Postprandial nutritional stress is known to be the cause of transient metabolic disturbances whose long-term recurrence contributes to the development of cardiometabolic diseases. Among the physiological changes occurring after a meal, the postprandial secretion of extracellular vesicles (EVs) is poorly documented. However, these nanostructures composed of cell membranes are of increasing interest because of the variations in their circulating levels in physiological stress situations and in the onset of cardiometabolic disorders. These structures sustain a cell-to-cell communication because of their content which confers them the capacity to propagate biological messages made up of lipid mediators, protein signals and nucleic acid molecules. The factors that modulate EV secretion and the biological consequences associated with these structures are still poorly understood. However, nutritional approaches based on plant foods rich in microconstituents such as polyphenols, known for their health benefits, have been shown to reduce the elevation of EV level in cardiometabolic disorders. However, the daily impact of our diet and these plant microconstituents on the secretion of postprandial EVs and their biological activities is not known. The Post'EVs project hypothesizes that the polyphenols provided by the plant food may favorably impact the biology of postprandial EVs, particularly in response to nutritional stress. To answer this question, the first objective is to characterize accurately the secreted EVs (population and content) following a pro-oxidative and pro-inflammatory postprandial stress and to determine the constituents allowing to identify specifically postprandial EVs. The project also aims to determine the biological role(s) of postprandial EVs, particularly on cardiometabolic functions. Post’EVs will also evaluate the capacity of certain bioactive plant microconstituents (mainly polyphenol) to modulate the secretion, content and biological functions of postprandial EVs in humans. To meet these objectives, the project will use human samples from an ongoing randomized controlled nutritional intervention study. It will combine for the first time an innovative EV identification technology with a multi-dimensional and untargeted analysis of EV constituents to provide the most comprehensive characterization of postprandial EV populations and their contents. It will determine the bioactivity of postprandial EVs on different cardiometabolic functions through ex vivo assessments. Finally, the proof of concept that polyphenols can modulate postprandial VEs will be done for hesperidin, the main polyphenol of the orange, which represents one of the 3 most consumed citrus fruits in the world and for which numerous studies show beneficial effects for health in connection with its polyphenol content. The achievement of the Post'EVs project is a need for understanding the role of postprandial EVs in the effects of our diet, and especially the polyphenol component , on our physiology and our health. As a whole, the project will shed new light on the postprandial response and its primary role in the development of cardiometabolic disorders. Beyond the knowledge in nutritional biology, this project will provide useful data on the characterization of EVs necessary in a perspective of the development of EVs as reliable biomarkers in health.

The B-STRONG project aims to provide new weapons in the fight against human muscle atrophy, a major public health problem. Indeed, the loss of muscle is associated with a reduction in the autonomy of patients (sedentary, malnourished, elderly, or suffering from cachexia) and with the development of metabolic inflexibility and insulin resistance. Up to now, no therapeutic or preventive strategy has proven to be fully effective to prevent or cure people suffering from muscle wasting. However, our past studies in the brown bear, a model of natural resistance to muscle atrophy during hibernation, pave the way to new research strategies. Through a bio-inspired approach, B-STRONG proposes to focus on the therapeutic potential of a modulation of the BMP/TGF-beta balance. Although therapies targeting inhibition of the deleterious effects of TGF-beta are numerous, the BMP signalling pathway, inseparable from that of TGF-beta, has been rarely targeted to date. However, our latest results show that maintaining BMP signalling and simulatenous inhibition of TGF-beta signalling are essential features of muscle preservation in hibernating brown bears, as they face atrophic conditions (prolonged physical inactivity and total fasting). We had also previously shown that hibernating bear serum has strong anti-proteolytic activity when applied to human muscle cells in vitro. Therefore, B-STRONG will identify the bear’s serum compounds that are responsible for protecting muscle mass via modulation of the BMP/TGF- beta balance, and it will decipher the signalling pathways involved. First, the molecular signature of the effects of bear serum on human primary myotubes will be established. Genetic and pharmacological strategies will be used to modulate key players in these pathways. In parallel, bear serum will be fractionated and fractions will be screened for their ability to trigger changes in the BMP/TGF-beta balance in cultured human cells. Active bear serum fractions/compounds will thus be identified, and then assessed for their potential to prevent or reverse an induced atrophy using in vitro muscle cell models. The ability of the most promising compound/target to prevent/reverse muscle loss will be explored in vivo in mouse models of induced muscle atrophy. Overall, the project will produce scientific knowledge regarding the regulation of muscle mass and identify active bear serum fractions and/or compounds capable of controlling muscle plasticity. All these aspects will be of major interest to the scientific and medical communities who hope for new levers to fight human muscle atrophy. To achieve these objectives, B-STRONG relies on 2 partners with complementary and internationally recognized expertise in their respective fields, analytical chemistry applied to animal adaptations to the environment and the pathophysiology and molecular mechanisms of muscle atrophy.

To regulate inflammatory response, the host produces two main families of inflammatory mediators that are the cytokines and the oxylipins. These mediators act in concert to initiate the cardinal signs of inflammation and orchestrate its resolution. However, in clinics or in research, oxylipins are largely overlooked and the inflammatory response remains mostly studied only in the context of cytokine production. This considerably underestimates the complexity of the inflammatory response. Consequently, we still have a poor understanding of the mechanisms of dysregulated inflammation and the management of many ICU-related disorders such as the severe complications of COVID-19 disease remains mostly supportive. We hypothesize that the assessing capacity of the host to produce oxylipins in response to an immune insult could provide a potential new tool to better understand and assess dysregulated inflammation and patient heterogeneity. Using highly standardized immunophenotyping tools and a well-defined healthy donor cohort, we will first characterize the healthy oxylipin response and how it is co-regulated in parallel to cytokine responses. We will then study COVID-19 as a proof of concept disease to test our hypothesis. VARIANCE aims at improving the understanding and clinical management of dysregulated inflammation and associated complications. Our investigations will be based on the production of oxylipins by stimulated whole blood (WB) cells used as a proxy to assess host immune responsiveness. The VARIANCE project involves 3 partners (INRAE-UNH; Institut Pasteur-CB UTechS and Institut Pasteur-Translational Immunologie) who gathers complementary and interdisciplinary expertise and skills in biology & biochemistry of oxylipins, immunology & variability of the immune response, cell biology, MS-based lipidomics, epidemiology and biostatistics. It also has outstanding resources including cutting-edge equipments and unique biocollections and data warehouse from three clinical studies (i.e. the Milieu Interieur population study, St James Covid-19 Bioresources and the RADIPEM studies).

The rising pressure on the global market of dietary proteins, combined with the wish to develop more sustainable food systems, pushes agro-industry to diversify their sources of agricultural raw materials. More and more attention is currently given to plant proteins, since plants can be grown in large amounts and in various conditions of culture, and since for many field plants the protein moiety is a co-product of starch or oil-extraction. One of the main limits of their use in human nutrition is the low nutritive value that has been assigned to them, because their composition in indispensable amino acids is often unbalanced with respect to the body requirements, and because their digestibility is generally slightly lower than that of animal proteins. However, by ‘cracking’ plant products and recombining plant proteins from various origins, it should be possible to define blends that display an adequate amino acid composition, and to build food products, with defined structures, ensuring a good amino acid bioavailability, with an optimal kinetics of absorption. These blends would be particularly interesting in the formulation of innovative, high quality foodstuffs, designed for targeted populations (e.g. elderlies, sportsmen) for whom milk proteins is currently the reference. For growing number of plant sources, processes for extraction and fractionation of proteins have been developed at the laboratory scale, and their transposition at the industrial scale is ongoing. Characterizing strategies of valorization of these proteins isolates is now the critical issue. A clear demonstration of the high potential of plant protein blends is currently lacking and it would open doors to agroindustrial innovations, with the development of new innovative products which could be tailored to the specific requirements of targeted populations. With P-Probs we intend to contribute to offer this vision by developing a blend of plant proteins of nutritional quality optimized to reduce the development of sarcopenia (muscle atrophy related to age) and cardiometabolic risk (a set of risk factors, including systemic and vascular inflammation) in the elderly. In this context, three amino acids appear to play a major role: leucine, which stimulates muscle protein synthesis; arginine, which affects vascular endothelial function and potentially modulates the perfusion of nutrients to the muscle; cysteine, which helps to fight oxidative stress by glutathione synthesis. Moreover, in elderlies, the kinetics of amino acid absorption, and thus the protein digestion rate, determines the effectiveness of their use in muscle protein anabolism. Thus, the final objective here will be to produce a food product including a blend of plant proteins, balanced in indispensable amino acids, rich in leucine, arginine and cysteine, and with appropriate digestion kinetics. A long-term preclinical study in rodents will test the effectiveness of the proposed protein blend to sustain muscle mass and alleviate the development of the metabolic deregulations associated with aging. In a last step, a food product based on the optimal mix of protein will be produced at the pilot scale, and tested in two clinical trials for its ability to stimulate postprandial protein anabolism, while reducing postprandial low-grade inflammation and vascular endothelial dysfunction, in elderlies. To achieve its objectives P-Probs will bring together nutrition scientists and two international agro-industrial groups specialized in plant raw material processing, and in food processing. P-Probs project is built as a proof of concept of the interest of plant proteins for the development of high value-added products, but going up to the development of a new food product, based on plant proteins, it will also have direct applications. As such it will pave the way for further innovation in the area of dietary ingredient formulation, and the design of new foods with defined nutritional benefits.