic relationships of microbiota, there are exciting developments in genetic and probiotic therapies for RCD.
Although the cause and symptoms of celiac disease can vary from patient to patient, in most cases, the disease is caused by the inability to break down gluten peptide properly. This results in the production of a smaller protein known as gliadin, which enters the cells of the small intestine and induces inflammation that eventually causes the death of these cells.4 This cell death creates gaps that allow even more gliadin into the walls of the small intestines to cause extensive damage to intestinal cells, resulting in some of the characteristic GI damage seen in celiac patients: villous atrophy, crypt hyperplasia, and mucosal remodeling.5
About 1-2% of CD patients develop RCD, a severe form of CD that is not responsive to a gluten-free diet.3 This puts the individual at high risk of intestinal lymphoma, which is a cancer affecting the immune system. RCD is almost always seen in in patients over the age of 50 who have not been treated for CD at an earlier stage.3 This is why one mother of a teenage son, Henry, who eluded diagnosis for 19 years is advocating for celiac blood tests as a best practice to help those with CD begin treatment early. She stresses that “only 1 in 6 patients with CD is diagnosed,” which puts CD positive individuals who are not diagnosed at risk of developing permanent intestinal damage.6 Specifically, the mother stresses the importance of self-treating presumed cases of CD with a gluten-free diet and getting tested to see if one is affected by comorbid diagnoses. People with CD are at risk of developing thyroid disease, stomach cancer, osteoporosis, and lymphoma, which makes it critical to be screened for CD in order to begin prevention or treatments for these comorbid conditions.6 In addition, there are a number of complications associated with CD and RCD such as enteropathy-associated T-cell lymphoma, which is an aggressive form of lymphoma caused by the overexposure of intestinal cells to factors causing inflammation in the region.3 Another common complication is severe malnutrition due to insufficient release of enzymes to break down food in the intestines, coupled with blocked iron receptors that prevent iron from food to be absorbed into the body resulting in anemia.5 For these reasons, an early diagnosis of CD is paramount to stop the potential progression of the condition into RCD.
Upon diagnosis, the best practice is to prescribe a gluten-free diet in combination with corticosteroids, which are used for their immunosuppression effects for patients with RCD.7 However, these drugs carry a number of adverse effects including elevated blood pressure, weight gain, and cataracts, making it unsuitable for sustained use.8 These problems have created a need for novel treatments that takes advantage of advances in genetic testing and modification and microbiota balance to allow for better RCD management. Current genetic research for RCD treatments focuses on two main pathways: inflammatory pathway and the prevention of gluten into gliadin. Treatments involved with the first pathway attempt to eliminate inflammatory factors that cause intestinal cell death and atrophy of the villi. Pertaining to the second pathway, treatments aim to prevent the degradation of gluten into gliadin, which is the component that induces the immune response in RCD. Scientists have identified IL-15 as a cytokine that induces inflammation and is developing an anti-IL-15 antibody that reduces the levels of IL-15.9 By extension, this would reduce inflammation and intestinal cell death. With a complete intestinal epithelium, the body can better prevent gliadin peptides from entering into the intestinal cell wall and inducing a further immune response. There is also ongoing research into IL-10, which is an anti-inflammatory factor that has been shown to be effective in mouse models for the treatment of other inflammation-associated GI diseases such as Crohn’s.10 Together these two therapies are designed to enhance natural anti-inflammatory pathways in the body to reduce intestinal epithelial damage associated with RCD.
There is additional research looking at how to alter the balance of microorganisms in the gut as a way to promote a better environment for the healing of damaged intestinal cells. This builds on our growing awareness that microorganisms service beneficial functions or have deleterious effects depending on their location within the body. A recent study shows an association between damage of enterocytes (intestinal cells) and a change in the composition of the microbiota within the GI tract. Specifically, researchers noticed a tendency for Gram-negative bacteria to flourish, which are often associated with infections leading to epithelial deterioration at this location.5 In addition to having Proteobacteria, a Gram-negative bacteria, as a dominant strain in the gut of children with CD, the study found that these children had lower levels of beneficial bacteria like Lactobacilli and Bifidobacteria compared to their healthy counterparts.5 Lactobacilli is known to protect intestinal epithelial cells against cellular damage from gliadin and Bifidobacteria is known to be able to induce lower levels of inflammatory factors and cytokines.5 In response to these results, researchers recommend the administration of probiotics to restore the intestinal microbiota by populating it with more Gram-positive bacteria than Gram-negative.5 This restoration of intestinal flora can benefit the host through (1) producing inhibitory substances against pathogens, (2) competing for nutrients, (3) degrading toxin receptors, (4) helping to regulate immunity, and (5) helping to digest or alter gluten peptides such that they will no longer be toxic to the host.5 While the extent of the effects of probiotics has not been fully elucidated, they do show promise for reducing the intestinal damage seen in CD and RCD.
Collectively, these genetic and probiotic treatments are designed to reduce inflammation of the intestinal epithelium and to alter the properties of the gluten to prevent the production of the toxic gliadin peptide. These treatments are part of the first steps to help improve the quality of life for patients with CD and RCD to ensure that they have alternative treatments in addition to the conventional gluten-free diet. In future years, it is anticipated that growing awareness of CD as a result of the gluten-free trend will continue to draw interest in this field. Additionally, the growing awareness of CD will also encourage people who suspect they have gluten sensitivity to get tested for CD early to prevent the progression of the disease and its comorbid conditions.
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Cite This Article:
Zhang B., Chan G., Zheng K., Ho J. Looking Beyond the Gluten-Free Diet. Illustrated by C. Suart. Rare Disease Review. March 2017. DOI:10.13140/RG.2.2.31210.82883.