Metabolomics reveal distinct molecular pathways associated with future risk of Crohn's Disease

Mingyue Xue ¹, Sun-Ho Lee ^1,2, Jingchen Shao ³

¹Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada.
²Division of Gastroenterology & Hepatology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
³Division of Mathematics and Statistics, Faculty of Art & Science, University of Toronto, Toronto, Ontario, Canada.
⁴Division of Gastroenterology and Nutrition, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
⁵IBD Center, The Hospital for Sick Children, Department of Pediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁶The Juliet Keidan Institute of Pediatric Gastroenterology and Nutrition, The Eisenberg R&D Authority, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel.
⁷Center of Excellence for Gastrointestinal Inflammation and Immunity Research, University of Alberta, Edmonton, Alberta, Canada.
⁸Department of Medicine, McMaster University Farncombe Family Digestive Health Research Institute, Hamilton, Ontario, Canada.
⁹Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Sainte-Justine Hospital, University of Montreal, Montreal, Quebec, Canada.
¹⁰Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Quebec, Canada.
¹¹Division of Gastroenterology, Hepatology & Nutrition, Children's Hospital of Eastern Ontario and University of Ottawa, Ottawa, Ontario, Canada.
¹²Canadian Gastro-Intestinal Epidemiology Consortium, Canada, British Columbia Children's Hospital, British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada.
¹³Department of Medicine, Queen's University, Kingston, ON, Canada.
¹⁴Department of Medicine, Division of Gastroenterology, University of Toronto, Toronto, Ontario, Canada.
¹⁵Hôpital Maisonneuve-Rosemont, Department of Medicine, Montreal University, Montreal, Quebec, Canada.
¹⁶Inflammatory Bowel Disease Clinical and Research Centre and Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
¹⁷Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology of Gastroenterology, University of Calgary, Calgary, Alberta, Canada.
¹⁸Department of Medicine, Division of Gastroenterology, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada.
¹⁹Biostatistics Department, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
²⁰Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
²¹Department of Nutritional Sciences, Temerty Faculty of Medicine at the University of Toronto, Toronto, Ontario, Canada.

⁰Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada.

Gut Microbes +

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September 5, 2025

View abstract on PubMed

Summary

Early metabolic changes in healthy relatives predict Crohn's disease (CD) development. Elevated quinolinate and lower ascorbate/isocitrate levels are linked to future CD risk, highlighting key metabolic pathways.

Area Of Science

Gastroenterology and Immunology
Metabolomics and Microbiome Research
Inflammatory Bowel Disease Pathogenesis

Background

Host-microbiome interactions are crucial in Crohn's disease (CD) pathogenesis.
Early metabolic alterations preceding CD onset are not well understood.
Prospective studies are needed to identify preclinical disease signatures.

Purpose Of The Study

To investigate preclinical metabolic signatures associated with future CD development.
To identify specific metabolites and metabolic pathways involved in early CD pathogenesis.
To explore relationships between metabolic profiles, host factors, and disease markers.

Main Methods

Nested case-control study within the CCC-GEM Project cohort (5,122 healthy first-degree relatives).
Analysis of baseline serum metabolomic profiles in 78 future CD cases and 311 matched controls.
Untargeted metabolomics combined with integrative analyses of proteomic, microbiome, and inflammatory markers.

Main Results

Identified 63 metabolites significantly associated with future CD risk.
Quinolinate (tryptophan catabolite) was elevated in individuals who later developed CD, correlating with inflammatory markers (CRP, fecal calprotectin, CXCL9).
Ascorbate and isocitrate were associated with reduced CD risk, showing negative correlations with CRP and CD-associated proteins.

Conclusions

Distinct molecular pathways contribute to early CD pathogenesis.
Metabolic profiling can identify individuals at high risk for developing CD.
Quinolinate, ascorbate, and isocitrate represent potential biomarkers for CD risk and progression.

Keywords:

Inflammatory bowel disease Ruminococcus torques gut barrier function risk biomarkers

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