Project: A comprehensive study of the innate immune surveillance against infection during post_x0002_prandial metabolism.

Project Topic The RESIST-PP project is designed to provide a causal relationship between diet, innate immunity and infection risk by extending our knowledge on postprandial inflammation and atherogenic dyslipidemia. While feeding can induce resistance to acute lethal sepsis, nutritional cues may also coordinate time-of_x0002_day sensitivity to infection, especially in developed-world populations who are in a fed-state most of the day. Ingestion of high-fat food results in a transient proinflammatory state via the metabolic endotoxemia pathway sustained by bacterial wall products derived from gut microbiota. RESIST-PP will (i) define the role of bacterial-derived metabolites at the postprandial phase in diet-associated susceptibility to infection and in septic patients with obesity and T2D in humans, (ii) model the interplay between peripheral immune cells, the blood microbiota and the postprandial risk of infection in humans and (iii) provide proof of principle studies in mice. Multiple approaches will be implemented in 3 work packages to provide a comprehensive overview of cellular and molecular perturbations and circulating biomarkers associated with postprandial colonization resistance and host defense: (1) Assessment of the innate immune surveillance against infection during postprandial metabolism in dysmetabolic and septic patients at various stages. (2) Molecular profiling of the postprandial reactivity of leukocytes and monocytes to serum metabolites of bacterial origin in retrospective and prospective cohorts. (3) Integration analysis of diet_x0002_related, metabolic-related and infection-related modules through Multi-block omics data. Our strategy involves multi-omics analysis, including immune phenotyping, profiling of innate immune receptor signaling, metabolomic and lipidomic analysis, micro-RNA, blood microbiome analysis and diet survey analysis with human samples in retrospective and prospective cohorts, combined with parallel studies in preclinical and in vitro infection models to investigate causal mechanisms at the molecular level. Understanding the underlying pathways and identification of novel molecular targets for therapeutic intervention will lead to better anti-infectious treatment options for diet-related metabolic disorders, such as cardiovascular disease. We anticipate that understanding the cause-and-effect relationship of postprandial inflammation is particularly relevant for early intervention and prevention of metabolic diseases but also will provide novel insights into diet-related infectious disease prevention and identify novel biomarkers for clinical use.
Network JPI HDHL

Project partner

Number Name Role Country
1 Institut national de la santé et de la recherche médicale Coordinator France
2 Institut national de la santé et de la recherche médicale Partner France
3 University of Hohenheim Partner France
4 Biomedical Research Institute of Murcia Partner Spain
5 University of Hohenheim c Germany
6 Institut national de la santé et de la recherche médicale c France