P700 The GEM Project: Stool metabolomic profile is associated with microbiome risk score and with future onset of Crohn’s disease in healthy first-degree relatives

Lee , S.H.(1);Raygoza Garay , J.A.(1);Turpin , W.(1);Smith , M.I.(1);Goethel , A.(1);Griffiths , A.(2);Moayyedi , P.(3);Espin-Garcia , O.(4);Abreu , M.(5);Aumais , G.(6);Bernstein , C.N.(7);Biron , I.(8);Cino , M.(9);Deslandres , C.(10);Dotan , I.(8);El-Matary , W.(11);Feagan , B.(12);Guttman , D.(13);Huynh , H.(14);Hyams , J.(15);Jacobson , K.(16);Mack , D.(17);Marshall , J.(3);Otley , A.(18);Panaccione , R.(19);Ropeleski , M.(20);Silverberg , M.S.(1);Steinhart , A.H.(1);Turner , D.(21);Yerushalmi , B.(22);Xu , W.(4);Croitoru , K.(1);

(1)Mount Sinai Hospital- University of Toronto, Division of Gastroenterology, Toronto, Canada;(2)The Hospital for Sick Children, Division of Gastroenterology, Toronto, Canada;(3)McMaster University- Farncombe Family Digestive Health Research Institute, Department of Medicine, Hamilton, Canada;(4)Dalla Lana School of Public Health- University of Toronto, Division of Biostatistics, Toronto, Canada;(5)Department of Medicine- University of Miami- Miller School of Medicine, Division of Gastroenterology, Miami, United States;(6)Hopital Maisonneuve-Rosemont, Department of Gastroenterology, Montreal, Canada;(7)University of Manitoba, Inflammatory Bowel Disease Clinical and Research Centre, Winnipeg, Canada;(8)Rabin Medical Center, Division of Gastroenterology, Petah-Tikva, Israel;(9)University of Toronto, Division of Gastroenterology and Hepatology, Toronto, Canada;(10)CHU Sainte-Justine, Department of Gastroenterology, Montreal, Canada;(11)University of Manitoba, Pediatric Gastroenterology, Winnipeg, Canada;(12)University of Western Ontario, Departments of Medicine- Epidemiology- and Biostatistics, London, Canada;(13)University of Toronto, Centre for the Analysis of Genome Evolution and Function, Toronto, Canada;(14)University of Alberta, Department of Pediatrics, Edmonton, Canada;(15)Connecticut Children’s Medical Center, Division of Digestive Diseases- Hepatology- and Nutrition, Hartford, United States;(16)British Columbia Children's Hospital, Department of Pediatrics, Vancouver, Canada;(17)Children’s Hospital of Eastern Ontario and University of Ottawa, Division of Gastroenterology- Hepatology & Nutrition, Ottawa, Canada;(18)Izaak Walton Killam Hospital- Dalhousie University, Division of Gastroenterology, Halifax, Canada;(19)University of Calgary, Department of Gastroenterology, Calgary, Canada;(20)Queen's University, Gastrointestinal Diseases Research Unit- Department of Medicine, Kingston, Canada;(21)Shaare Zedek Medical Center- The Hebrew University of Jerusalem, The Juliet Keidan Institute of Pediatric Gastroenterology and Nutrition, Jerusalem, Israel;(22)Soroka University Medical Center and Faculty of Health Sciences- Ben-Gurion University of the Negev, Pediatric Gastroenterology Unit, Beer-Sheva, Israel; Crohn’s and Colitis Canada Genetics Environment Microbial Project Research Consortium


We recently developed and validated a microbial composition-based risk score (MRS) that predicts future risk of Crohn’s disease (CD) development among healthy first-degree relatives (FDR) of CD patients. We hypothesized that stool metabolomic profiles may mediate the effect of microbiome-based risk on future onset of CD.


Healthy FDRs of CD patients were recruited as part of the CCC-GEM Project. Stool metabolomics data were available in the nested case-control cohort (a subset of CCC-GEM cohort) whereby FDRs who later developed CD (n=56) were matched approximately 1:1 by age, sex, follow-up duration, and geographical location with control FDRs remaining healthy (n=66). Stool metabolomics were assessed using the Metabolon’s DiscoveryHD4™ platform, and the stool microbiome characterized by 16s rDNA amplicon sequencing. A multivariable conditional logistic regression model was evaluated on the disease development as a function of individual stool metabolites. Spearman correlation evaluated the rank values between stool metabolites and the MRS.


122 healthy FDRs (median age 15 years, 60% female) were followed for a median 5.2 years. Among 1,029 stool metabolites that were analyzed, 79 were associated with future risk of CD (p<0.05); however, none remained significant after adjustment for false-discovery rate. Considering the exploratory nature of this study with limited sample size, we focused on the top seven metabolites associated with CD onset (p<0.01). Of these, two stool metabolites (dimethylglycine, methylmyristate) were associated with increased risk of CD onset while five (cytosine, guanine, cytidine, hydroxyglutarate, nervonate) were associated with decreased risk of CD development. The two metabolites positively associated with CD onset were also positively correlated with the MRS, while the five metabolites negatively associated with CD onset, were also negatively correlated with the MRS. Meanwhile, 24 stool metabolites had significant correlation with MRS (false-discovery rate-corrected p<0.2). Among those, a total of four stool metabolites (cytosine, guanine, methymyristate, cytidine) overlapped with the top seven stool metabolites associated with CD onset.


Changes in stool metabolite profiles may predict future risk of CD. A subset of these metabolites has significant correlation with the MRS with consistent direction of effect. This may suggest that these particular stool metabolites mediate the putative effects of the gut microbiome on CD risk. Further validation in the entire GEM cohort is warranted.