Oxidative Stress in Children with Celiac Disease

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Celiac disease is a genetic digestive disorder triggered by consumption of the protein gluten, which is found in bread, pasta, cookies, pizza crust and many other foods containing wheat, barley or rye. Researchers now report that there is a factor independent of diet that contributes to oxidative stress in celiac disease patients; children with celiac disease have higher than normal levels of two oxidative DNA damage biomarkers, regardless of what they eat [1].

Celiac disease is an autoimmune disease in which the consumption of gluten — a protein found in all forms of wheat, including spelt, kamut, semolina and triticale, as well as in barley and rye — induces an inflammatory reaction that destroys the gut. It occurs in almost 1% of the population, although in the United States as many as 97% of cases remain undiagnosed. Most autoimmune diseases are thought to be caused by an interaction between a genetic predisposition and an environmental trigger, but celiac disease is the only one for which the environmental trigger is known: gluten.

Normal intestine vs celiac disease

The inner surface of our small intestine is folded up and down into fingerlike projections, called villi or villus, to increase the surface area available for absorbing nutrients. In people with celiac disease, the presence of gluten causes inflammation that flattens these villi so that nutrients cannot be absorbed. This explains the highly varied clinical symptoms that can be suffered by patients with celiac: anemia because of the lack of iron, brittle bones because of the lack of calcium, gastrointestinal distress and failure to thrive. Fortunately, complete elimination of gluten from the diet, while quite onerous, can halt the inflammation and reverse any damage it has caused.

Increased production of the proinflammatory cytokines interferon gamma (IFNG) and Tumor Necrosis Factor alpha (TNF) have been observed in patients with active celiac disease. These cytokines can produce a large amount of reactive oxygen species, which oxidatively damage DNA. Oxidatively damaged DNA may be used as a marker for predicting later cancer development. Two recent studies have shown an increased risk of cancer for patients with celiac disease, especially for B- and T-cell lymphoma, a type of cancer involving lymphocytes (cells of the immune system) [2-3]. In the present study, scientists aimed to quantify the level of oxidatively damaged DNA in children with celiac disease [1]. None of the children had histories of cancer or any chronic inflammatory disease.

Oxidative DNA damage in children with celiac disease

To determine if celiac disease enhances oxidative DNA damage — and, by extension, if this is the means by which celiac increases cancer risk — researchers looked at three groups of children. One consisted of children with celiac disease, confirmed by villous atrophy observed after an endoscopy and who continued to eat gluten; another of children also with histologically confirmed celiac disease who had maintained a gluten-free diet for an average of 10 years; and a group of healthy controls. The scientists measured the level of oxidatively damaged DNA in leukocytes as well as the level of the antioxidants vitamin A, vitamin C and vitamin E, and uric acid in the blood. Antioxidant vitamins and uric acid are free radical scavengers that can decrease oxidative stress. Researchers also measured the levels of 8-oxodG (7,8-dihydro-8-oxo-2′-deoxyguanosine) and 8-oxoGua (7,8-dihydro-8-oxoguanine) excreted in the urine. These are the most widely studied biomarkers (i.e. a molecular signature) of oxidative DNA damage and, as they are found in urine rather than blood, they are easier to attain from children.

Scientists found that all of the markers for oxidative DNA damage were higher in celiac patients than in controls. Only the level of urinary 8-oxoGua was reduced by a gluten-free diet; the level of 8-oxodG, both in blood and in urine, was higher in celiac patients regardless of diet. Likewise, antioxidant parameters were lower in celiac patients than in healthy controls. Vitamins A and E were higher in those children who conformed to the gluten-free diet but vitamin C and uric acid were reduced equally in all celiacs, regardless of what they ate.

The level of 8-oxodG in DNA is one of the most important parameters we have for assessing oxidative damage. It is a mutated form of guanine, one of the molecules that comprises DNA, that is generated by oxidative stress. Thus, its concentration reflects the amount of oxidative DNA damage a given cell has undergone but can also reveal insights into how well the cell can repair its damaged DNA. Since patients with celiac disease had increased levels of 8-oxodG in both blood and urine, the data suggests that the DNA damage repair pathway may be compromised. A study of people with celiac disease who developed adenocarcinoma found that this was indeed the case, and the DNA repair mechanism may play a role in the prevention of the mutagenic effect of 8-oxodG [2].

The (relatively) good news out of all this for patients with celiac disease is the level of vitamin A, the strongest of the antioxidant vitamins, while reduced in children who ate gluten, was statistically the same in those celiacs adhering to their gluten-free diet as it was in healthy controls. This result suggest that consumption of a gluten-free diet helps to mitigate oxidative DNA damage in celiac patients. The authors note that in addition to strictly adhering to their gluten free diet, people with celiac disease should consider vitamin A and E supplements to reduce their cancer risk.

For more information on celiac disease, visit the Celiac Disease Center at the University of Chicago and the MedlinePlus page on Celiac Disease.

References

1. Szaflarska-Poplawska et al. Oxidatively damaged DNA/oxidative stress in children with celiac disease. Cancer Epidemiol Biomarkers Prev. 2010 Aug;19(8):1960-5.
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2. Freeman HJ. Malignancy in adult celiac disease. World J Gastroenterol. 2009 Apr 7;15(13):1581-3.
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3. Gao et al. Increased risk for non-Hodgkin lymphoma in individuals with celiac disease and a potential familial association. Gastroenterology. 2009 Jan;136(1):91-8. Epub 2008 Sep 25.
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4. Boiteux et al. Repair of 8-oxoguanine in Saccharomyces cerevisiae: interplay of DNA repair and replication mechanisms. Free Radic Biol Med. 2002 Jun 15;32(12):1244-53.
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