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).

Obesity/overdrive are a major public health problem that, combined with chronic inflammation, lead to metabolic complications and many pathologies. In addition, it is established that obesity/overweight "maintain themselves", in particular through the installation of this low-grade inflammation. By acting on inflammation, a real effect on weight loss could be promoted. Therefore, the search for innovative bioactives targeting overweight has a dual purpose: preventive (with a health effect) and cosmetic (with a slimming purpose). The joint laboratory will aim to associate, on the one hand, the "Cellular Micro-Environment, Immunomodulation and Nutrition" (ECREIN) - team of the "Human Nutrition Unit" (UNH, UMR 1019) - which focuses scientific expertise on immunocompetent cells (CICs) and the impact of innovative bioactives (plants and probiotics), and on the other hand, the SME GREENTECH SA (Saint-Beauzire), world leader in plant biotechnology. The ambition of this joint laboratory is to develop a new generation of "phyto-probiotics" (i.e. nutraceuticals) with a health effect and/or slimming effect (prevention of pathologies related to chronic low noise inflammation associated with overweight/obesity) by considering the scientific and technological knowledge/skills of the academic and industrial teams. Thanks to ECREIN's strong expertise in biology and GREENTECH/ECREIN's phytochemistry, PHYTOPROB'INOV will be structured around 4 working axis which will allow to: 1. Select plants/bacteria and their bioactives targeting adipocytes and inflammation, 2. Identify molecular and cellular mechanisms for selected plant/bacteria (probiotics)/bioactives of interest, 3. Develop methods to evaluate interactions (including synergies) between selected products in order to develop a new generation of innovative products with a "phyto-probiotic" mode of action that can be used in the context of overweight/obesity associated with an inflammatory condition, 4. Promote innovative products of academic and industrial interest. In the PHYTOPROB’INOV project, we wish to promote as innovative products, on the one hand, plant extracts/bioactives that offer considerable medicinal resources since they are not well investigated chemically/biologically and, on the other hand, probiotics/post-biotics capable of modulating the balance of the intestinal flora. These may have a role to play in the management of overweight/obesity given the complex links between inflammation, overweight/obesity and microbiota. We will identify and select plants/bacteria with individual and potentially synergistic effects, targeting adipocytes and inflammation. In this project, we have chosen to focus on adipocytes (Ad) and their major secretions, which fall strongly within the scope of the ECREIN team, which already has significant experience through previous projects on the selection/evaluation of anti-inflammatory activities for plant actives and probiotics and wishes to strengthen its links with the industrial sector. The creation of this joint laboratory will allow SME GREENTECH to benefit scientific expertise (exploration of CICs in particular) of academic researchers, but also to develop together, different original experimental models and technological innovations necessary for the evaluation of products/bioactives. Labcom PHYTOPROB'INOV will allow the establishment of a sustainable collaborative structure between GREENTECH and ECREIN dedicated to the research and development of innovative "Phyto-probiotics" targeting overweight/obesity and inflammation for health (preventive micronutritional management, as an alternative or associated with drug treatments) and cosmetic (local or systemic effect) purposes.