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Anti-Microbial Antibody Response is Associated With Future Onset of Crohn's Disease Independent of Biomarkers of Altered Gut Barrier Function, Subclinical Inflammation, and Genetic Risk.

Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Gastroenterology & Hepatology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto and Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada. The Juliet Keidan Institute of Pediatric Gastroenterology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel. Division of Gastroenterology, Hepatology & Nutrition, Children's Hospital of Eastern Ontario and University of Ottawa, Ottawa, Ontario, Canada. Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, CHU Sainte-Justine, University of Montreal, Quebec, Canada. Division of Gastroenterology, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada. Hôpital Maisonneuve-Rosemont, Department of Medicine, University of Montreal, Montreal, Quebec, Canada. Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada. Canadian Gastro-Intestinal Epidemiology Consortium, Canada, British Columbia Children's Hospital, British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada. Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Quebec, Canada. Division of Gastroenterology and Nutrition, Stollery Children's Hospital, University of Alberta, Edmonton, Alberta, Canada. Prometheus Laboratories, San Diego, California. Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada. Division of Gastroenterology, The Hospital for Sick Children, Toronto, Ontario, Canada. Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto and Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Genetics and Genome Biology, The Hospital for Sick Children Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada. Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto and Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. Electronic address: Wei.Xu@uhnresearch.ca. Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Gastroenterology & Hepatology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address: Ken.Croitoru@sinaihealth.ca.

Gastroenterology. 2021;(5):1540-1551
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Abstract

BACKGROUND AND AIMS Altered host immune reactivity to microbial antigens is hypothesized to trigger the onset of Crohn's disease (CD). We aimed to assess whether increased serum anti-microbial antibody response in asymptomatic first-degree relatives (FDRs) of CD patients is an independent risk factor for future CD development. METHODS We measured host serum antibody response to 6 microbial antigens at enrollment (Prometheus enzyme-linked immunosorbent assay test: anti-Saccharomyces cerevisiae antibodies immunoglobulin A/immunoglobulin G, anti-OmpC, anti-A4-Fla2, anti-FlaX, anti-CBir1) and derived the sum of positive antibodies (AS). We used samples at enrollment of prospectively followed healthy FDRs from a nested case-control cohort of the Crohn's and Colitis Canada Genetics Environment Microbial Project. Those who later developed CD (n = 77) were matched 1:4 by age, sex, follow-up duration, and geographic location with control FDRs remaining healthy (n = 307). To address our research aims, we fitted a multivariable conditional logistic regression model and performed causal mediation analysis. RESULTS High baseline AS (≥2) (43% of cases, 11% of controls) was associated with higher risk of developing CD (adjusted odds ratio, 6.5; 95% confidence interval, 3.4-12.7; P < .001). Importantly, this association remained significant when adjusted for markers of gut barrier function, fecal calprotectin, C-reactive protein, and CD-polygenic risk score, and in subjects recruited more than 3 years before diagnosis. Causal mediation analysis showed that the effect of high AS on future CD development is partially mediated (42%) via preclinical gut inflammation. CONCLUSIONS Our results suggest that increased anti-microbial antibody responses are associated with risk of future development of CD, independent of biomarkers of abnormal gut barrier function, subclinical inflammation, and CD-related genetic risks. This suggests that anti-microbial antibody responses are an early predisease event in the development of CD.

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Publication Type : Multicenter Study ; Observational Study

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