Background: Genetic analyses have identified many variants associated with the risk of inflammatory bowel disease (IBD) development. Among these variants, the ones located within the NOD2 gene have the highest odds ratio of all IBD genetic risk variants. Also, patients with Crohn’s disease (CD) have been shown to have an altered gut microbiome, which might be a reflection of inflammation itself or an effect of other parameters that contribute to the risk of the disease. Since NOD2 is an intracellular pattern recognition receptor that senses bacterial peptidoglycan in the cytosol and stimulates the host immune response (Al Nabhani et al., PLoS Pathog 13:e1006177, 2017), it is hypothesized that NOD2 variants represent perfect candidates for influencing host-microbiome interactions. We hypothesized that NOD2 risk variants affect the microbiome composition of healthy first degree relative (FDR) of CD patients and thus potentially contribute to an altered microbiome state before disease onset. Methods: Based on this, we studied a large cohort of 1546 healthy FDR of CD patients and performed a focused analysis of the association of three major CD SNPs in the coding region of the NOD2 gene, which are known to confer a 15–40-fold increased risk of developing CD in homozygous or compound heterozygous individuals. Results: Our results show that carriers of the C allele at rs2066845 was significantly associated with an increase in relative abundance in the fecal bacterial family Erysipelotrichaceae. Conclusions: This result suggests that NOD2 polymorphisms contribute to fecal microbiome composition in asymptomatic individuals. Whether this modulation of the microbiome influences the future development of CD remains to be assessed.
Bibliographical noteFunding Information:
This study was supported by grants from Crohn’s and Colitis Canada Grant #CCC-GEMIII, Canadian Institutes of Health Research (CIHR) Grant #CMF108031 and the Helmsley Charitable Trust. Williams Turpin is a former recipient of a Postdoctoral Fellowship Research Award from the CIHR Fellowship/ Canadian Association of Gastroenterology (CAG)/ Ferring Pharmaceuticals Inc. and of a fellowship from the Department of Medicine, Mount Sinai Hospital, Toronto. Williams Turpin is partially supported by the Biocodex Microbiota Foundation. Sun-Ho Lee, Juan Antonio Raygoza Garay, are recipient of fellowship from the Department of Medicine, Mount Sinai Hospital, Toronto. Mark Silverberg is supported in part by the Gale and Graham Wright Chair in Digestive Diseases. Kenneth Croitoru is partially supported by a Canada Research Chair in Inflammatory Bowel Diseases. Osvaldo Espin-Garcia is a recipient of a CIHR STAGE fellowship. Acknowledgments
We thank the members of the CCC GEM Global Project Office. The CCC IBD GEM Project research team is composed of: Maria Abreu, Paul Beck, Charles Bernstein, Kenneth Croitoru, Leo Dieleman, Brian Feagan, Anne Griffiths, David Guttman, Kevan Jacobson, Gilaad Kaplan, Denis O. Krause*(* deceased), Karen Madsen, John Marshall, Paul Moayyedi, Mark Ropeleski, Ernest Seidman*(* deceased), Mark Silverberg, Scott Snapper, Andy Stadnyk, Hillary Steinhart, Michael Surette, Dan Turner, Thomas Walters, Bruce Vallance, Guy Aumais, Alain Bitton, Maria Cino, Jeff Critch, Lee Denson, Colette Deslandres, Wael El-Matary, Hans Herfarth, Peter Higgins, Hien Huynh, Jeff Hyams, David Mack, Jerry McGrath, Anthony Otley, and Remo Panancionne. The CCC GEM Project recruitment site directors include Maria Abreu, Guy Aumais, Robert Baldassano, Charles Bernstein, Maria Cino, Lee Denson, Colette Deslandres, Wael El-Matary, Anne M. Griffiths, Charlotte Hedin, Hans Herfarth, Peter Higgins, Seamus Hussey, Hien Hyams, Kevan Jacobson, David Keljo, David Kevans, Charlie Lees, David Mack, John Marshall, Jerry McGrath, Sanjay Murthy, Anthony Otley, Remo Panaccione, Nimisha Parekh, Sophie Plamondon, Graham Radford-Smith, Mark Ropeleski, Joel Rosh, David Rubin, Michael Schultz, Ernest Seidman, Corey Siegel, Scott Snapper, Hillary Steinhart, and Dan Turner.
© 2020, The Author(s).
- Fecal microbiota
- Healthy human
- Inflammatory bowel disease