Associations of NOD2 polymorphisms with Erysipelotrichaceae in stool of in healthy first degree relatives of Crohn’s disease subjects
Authors: Turpin Williams , Bedrani Larbi , Espin-Garcia Osvaldo , Xu Wei , Silverberg Mark S. , Smith Michelle I. , Garay Juan Antonio Raygoza , Lee Sun-Ho , Guttman David S. , Griffiths Anne , Moayyedi Paul , Panaccione Remo , Huynh Hien , Steinhart Hillary A. , Aumais Guy , Dieleman Levinus A. , Turner Dan ,   CCC IBD GEM Project research team, Abreu Maria , Beck Paul , Bernstein Charles , Croitoru Kenneth , Dieleman Levinus , Feagan Brian , Griffiths Anne , Guttman David , Jacobson Kevan , Kaplan Gilaad , Krause Denis O. , Madsen Karen , Marshall John , Moayyedi Paul , Seidman Ernest , Silverberg Mark , Stadnyk Andy , Steinhart A. Hillary , Surette Michael , Turner Dan , Walters Thomas , Vallance Bruce , Aumais Guy , Bitton Alain , Cino Maria , Critch Jeff , Denson Lee , Deslandres Colette , El-Matary Wael , Herfarth Hans , Higgins Peter , Huynh Hien , Hyams Jeff , Mack David , McGrath Jerry , Otley Anthony , Panancionne Remo , Baldassano Robert , Griffiths Anne M. , Hedin Charlotte , Hussey Seamus , Hyams Hien , Keljo David , Kevans David , Lees Charlie , Murthy Sanjay , Panaccione Remo , Parekh Nimisha , Plamondon Sophie , Radford-Smith Graham , Ropeleski Mark , Rosh Joel , Rubin David , Schultz Michael , Siegel Corey , Snapper Scott , Paterson Andrew D. , Croitoru Kenneth 
Published: October 2020

Abstract
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.