Periodic Reporting for period 1 - INITIALISE (Inflammation in human early life: targeting impacts on life-course health)
Reporting period: 2023-01-01 to 2024-06-30
Human immune system development in early life, including in utero, impacts the risks of several diseases later in life. Yet, the mechanisms of early life immune imprinting are poorly understood in humans due to difficulties in obtaining samples and the challenges of deriving the most important data from small sample volumes available. Furthermore, these studies are complicated by the many simultaneous exposures with potential impacts on developing immune cells, colonising microbes, and immune-microbe mutualism. To better understand such interactions, a combination of large population studies with longitudinal data plus long-term follow-up and detailed studies in smaller sets of children are needed. INITIALISE is pursuing such a combined approach using intersecting multiple cohorts and existing biobanks, applying state-of-the-art technologies for exposure analyses and immune system investigation to understand the environmental factors shaping human immune systems early in life, their mechanisms of action, and impact on life-course health (Figure 1, showing scientific concept of INITIALISE). INITIALISE partners were brought together with the overall aim to improve life-course health by focusing on shaping of the immune system in the early, most vulnerable period of life including the prenatal period. The specific objectives of INITIALISE are:
• Objective 1 is to elucidate how exposures and genome impact gut microbiome, host immune system and metabolism, and how the interplay between these factors impacts life-course health.
• Objective 2 is to define the role of immune system maturation as a mediator between exposures and life-course health.
• Objective 3 is to perform a pilot clinical study, targeting the immune system, for personalised disease prevention.
• Objective 4 is to set up a collaborative data science platform for the investigation of early-life factors linked with life-course health.
• Objective 1 is to elucidate how exposures and genome impact gut microbiome, host immune system and metabolism, and how the interplay between these factors impacts life-course health.
• Objective 2 is to define the role of immune system maturation as a mediator between exposures and life-course health.
• Objective 3 is to perform a pilot clinical study, targeting the immune system, for personalised disease prevention.
• Objective 4 is to set up a collaborative data science platform for the investigation of early-life factors linked with life-course health.
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).
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).
INITIALISE research has already shown in initial phase of the project (RP1) that gut microbiome and immunomodulatory metabolites may impact lifecourse health (1, 2; listed in previous section). Future research within INITIALISE will identify key immune-system factors associated with multitude of future health-related outcomes, thus allowing also for investigations of specific and common early-life immune-system factors linked to specific adverse health outcomes. A clinical demonstrator will be performed targeting selected immune-system factors, aiming for disease prevention.