Article Text
Abstract
Objective IBD is characterised by dysbiosis, but it remains unclear to what extent dysbiosis develops in unaffected at-risk individuals. To address this, we investigated age-related patterns of faecal and serum markers of dysbiosis in high-risk multiplex IBD families (two or more affected first-degree relatives).
Design Faecal and serum samples were collected from multiplex IBD and control families (95 IBD, 292 unaffected, 51 controls). Findings were validated in independent cohorts of 616 and 1173 subjects including patients with IBD, infants born to mothers with IBD and controls. 16S rRNA gene sequencing and global untargeted metabolomics profiling of faeces and serum were performed.
Results Microbial and metabolomic parameters of dysbiosis progressively decreased from infancy until age 8. This microbial maturation process was slower in infants born to mothers with IBD. After age 15, dysbiosis steadily increased in unaffected relatives throughout adulthood. Dysbiosis was accompanied by marked shifts in the faecal metabolome and, to a lesser extent, the serum metabolome. Faecal and serum metabolomics dysbiosis indices were validated in an independent cohort. Dysbiosis was associated with elevated antimicrobial serologies but not with faecal calprotectin. Dysbiosis metrics differentiated IBD from non-IBD comparably to serologies, with a model combining calprotectin, faecal metabolomics dysbiosis index and serology score demonstrating highest accuracy.
Conclusion These findings support that dysbiosis exists as a pre-disease state detectable by faecal and serum biomarkers for IBD risk prediction. Given the expansion of disease-modifying agents and non-invasive imaging, the indices developed here may facilitate earlier diagnoses and improved management in at-risk individuals.
- INTESTINAL BACTERIA
- INFLAMMATORY BOWEL DISEASE
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information. Sequence data have been deposited in NCBI Bioproject under PRJNA1053656 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA1053656 https://www.ncbi.nlm.nih.gov/bioproject/PRJNA1053656) and metabolomics data along with associated metadata are included in supplemental data files.
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Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information. Sequence data have been deposited in NCBI Bioproject under PRJNA1053656 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA1053656 https://www.ncbi.nlm.nih.gov/bioproject/PRJNA1053656) and metabolomics data along with associated metadata are included in supplemental data files.
Footnotes
Contributors JPJ is the guarantor. JPJ: Conceptualisation, methodology, software, validation, formal analysis, data curation, writing—original draft, writing—review and editing, visualisation. EAS: Conceptualisation, investigation, data curation, writing—review and editing. DSH: Investigation, data curation, writing—review and editing, project administration. JY: Software, formal analysis. VL: Formal analysis, investigation. GB: Investigation, data curation. GB: Investigation. KG: Investigation, formal analysis, data curation. PR-M: Investigation. JH: Validation, data curation. AH: Conceptualisation, writing—review and editing. EL-S: Conceptualisation, writing—review and editing. JW: Conceptualisation. CL: Investigation. PD: Investigation. JT: Investigation. J-FC: Conceptualisation, writing—review and editing. JC: Conceptualisation, writing—review and editing. IP: Validation, writing—review and editing. JF: Conceptualisation, writing—review and editing. JB: Conceptualisation, writing—review and editing, supervision, funding acquisition. MD: Conceptualisation, writing— review and editing, supervision, funding acquisition.
Funding This study was funded by a grant from Janssen Research and Development, LLC, and by a generous donation from Julie and Bruce Goldsmith. The MECONIUM study was supported by the Crohn’s and Colitis Foundation. This work was also supported in part through the computational and data resources and staff expertise provided by Scientific Computing and Data at the Icahn School of Medicine at Mount Sinai and supported by the Clinical and Translational Science Awards (CTSA) grant UL1TR004419 from the National Center for Advancing Translational Sciences. JPJ was supported by VA IK2CX001717. MCD and JC were supported by R01 DK123758-01 from the National Institute of Diabetes and Digestive and Kidney Diseases.
Competing interests GB, AH, EL-S and JW are current employees of Johnson & Johnson Innovative Medicine. MD and J-FC are consultants for Johnson & Johnson Innovative Medicine and Prometheus Labs. All other authors do not have disclosures.
Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
Provenance and peer review Not commissioned; externally peer reviewed.
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