AUTHOR=González-García Bárbara P. , Marí Sergi , Cilleros-Portet Ariadna , Hernangomez-Laderas Alba , Fernandez-Jimenez Nora , García-Santisteban Iraia , Bilbao Jose Ramon 

TITLE=Two-Sample Mendelian Randomization detects bidirectional causality between gut microbiota and celiac disease in individuals with high genetic risk

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1082862

DOI=10.3389/fimmu.2023.1082862

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>Celiac Disease (CeD) is an autoimmune disorder triggered by gluten intake in genetically susceptible individuals. Highest risk individuals are homozygous for the Human Leucocyte Antigen (HLA) DQ2.5 haplotype or DQ2.5/DQ2.2 heterozygous. Both the HLA-DQ2-positive high genetic risk individuals and those that have developed the disease have altered intestinal microbiota, but it remains unclear whether these alterations are a cause or a consequence of CeD.</p></sec><sec><title>Objective</title><p>To investigate a potential bidirectional causality between gut microbiota (GM) and CeD in HLA-DQ2 high genetic risk individuals.</p></sec><sec><title>Materials and Methods</title><p>We performed a bidirectional Two-Sample Mendelian Randomization (2SMR) test using summary statistics from the largest publicly available Genome-Wide Association Study (GWAS) of GM and the summary statistics of the Immunochip CeD study of those individuals with the HLA-DQ2 high-risk haplotype. To test whether changes in GM composition were causally linked to CeD, GM data were used as exposure and CeD data as outcome; to test for reverse causation, the exposure and outcome datasets were inverted.</p></sec><sec><title>Results</title><p>We identified several bacteria from <italic>Ruminococcaceae</italic> and <italic>Lachnospiraceae</italic> families of the Firmicutes phylum as potentially causal in both directions. In addition, our results suggest that changes in the abundance of <italic>Veillonellaceae</italic> family might be causal in the development of CeD, while alterations in <italic>Pasteurellaceae</italic> family might be a consequence of the disease itself.</p></sec><sec><title>Conclusion</title><p>Our results suggest that the relationship between GM and HLA-DQ2 high risk individuals is highly complex and bidirectional.</p></sec>