In order to reach Objective 1, INITIALISE assembled multiple clinical cohorts and set up multiple analytical platforms for multi-omics studies. Datasets will be generated that allow investigations linking early-life exposures with life-course health. Within the Reporting Period 1 (RP1), the primary aim was to set the stage for and to initiate multi-omics studies in INITIALISE clinical cohorts. Cohort inventories of available samples and data were made, and samples were selected for multi-omics analyses (metabolomics/exposome, proteomics by OLINK Explore 384 Inflammation panel, shotgun metagenomics and metabolomics of stool samples, and glycomics). The multi-omics analyses have been initiated within RP1. As one of the highlights, in the ABIS cohort (collaboration of four INITIALISE participants), we found and published in the journal Cell, that infant microbes and metabolites point to future neurodevelopmental disorders (1).
In order to reach Objective 2, INITIALISE relies on established clinical studies, biobanks, and model systems, which will allow mechanistic investigations and generate new knowledge on how, e.g. gut microbiome and chemical exposures impact immune system development. All planned (as described in DoA) investigations addressing the Objective 2 have been initiated in RP1. These include (a) investigations of prenatal immune system development with respect to impacts of lifestyle and chemical exposures [study of human fetuses], (b) investigation of gut microbiome in early immune system development [two longitudinal clinical studies focusing on general and at-risk populations], (c) investigations of chemical exposures and gut microbiome mediated metabolites on immune cells, and (d) studies of immunological self-tolerance in progression to autoimmune disease. Each of these research lines already involves two or more INITIALISE partners. Notably, the widening partner GENOS that joined INITIALISE in 2024 has already contributed new data and promising preliminary results to two research lines, (a) and (b).
As one of the highlights in RP1, in the study of human fetuses, we have shown that prenatal exposure to perfluorinated substances (PFAS) impacts hepatic metabolism in human fetuses, particularly the bile acid metabolism. This work was published in the Lancet Planetary Health (2). Of note, the conjugates of secondary bile acids LCA and UDCA were particularly dysregulated with high PFAS exposure (suggesting placental transfer as these bile acids are microbially regulated) these bile acids are known to be immunomodulatory (3). Furthermore, itaconate, a known anti-inflammatory metabolite (4), was markedly decreased with high PFAS exposure.
The clinical study addressing the Objective 3 of INITIALISE is set to be designed during RP2 and conducted in RP3. The planning for the study was initiated in Y2 of the project, at the annual consortium meeting in Naples (3/2024), i.e. in RP1. A working group including representatives from seven project partners was appointed to work on the study design and other considerations related to the work package.
Addressing the Objective 4 of INITIALISE, the initial data management plan was set-up. Survey of existing data and plan for future sample analyses has been conducted and is guiding the multi-omics analyses that were initiated before end of PR1 (see Objective 1). Cloud directory and GitHub for sharing the code and data processing and analysis pipelines were set-up.
REFERENCES
1. A. P. Ahrens et al., Infant microbes and metabolites point to childhood neurodevelopmental disorders. Cell 187, 1853-1873 e1815 (2024).
2. T. Hyotylainen et al., In utero exposures to perfluoroalkyl substances and the human fetal liver metabolome in Scotland: a cross-sectional study. Lancet Planet Health 8, e5-e17 (2024).
3. M. H. Lee et al., How bile acids and the microbiota interact to shape host immunity. Nat Rev Immunol, (2024).
4. E. L. Mills et al., Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556, 113-117 (2018).
