Abstract
A healthy immune status is strongly conditioned during early life stages. Insights into the molecular drivers of early life immune development and function are prerequisite to identify strategies to enhance immune health. Even though several starting points for targeted immune modulation have been identified and are being developed into prophylactic or therapeutic approaches, there is no regulatory guidance on how to assess the risk and benefit balance of such interventions. Six early life immune causal networks, each compromising a different time period in early life (the 1st, 2nd, 3rd trimester of gestations, birth, newborn, and infant period), were generated. Thereto information was extracted and structured from early life literature using the automated text mining and machine learning tool: Integrated Network and Dynamical Reasoning Assembler (INDRA). The tool identified relevant entities (e.g., genes/proteins/metabolites/processes/diseases), extracted causal relationships among these entities, and assembled them into early life-immune causal networks. These causal early life immune networks were denoised using GeneMania, enriched with data from the gene-disease association database DisGeNET and Gene Ontology resource tools (GO/GO-SLIM), inferred missing relationships and added expert knowledge to generate information-dense early life immune networks. Analysis of the six early life immune networks by PageRank, not only confirmed the central role of the “commonly used immune markers” (e.g., chemokines, interleukins, IFN, TNF, TGFB, and other immune activation regulators (e.g., CD55, FOXP3, GATA3, CD79A, C4BPA), but also identified less obvious candidates (e.g., CYP1A2, FOXK2, NELFCD, RENBP). Comparison of the different early life periods resulted in the prediction of 11 key early life genes overlapping all early life periods (TNF, IL6, IL10, CD4, FOXP3, IL4, NELFCD, CD79A, IL5, RENBP, and IFNG), and also genes that were only described in certain early life period(s). Concluding, here we describe a network-based approach that provides a science-based and systematical method to explore the functional development of the early life immune system through time. This systems approach aids the generation of a testing strategy for the safety and efficacy of early life immune modulation by predicting the key candidate markers during different phases of early life immune development.
Highlights
The first 1,000 days of life is a period of growth and development in which the foundations of lifelong immune homeostasis and microbial colonization are established in humans [1]
The literature covering the information on mechanisms involved in early life immune health is scattered across thousands of scientific papers
In our methodology we identified 107 genes that have been described in the selected early life literature already during gestation and remained expressed throughout the infant period (Supplementary Figure 1)
Summary
The first 1,000 days of life is a period of growth and development in which the foundations of lifelong immune homeostasis and microbial colonization are established in humans [1] Alterations during this period, due to environmental and host factors, are considered to be potential determinants of health-outcomes later in life [2,3,4]. A need for a science-based system approach to assess the safety and benefit of nutritional immune interventions, with a special focus on early life is clear. With such an approach animal testing can be reduced, refined or replaced
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