Long-term and acute effects of gliadin on small intestine of patients on potentially pathogenic networks in celiac disease

Abstract

Celiac disease (CD) is a complex, immune-mediated intolerance to gliadin that develops in genetically susceptible individuals. Although the main driving force of the disease is an aberrant autoimmune response, several other pathogenic mechanisms, many still unidentified, are also involved. In order to describe at a network level the alterations provoked by a gliadin insult on the intestinal mucosa of patients, we compared the expression profiles of biopsies from 9 active and 9 treated patients (long-term effects of gliadin), and of 10 biopsies from gluten-free diet treated patients that were incubated in vitro with or without gliadin (acute effects) and integrated significantly altered transcripts into potentially pathogenic biological processes. Using information on Kyoto Encyclopedia of Genes and Genomes pathways and Gene Ontology terms represented among the differentially expressed genes, we observed important dysfunction in several complex networks, including those related to cell–cell communication, intracellular signaling, ubiquitin–proteasome system, cell cycle/apoptosis and extracellular matrix. The reconstruction of the role of these biological networks in the development of the intestinal lesion in CD provides a comprehensive picture of key events that contribute to the disease, and could point towards novel functional candidates that might be potential therapeutic targets or responsible for genetic susceptibility.

Keywords::

• Celiac disease
• gene expression profile
• gliadin
• biological pathway

Acknowledgements

This work was partially funded by Research Project grants 06/111030 from the Basque Department of Health and 04/1170 and 07/0796 from the Instituto de Salud Carlos III of the Spanish Ministry of Health and a Research Award from the Celiac Patient Association from Madrid. Ainara Castellanos-Rubio and Izortze Santín are predoctoral fellows supported by grants from the Spanish Ministry of Education and the University of the Basque Country, respectively. Ainhoa Martin-Pagola is a Postdoctoral fellow supported by the University of the Basque Country and Jose Ramon Bilbao is co-funded by the I3SNS Program of the Spanish Ministry of Health (CES05/036).

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.