Celiac disease (CD) is a chronic systemic autoimmune disorder that occurs in genetically predisposed individuals and is characterized by loss of tolerance to dietary gluten protein.
More than 30% of the population carries the predisposing gene and is exposed to gluten, yet only 2 to 3% develop CD in their lifetime. This suggests that other factors such as the intestinal microbiota may also contribute to CD pathogenesis.
Several studies have looked into the link between microbiome changes and the onset of CD but these studies have mostly used 16S rRNA sequencing to analyze intestinal microbiota, which cannot provide information about functional characteristics of the microbiota nor provide taxonomic data at the strain level. Furthermore, metabolomic analysis was generally limited to serum (as opposed to fecal) metabolites, which do not provide direct information about metabolic activity of the gut microbiota.
The authors of the current study argue that to gain mechanistic insight into the pathogenesis of CD and other autoimmune diseases, research needs to transition from case–control microbiome studies to prospective longitudinal studies, which prospectively examine subjects at multiple time points before disease development.
They therefore developed a prospective cohort study for CD, the Celiac Disease Genomic, Environmental, Microbiome, and Metabolomic (CDGEMM) study, where they have been following approximately 500 infants in the United States, Italy, and Spain who have a first-degree relative with CD and therefore are at a high risk of developing CD. This study has been collecting extensive blood and faecal samples and voluminous environmental data on each participant since 2014.
In the current study, they present proof of concept intersubject and intrasubject analyses using fecal metagenomic and metabolomic data collected at multiple time points before onset of CD in 10 cases and 10 matched controls in order to identify alterations in the intestinal microbiota and metabolome, which may serve as markers of progression toward CD onset.
They found significant changes in the intestinal microbes, pathways and metabolites as early as 18 months before disease onset – much earlier than expected.
Changes included an increased abundance of pro-inflammatory species and decreased abundances of protective and anti-inflammatory species.
The authors say this study demonstrates the power of next-generation sequencing coupled with bioinformatics to detect these important changes.
Senior author Alessio Fasano, MD, director of the Center for Celiac Research and Treatment at MGHfC adds: “This approach will help us to develop novel strategies for the diagnosis and treatment of a variety of conditions in which the microbiome could play a pathogenic role.”
He suggests that these findings, if confirmed by larger datasets, may represent specific therapeutic targets for disease interception and possible prevention of coeliac disease onset through microbiome manipulation during the preclinical phase.
“With these findings, we anticipate that we will be able to distinguish who will remain healthy and who will develop coeliac disease months before the onset of the disease,” adds Fasano.
Source: Proceedings of the National Academy of Sciences of the United States of America
Leonard. M.M., et al
“Microbiome signatures of progression toward celiac disease onset in at-risk children in a longitudinal prospective cohort study”