In celiac disease, a gluten-free diet does not fully restore the normal intestinal function at the molecular level
The Research Group on Intestinal Signalling and Epigenetics investigated what happens at the molecular level in the small intestine of celiac disease patients when they are on a strict gluten-free diet and during a gluten exposure. The study used intestinal biopsy specimens from healthy individuals and celiac patients who had been on a gluten-free diet an average of 16 years. In addition, the celiac patients were exposed to a controlled low daily dose of gluten for ten weeks.
The results show that even though the intestinal villi structure and the number of inflammatory cells in celiac patients on a gluten-free diet were similar to those of healthy individuals, the groups differed significantly on the molecular level.
“The gene expression levels in the small intestine of celiac patients on a gluten-free diet differed significantly from those of healthy individuals. In every case, the gene expression levels of celiac patients on a gluten-free diet were found to be halfway between that of healthy non-celiacs and gluten-challenged celiac patients. In particular, the number of genes necessary for the absorption of micronutrients and vitamins – such as zinc, calcium and folate – was significantly lower in patients on a gluten-free diet even though their gut structure was normal in other ways,” Research Director, Docent Keijo Viiri says.
Previous studies have shown that celiac disease patients can suffer from micronutrient and vitamin deficiencies even when they are on a strict gluten-free diet. “The study we published suggests that this may be caused by the deficient expression of the genes that are necessary for the absorption of micronutrients and vitamins,” Viiri notes.
The study also found that gluten exposure triggers an overactive signalling called wnt in the small intestine of patients with celiac disease. Wnt signalling is an important intercellular communication mechanism that maintains the stem cells in the crypts of small intestinal mucosa. The gluten-triggered overactive wnt signalling inhibits the differentiation of the epithelial cells in intestinal mucosa resulting in the malabsorption of micronutrients and vitamins.
“Surprisingly, we found that wnt signalling is already overactive even in celiac patients who had been on a strict gluten-free diet for a long time. As a result, the expression of the micronutrient and vitamin transporter genes is lower, which leads to inadequate absorption. Fully normal intestinal function was not restored in these patients,” Keijo Viiri says.
As it was found that the traditional celiac disease diagnosis based on a histopathological examination of the mucosal structure – the height of intestinal villi, crypt depth ratio, and the number of inflammatory cells – is insufficient to fully measure the status of intestinal health, the so-called molecular morphometry tool, based on gene expression, was developed to measure intestinal structure and inflammation.
“As a clinical outcome of this study we can conclude that even though a gluten-free diet is a prerequisite for therapy as it significantly improves the condition of the small intestine in celiac disease, adjunctive therapies could have a significant health benefit. It is vital to ensure at least an adequate intake of micronutrients and vitamins as part of a gluten-free diet. In addition, the molecular morphometry tool we developed provides an objective measurement of the small bowel injury in celiac disease diagnostics and it may be used to study drug responses in clinical trials,” Viiri concludes.
The study was funded by the Academy of Finland, Business Finland, the Pediatric Research Foundation, Sigrid Jusélius Foundation, Mary och Georg C. Ehrnrooths stiftelse, Laboratoriolääketieteen Edistämissäätiö and the Competitive State Research Financing of the Expert Responsibility Area of Tampere University Hospital.
Valeriia Dotsenko, Mikko Oittinen, Juha Taavela, Alina Popp, Markku Peräaho, Synnöve Staff, Jani Sarin, Francisco Leon, Jorma Isola, Markku Mäki, Keijo Viiri: Genome-wide transcriptomic analysis of intestinal mucosa in celiac disease patients on a gluten-free diet and post gluten challenge.
American Journal of Cellular and Molecular Gastroenterology and Hepatology. Accepted on 24 July 2020. doi https://doi.org/10.1016/j.jcmgh.2020.07.010
Academy Research Fellow, Docent Keijo Viiri leads the Research Group on Intestinal Signalling and Epigenetics at Tampere University. The main goal of the group is to identify the regulatory mechanisms of intestinal homeostasis and related disorders such as celiac disease. Contact information: keijo.viiri [at] tuni.fi, tel. +358 40 554 9648.
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