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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., Competing Interests: 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., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Formation of mutagenic heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs) is one pathway believed to drive the association of colon cancer with meat consumption. Limited data exist on the associations of individual HCAs and PAHs in red or white meat with colon cancer. Analyzing data from a validated meat preparation questionnaire completed by 1062 incident colon cancer cases and 1645 population controls from an ongoing case-control study, risks of colon cancer were estimated using unconditional logistic regression models, comparing the fourth to the first quartile of mutagen estimates derived from a CHARRED based food frequency questionnaire. Total dietary intake of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) [adjusted odds ratio (aOR) = 1.87, 95% confidence interval (CI) = 1.44-2.44, P(trend) < 0.0001], 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx) (aOR = 1.68, 95% CI = 1.29-2.17, P(trend) = 0.001) and meat-derived mutagenic activity (aOR = 1.77, 95% CI = 1.36-2.30, P(trend) < 0.0001) were statistically significantly associated with colon cancer risk. Meat type specific analyses revealed statistically significant associations for red meat-derived MeIQx, DiMeIQx, and mutagenic activity but not for the same mutagens derived from white meat. Our study adds evidence supporting red meat-derived, but not white-meat derived HCAs and PAHs, as an important pathway for environmental colon cancer carcinogenesis.