Obesity is associated with increased severity of infectious diseases. There is an urgent need to provide adapted lifestyle recommendation to reduce that risk which could be due to low grade inflammation and increased immune checkpoint (ICP) overexpression such as the PD-1/PDL1 pathway that leads to exhaustion of T-cells. Nutrim_Check is a new translational research collaborative network involving 4 groups of investigators that is organized into 6 complementary work-packages. Combining expertise in nutrition, metabolism, immunology and large-scale data analysis, our aim is to assess the interaction between NUTRition, IMmune CHECKpoints, and immune and metabolic health. Thanks to access to databases and biobanks with blood and adipose tissue samples from existing cohorts of subjects with metabolic deterioration, we will characterize obesity-related and cell and tissue-specific T cell dysfunction (ICP expression) and explore the interaction between dietary patterns, nutrients, gut microbiota (GM), metabolites and ICP modification (WP1). We will evaluate if T cell dysfunction can be rescued after dietary intervention known to improve metabolism and inflammation in a pilot study (WP2, i.e. called the pro immune diet). Mechanistic insights linking changes of T cell ICP expression will be addressed using ex vivo and in vitro models from human cells and detailed immune cell characterization will be undertaken (WP3). The infectious model of investigation will be the COVID-19, but this project extends broadly to viral infection vulnerability. Of note, an holistic and standardized mass cytometry approach will be used to obtain a detailed phenotyping of the immune populations. Patients from the pilot nutritional intervention will also be phenotyped in depth at the molecular level (metagenomics and metabolomics, WP4) and large-scale data analysis will be undertaken thanks to local expertise in biostatistic and machine learning (WP5). We will explore a novel not yet explored idea that chronic inflammatory tone due to increased expression of ICP contributes to adaptive immune evasion and sustained viral infection in dietary-related diseases. We propose this phenomenon may be fixable by nutritional amelioration in vulnerable populations such as people with obesity and metabolic diseases. Thanks to precise coordination (WP6), the project will provide information of academic and industrial interest with new information on food compounds known to broaden their spectrum of consumption, with emphasis on the immune response. The communication and dissemination Strategy will address the various target groups including the public, food, pharma and healthcare sectors and policy makers

BETTER4U aims at the identification and personalized management of all weight gain determinants to battle the increasingly rising numbers of overweight/obesity, via homogenous, globally adaptable and practically assessed public health initiatives and key interventions. Building on previous key projects and biobanks, the project will focus on the hitherto neglected impact of the polygenic background of weight gain on the effectiveness of lifestyle interventions for weight management in people with overweight/obesity. BETTER4U aims to probe into the global obesity challenge, study the problem and offer solutions in a tangible realistic way with the assistance of modern AI technologies and the contribution of experts around the world. BETTER4U will be realized through the following objectives: 1. To comprehensively understand and decipher genetics, metabolomics, microbiota, socio-economic, geographical, cultural and lifestyle features linked to weight gain throughout the life course, via meta-analyses (BETTER4U data from >50 studies, >1 million individuals) and extensive literature meta-review. 2.To develop the BETTER4U intervention methodology for weight gain prevention, based on a causal AI model of obesity determinants and a pilot study in 7 European countries. 3.To deploy technology-assisted, real-time monitoring tools to measure detailed behavioral indicators and their relation to the environmental context. 4.To evaluate the efficacy of the novel BETTER4U intervention methodology in a controlled, randomized clinical trial, based on individually-tailored recommendations for lifestyle change. 5.To maximize transferability and applicability of the BETTER4U intervention methodology by identifying implementation barriers and facilitators, as well as to evaluate implementation outcomes in both participants and stakeholders. 6. To develop and disseminate the BETTER4Uobesity prevention intervention methodology guidelines using a people-centred, sustainable care approach.

Type 2 diabetes is a major health burden worldwide. The disease is primarily characterized by chronic hyperglycemia and lipoprotein metabolism disorders, reducing both the quality of life and life expectancy, especially by promoting cardiovascular complications. Therefore, patients with type 2 diabetes display an increased risk of cardiovascular diseases compared with the general population. Since traditional clinical markers cannot fully explain this phenomenon, the identification of new relevant biomarkers is essential for a better stratification and a better care of the most at-risk diabetic patients. In that context, post-translational modifications of proteins are promising as such structural changes are varied and sensitive to environmental factors associated with diabetes. Besides, post-translational modifications modify the structure of proteins, change the affinity of proteins for biological partners or targets, and act directly on their functionalities. Interestingly, apolipoproteins constitute the structural and regulatory protein component of lipoproteins, responsible for the transport of hydrophobic lipids in the bloodstream. Abnormal apolipoprotein concentrations have been associated with many metabolic and cardiovascular disorders, and plasma apolipoproteins can predict cardiovascular diseases better than plasma lipids. As abnormalities in lipoprotein metabolism are important in type 2 diabetes, we hypothesize that the hyperglycemic environment associated with diabetes overexposes apolipoproteins to post-translational modifications. These structural changes might contribute to critical modifications in lipoprotein functions and turnovers leading to the residual cardiovascular disease risk observed in patients with type 2 diabetes. Due to their involvement in lipid metabolism and atherogenesis, circulating apolipoproteins appear are of interest for the identification of new relevant biomarkers relating to such modifications. In addition, targeted mass spectrometry-based approaches are very efficient for high-throughput analysis of apolipoproteins in biological fluids. However, methodological challenges exist for the study of post-translational modifications because of their low stoichiometric levels and their diverse chemical natures. POTOMAC aims to identify relevant apolipoprotein post-translational modifications via the fundamental approaches of targeted proteomics to functional experiments of biochemistry and cell biology in order to propose a set of new peptide biomarkers related to major apolipoprotein post-translational modifications that will be reliable for large-scale profiling in humans and better stratification of cardiovascular disease risk in patients with type 2 diabetes. Our objectives are: 1) to select relevant apolipoprotein post-translational modifications associated with type 2 diabetes and to perform mass spectrometry characterization of novel specific peptide biomarkers reflecting these modifications, 2) to select the best candidates based on their associations with lipoprotein metabolism dysfunctions determined in vivo, ex vivo, and in vitro, 3) to validate peptide candidates in clinical settings including human cohorts and interventional clinical trials, and 4) to determine their clinical relevance in comparison with the large-scale evaluation of metabolism dysregulation (oxidative stress, inflammation) obtained by complementary approaches. Ultimately, we believe that the combination of the information, namely the concentrations of apolipoproteins and their post-translational modification levels, will help to better understand the mechanisms associated with the disease development and will open new therapeutic avenues.