The Western lifestyle, as well as the socioeconomic habitat, segregate genetic from environmental factors that lead to pathological inflammation and metabolic diseases. Understanding how these environmental factors influence the immune response is of importance, as in modern societies, the first generation of young people with shortened life expectancy due to environmental changes has become a reality. Our previous work showed that a Western diet (WD) rapidly causes a systemic inflammation that leads to expansion and long-lasting reprogramming of bone marrow-derived myeloid precursor cells. Mechanistically, bone marrow activation is linked to the development of chronic inflammatory diseases, in which metabolic inflammation (metaflammation) is part of the pathogenesis. Ongoing chronic and sterile inflammation, driven by genetic as well as environmental factors, is a detrimental process in aging organisms and leads to a plethora of pathologies including diabetes, neurodegeneration, and atherosclerosis.
To better understand how WD causes systemic inflammation and organ pathology, we have performed an unbiased approach to study the potential contribution of the environment to metaflammation and disease development. We fed more than 500 inbred mice a WD for eight weeks and assessed more than 1,100 measured features, which - amongst others - included portal vein metabolites, the gut microbiome, systemic inflammation, as well as liver and cardiovascular pathology. Using a bioinformatic approach that combined machine learning techniques and artificial intelligence, we then assessed the influence of each of these factors in induction of metaflammation and organ pathology. Alongside known risk factors, the implementation of gradient boosting regression and random forest classification algorithms revealed that a variety of gut-derived factors were either found in strong positive or inverse correlation with inflammation and disease pathology.
In this project, we aim at deciphering detrimental from protective factors that are causally involved in WD-associated inflammatory pathologies, which are reflected by liver inflammation and atherosclerotic disease. We will analyse how the individual identified factors influence innate immune pathway activation, the metabolic status, as well as innate immune memory function (Aim 1). In vitro screening assays will be performed to test the most strongly correlated factors for their function in systemic metaflammation, emergency haematopoiesis and innate immune reprogramming, in murine models of metaflammation (Aim 2). Finally, we will assess the potential relevance of preclinical models in human metaflammation. In the sera of Rhineland study participants, we will perform gene ontology (GO) term, biological pathway (BP), molecular function (MF), and cellular compartment (CC) analyses to identify factors that correlate to (extreme) endophenotypes, such as healthy obese or obese with high metaflammation levels (Aim 3).