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

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

doi:10.3389/fimmu.2023.1082862

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

Front Immunol. 2023 Jun 30:14:1082862. doi: 10.3389/fimmu.2023.1082862. eCollection 2023.

Authors

Bárbara P González-García¹, Sergi Marí¹, Ariadna Cilleros-Portet¹, Alba Hernangomez-Laderas¹, Nora Fernandez-Jimenez¹, Iraia García-Santisteban¹, Jose Ramon Bilbao^{1

2}

Affiliations

¹ Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU) and Biocruces Bizkaia Health Research Institute, Leioa, Spain.
² Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.

Abstract

Background: 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.

Objective: To investigate a potential bidirectional causality between gut microbiota (GM) and CeD in HLA-DQ2 high genetic risk individuals.

Materials and methods: 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.

Results: We identified several bacteria from Ruminococcaceae and Lachnospiraceae families of the Firmicutes phylum as potentially causal in both directions. In addition, our results suggest that changes in the abundance of Veillonellaceae family might be causal in the development of CeD, while alterations in Pasteurellaceae family might be a consequence of the disease itself.

Conclusion: Our results suggest that the relationship between GM and HLA-DQ2 high risk individuals is highly complex and bidirectional.

Keywords: HLA-DQ2; Mendelian randomization; bidirectional causality; celiac disease; gut microbiota.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Celiac Disease*
Gastrointestinal Microbiome* / genetics
Genome-Wide Association Study
Humans
Mendelian Randomization Analysis
Risk Factors

Grants and funding

This work was supported by the Basque Dpt. of Health Projects GVSAN2018111086, GVSAN2019111085, and GVSAN2020111043 to JR-B, NF-J, and IG-S, respectively; by the Basque Government IT1739-22 grant to JR-B; by the Spanish Ministry of Equity Instituto de las Mujeres 12-4-ID22 to IG-S; by MCIN/AEI/10.13039/501100011033 PID2019-106382RB-I00 to JR-B; by the Instituto de Salud Carlos III grant PI21/0149 to NF-J, and by the Mexican National Council for Science and Technology grant 2021-000007-01EXTF-00209 to BG-G.