An EHU study indicates that a drug already approved for use in humans could help to reduce the inflammation associated with coeliac disease
The research, conducted by the FunImmune group, shows that some viral infections may contribute to the development of coeliac disease by inducing changes in RNA. These changes may facilitate intestinal inflammation. The results are helping us to better understand how autoimmune diseases start, and are opening the door to new forms of prevention, such as vaccines against certain viruses or the development of new treatments.
Coeliac disease is an autoimmune disorder that is triggered when a genetically predisposed individual consumes gluten. However, genetics alone does not account for why some people develop the disease whereas others do not. In recent years, several studies have indicated that certain viral infections, especially those caused by reoviruses, could act as triggers. In humans, reovirus infection is quite common; it does not usually produce symptoms, only minor discomfort.
The EHU’s FunImmune group had already demonstrated that certain chemical changes in RNA, known as m6A methylation, influence the inflammatory response to gluten and the development of coeliac disease. That is why, in this new study, they wanted to see whether reovirus infection is also linked to these changes in RNA, as explained by Dr Ainara Castellanos-Rubio, Ikerbasque Research Associate in the Department of Genetics, Physical Anthropology and Animal Physiology.
The study conducted by Dr Maialen Sebasti?n de la Cruz concluded that viral infections may alter certain chemical markers in RNA (the so-called m6A methylations). These changes leave a kind of “memory” in the cells that can induce inflammation related to coeliac disease.
What is more, the results show that when a viral infection combines with gluten consumption, specific changes occur in the RNA of a gene that is very important for controlling the inflammatory response, as Castellanos explained.
Another piece in a complicated jigsaw
Cell models and intestinal biopsies from individuals with coeliac disease were used in the study. First, they analysed whether these patients had been in contact with a reovirus and found that many had more antibodies against the virus, indicating that they had been infected at some point. “Firstly, we confirmed that coeliac patients did indeed have more anti-reovirus antibodies,” said Castellanos. “This means that at some point they had had a reovirus infection. And then we began to look at which genes could be modified by these infections and, at the same time, could harbour these modifications that we had previously found to be related to gluten response. So, we found a specific gene (which is unlikely to be the only one) involved in the inflammatory and antiviral response, and we focused on finding out how inflammation is regulated by its modification and how viruses and gluten can affect it.”
With all that, the EHU researchers confirmed that “the combination of having had the virus and exposure to gluten in the diet can cause this gene to mutate and generate a heightened inflammatory response that may ultimately contribute to the development of coeliac disease”. In other words, “when both factors (gluten and the reovirus) are present, many more methylations (or modifications) occur in this gene, generating much more inflammatory protein, which sets off an inflammatory cascade that can contribute to the development of coeliac disease”, explained the FunImmune lab researcher. However, she maintained that “this does not mean that everyone who has the genetic risk and becomes infected with the reovirus will develop coeliac disease, but we have found that it can contribute to it”.
These findings reinforce the idea that viral infections play a significant role in the development of coeliac disease and demonstrate, for the first time, that RNA modifications can act as a mechanism linking infection to inflammation.
Furthermore, the study is opening the door to new therapeutic strategies with the aim of reducing the risk or progression of the disease; they are based on drugs capable of preventing or reversing these changes. Significantly, the researchers observed that this effect can be reversed by using drugs that modulate these RNA modifications, such as simvastatin (a drug already tested for use in humans). However, the EHU researcher admitted that this fact is still in its early phase. “Although we saw in the laboratory that this drug appeared to reduce this specific methylation by lowering inflammatory levels, the studies were conducted on cells or biopsies.” Right now, the lab of the EHU’s FunImmune group is continuing to analyse methylation markers: “We continue to look for compounds that can change these markers, and we are finding that there are many natural compounds that appear to regulate them.”
Castellanos highlighted the complexity of coeliac disease: “Many pieces are needed to complete the jigsaw. Our laboratory is currently the only one working on RNA modifications in coeliac disease, and this study has helped to add another piece to the jigsaw. But we need more pieces because it is very complex. Basic science is essential if the leap to the clinical setting is to be made.”
Additional information
This study is within the framework of the PhD thesis written up by Maialen Sebastian de la Cruz in the department of Genetics, Physical Anthropology and Animal Physiology of the EHU-University of the Basque Country, supervised by Dr Ainara Castellanos Rubio and Dr Jos? Ram?n Bilbao Catal?. Members of Columbia University Irving Medical Center (New York) collaborated in the study.
Bibliographic reference
Maialen Sebastian de la Cruz, Ane Olazagoitia-Garmendia, Izei Pascual-Gonzalez, Luis Manuel Mendoza, Maria Legarda, Carlos Tutau, Luis Bujanda, Sankar Ghosh, Izortze Santin, Thomas S. Postler, Jose Ramon Bilbao, Ainara Castellanos-Rubio
m6A RNA methylation modulates antiviral response in celiac disease
Genes & immunity
DOI: 10.1038/s41435-025-00373-z