Abstract Background Inflammatory bowel disease (IBD) is caused by a combination of genetic susceptibility, lifestyle, and environmental exposures1. Increasing evidence from epidemiological and molecular studies suggests that early-life biological exposures may shape the later immune development, including the risk of IBD2. Neonatal samples collected a few days after birth capture a critical window that reflects the infant’s innate physiology, the maternal environment, and immediate postnatal exposures3. We investigated whether the neonatal metabolome, an at-birth dynamic measure of gestational exposures, predicts the development of IBD. Methods We profiled dried blood spots from the Danish Neonatal Screening Biobank of 520 newborns who later developed IBD, and 520 matched controls, using untargeted metabolomics via high-resolution mass spectrometry, resulting in 1,350 reliably measured metabolites. Genotyping and cytokine levels were also available for, respectively, 97% and 35% of the metabolome cohort. We assessed gestational and perinatal effects with PERMANOVA, and gradient boosting was used for prediction. Results Consistent with previous work4, gestational age, delivery mode, and sex explain a modest portion of the variance in the neonatal metabolome, contributing 0.7%, 0.3%, and 0.25%, respectively. Metabolite measurements explained minimal variance with respect to future IBD onset (R² = 0.09%, p-value = 0.390) and showed no predictive value for disease status (AUC = 0.51 (95% CI 0.50–0.52), p-value = 0.585). Stratifying by disease subtype and onset age did not improve prediction, although the cohort was underpowered for early-onset IBD. In contrast, genetic risk scores were modestly predictive of IBD onset (AUC = 0.68, p-value 2.53 × 10−¹² for CD; AUC = 0.66, p-value 2.24 × 10−9 for UC). Genetic and at-birth metabolomic scores were not significantly correlated. Finally, the predictive value for the inflammatory cytokine profiles was similarly weak (AUC = 0.56 (95% CI 0.55-0.58)). Conclusion Using a large and comprehensively profiled cohort, we demonstrate that neonatal metabolomic profiles capture signatures of the gestational environment. However, these environmental imprints do not translate into a predictive model. Our findings suggest that the majority of IBD risk accumulates later in life, and is not substantially driven by gestational and perinatal factors that impact the early-life metabolomic profile. Limitations include the broad metabolome profiling technique, which nevertheless does not capture all circulating metabolites, as well as the limited number of very early-onset cases. References: 1.Ananthakrishnan AN, Bernstein CN, Iliopoulos D, et al. Environmental triggers in IBD: a review of progress and evidence. Nat Rev Gastroenterol Hepatol. 2018;15(1):39-49. doi:10.1038/nrgastro.2017.136 2.Agrawal M, Sabino J, Frias-Gomes C, et al. Early life exposures and the risk of inflammatory bowel disease: Systematic review and meta-analyses. EClinicalMedicine. 2021;36:100884. doi:10.1016/j.eclinm.2021.100884 3.Ernst M, Rogers S, Lausten-Thomsen U, et al. Gestational age-dependent development of the neonatal metabolome. Pediatr Res. 2021;89(6):1396-1404. doi:10.1038/s41390-020-01149-z 4.Mansell T, Vlahos A, Collier F, et al. The newborn metabolome: associations with gestational diabetes, sex, gestation, birth mode, and birth weight. Pediatr Res. 2022;91(7):1864-1873. doi:10.1038/s41390-021-01672-7 Conflict of interest: Fracchia, Alice: No conflict of interest Rudbæk, Jonas: No conflict of interest Chakradeo, Kaustubh: No conflict of interest Jess, Tine: Personal Fees: Consultancy for Ferring, Pfizer, Johnson & Johnson Ottosson, Filip: No conflict of interest Sazonovs, Aleksejs: No conflict of interest
Fracchia et al. (Thu,) studied this question.