Cigarette smoking and unhealthy diet (SCUD) are major behavioral risk factors that contribute to the alarming rise in non-communicable inflammatory diseases. Cigarette smoking is often associated with unhealthy patterns of nutrient intake thus increasing the risk of developing metabolic disorders notably through its impact on intestinal homeostasis. Importantly, obesity and smoking promote inflammatory disorders associated with gut microbiota alteration (referred to as dysbiosis). Among the factors playing a key role in the association between inflammation and dysbiosis are cytokines such as IL-22 and IL-20 subfamily members (IL-19, IL-20, IL-24). IL-22 signals through a IL-22RA1/IL-10RB heterodimeric receptor whereas the IL-20 signaling is dependent of the IL-20RB chain. Although these cytokines share common properties particularly on epithelia, some recent reports and our preliminary datas showed a functional antagonism between IL-22 and the IL-20-related cytokines, particularly during cigarette smoke exposure. Indeed, we showed that the increased susceptibility to respiratory infection resulting from CS exposure is associated with a defect in IL-22 production and is abrogated by treatment with anti-IL-20RB antibodies. To study the consequences of SCUD exposure, we have developed an experimental murine model in which we reproduce the main metabolic and inflammatory features of SCUD exposure found in humans. In this model, we will test the hypothesis that an imbalance between IL-20 and IL-22 is responsible for the inflammatory disorders associated with SCUD through the induction of gut and/or lung microbial dysbiosis. We propose that targeting of the IL-20/IL-22 balance may represent a new preventive/therapeutic approach to prevent the pulmonary, intestinal and metabolic disorders associated with SCUD. For this, TheraSCUD2022 project integrates 3 workpackages (WP) aiming, by multidisciplinary approaches: 1) to describe the role of the IL-20 cytokine subfamily members in the alterations resulting from SCUD; 2) to characterize the IL-20/IL-22 signaling pathways that are involved in these health consequences, by using appropriate deficient (KO) mice and recombinant cytokines; 3) to propose novel therapeutic approaches controlling the IL-20/IL-22 dysbalance and limiting the SCUD-related disorders. For this, both blocking anti-IL-20RB and neutralizing anti-IL-20 antibodies will be used for the treatment of mice exposed to SCUD. By addressing the association between environmental stress and non-communicable chronic inflammatory diseases, TheraSCUD2022 will decipher the mechanisms leading to the development of these major life-threatening pathologies. Our data mining strategies will allow the identification of the factors involved in the combined effects of SCUD (particularly among the IL-22/ IL-20 pathways) and should define biological markers for these diseases. Namely, we will decipher the interplay between IL-20/IL-22 cytokines, microbiota, metabolism and their consequences on SCUD-induced physiopathology. By proposing antibodies blocking the IL-20 pathway, we shall offer new therapeutic interventional strategies in diseases associated with SCUD by restoring microbiota and immune homeostasis. In summary, our project is dedicated to greatly improve our knowledge about the consequences of SCUD exposure, the physiopathological mechanisms involved, to define markers for the incoming or the progression of SCUD-related diseases and to propose therapeutic strategy. Altogether our project well respond to the Axis 3 of the challenge 4 and also concerns some aspects of the axis 6 (microbiota) and 13 (One Health). By its originality and its potential impact for socio-economically disadvantaged populations, TheraSCUD2022 should lead to major scientific, economic and social outcomes.

As the third most large crop production, wheat has a huge economic importance. It is also a major contributor to the human diet providing about 20% of the total energy and 22% of the total protein. Wheat-based food consists of various processed products. Processing is possible thanks to the viscoelastic properties of the dough due to the gluten network, which is formed by storage proteins (glutenin and gliadin) mixed with water. While gluten is necessary for processing, it also triggers gluten-related disorders, which encompass allergy, coeliac disease and non-coeliac gluten sensitivity (NCGS). NCGS is badly characterized and difficult to objectively diagnose, as no clinical biomarker is available. Over the past decade, NCGS is more and more self-diagnosed, which makes the gluten-free diet more frequent, without objective clinical criteria. Thus, it opens a societal debate on the relevance of gluten-free diets for people without coeliac disease or wheat allergy. In addition, gluten avoidance hardly impacts the wheat sector. In this context, the GlutN project aims at deciphering some mechanisms able to cause NCGS, postulating its prevalence, and identifying clinical biomarkers to facilitate its diagnosis. As bread is the main form of gluten ingestion, GlutN will propose processes to bake specific breads adapted to NCGS patients. The underlying hypothesis is that NCGS may be triggered by strong interactions between protein and starch making a gluten-starch complex, which could be resistant to digestion. Thus, starch and storage protein, being the major components of wheat grain, will both be considered, as they constitute in bread a compact matrix with starch granules entrapped in a protein network. To reach the objectives, GlutN is based on an translational multidisciplinary approach from plants to patients. Besides the management task, GlutN is structured in six operative tasks. First, gluten-free consumers will be profiled in an overall approach (sociodemographic, dietary patterns, health status and motives) thanks to an epidemiological study. Then, tasks 2 to 4 will help to relate the structuration of the gluten/starch matrix in bread to document: - the diversity of gluten/starch-related genes, gluten composition and starch features, which will be analyzed in a set of 75 lines comprising old and modern cultivars (Task 2). Based on their genotypic and phenotypic data, 10 lines will be selected. - the baking processes (Task 3). The 10 lines will be transformed using three different baking processes. For each bread, the structure of the gluten/starch complex will be analyzed by microscopy and NMR technics. Breads will be evaluated by sensory analysis to identify those having a better hedonic value and those expected to be selected for commercial development. Five kinds of breads with different structure of the gluten/starch matrix will be selected. - the in-vitro digestibility from the mouth (mastication) to the gut (Task 4) of the five breads. The two most digestible breads will be selected. Task 5 is a clinical trial on NCGS patients (diagnosis based on history, clinical symptoms and clinical response to a gluten-free diet).They will be included in a randomized double-blind cross over study with periods of diet containing or not gluten. Biological samples will be analyzed by metabolomics to identify specific biomarkers. Finally, NCGS patients will be submitted to two “new” breads to evaluate their clinical and biological tolerance. As gluten became a societal issue, Task 6 will be dedicated to communication and dissemination. The results of the project will be disseminated to the cereal, bakery and health sectors as well as the general population by press release. In conclusion, GlutN is expected to have fundamental insights (NCGS basis), economic (NCGS clinical biomarkers for objectifying the diagnosis, specific wheat cultivars/breads), and societal insights (dissemination to help consumers and stakeholders).

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.