Abstract Background Early life may shape the risk of later IBD development1–4; however, research on molecular neonatal features in individuals who later develop IBD is lacking. We explored metabolomes at birth in individuals who later developed IBD using unique neonatal dried blood spots (DBS). Methods We analysed neonatal DBS samples from 520 individuals with pediatric- or adult-onset IBD (CD = 276, UC = 244) and 1:1 matched controls, based on sample acquisition date, time of sampling (days after birth), gestational age or birth weight, and sex. We performed untargeted metabolomics and employed multivariate analysis, followed by a feature selection method built on conditional logistic regression with a LASSO component to reveal metabolites for further analysis. The following analysis was conducted using conditional logistic regression adjusted for multiple testing based on the total number of selected metabolite features. We also employed genotype and inflammatory marker information available for a subset of the cohort to investigate functional properties of the identified individual metabolites. Results We measured 1,249 metabolites that passed quality control. Although the global metabolomic composition did not differ significantly between cases and controls, the feature selection method revealed 21 neonatal metabolites associated with later CD development and four with UC. These metabolites belonged to the classes of amino acids and derivatives, nucleotides/nucleosides, peptides, and acylcarnitine. We further observed an association between specific neonatal metabolites and age of IBD onset: 7 metabolites associated with pediatric-onset CD, two with adult-onset CD, two with pediatric-onset UC, and two with adult-onset UC. Additionally, several feature-selected metabolites showed positive correlations with inflammatory markers, including IL-4, TNF-α, IL-6, and IFN-γ, and some were linked to genetic variants. Conclusion We identify specific neonatal metabolites in individuals with later development of IBD, related to IBD subtypes and age at diagnosis. This expands on the role of early life in development of IBD and sheds novel light on disease pathogenesis. References: 1.Rudbaek, J. J. et al. Inflammatory Markers at Birth and Risk of Early-Onset Inflammatory Bowel Disease. Gastroenterology (2024) doi:10.1053/J.GASTRO.2024.07.007. 2.Agrawal, M. et al. Early life exposures and the risk of inflammatory bowel disease: Systematic review and meta-analyses. EClinicalMedicine 36, (2021). 3.Torres, J. et al. Infants born to mothers with IBD present with altered gut microbiome that transfers abnormalities of the adaptive immune system to germ-free mice. Gut 69, 42–51 (2020). 4.Kim, E. S. et al. Longitudinal Changes in Fecal Calprotectin Levels Among Pregnant Women With and Without Inflammatory Bowel Disease and Their Babies. Gastroenterology 160, 1118-1130.e3 (2021). Conflict of interest: Rudbæk, Jonas: No conflict of interest Koziol, Adam Leslie: No conflict of interest Fracchia, Alice: No conflict of interest Ernst, Madeleine: No conflict of interest Jess, Tine: Personal Fees: Consultancy fees / travel costs from Ferring and Pfizer Ottosson, Filip: No conflict of interest
Rudbaek et al. (Thu,) studied this question.