To achieve a more sustainable future for all, there is growing interest in the use of plant-based diets for human nutrition. Recent findings suggest that replacing animal protein-rich foods with plant-based protein sources could be associated with health benefits and successful aging. Aging is associated with a decline in muscle mass and function that leading to adverse health outcomes and poor quality of life. Thus, the quality of dietary protein has a major role in maintaining muscle health in the elderly. Although plant-based diets could have health benefits for elderly, plant proteins are less anabolic than animal-derived proteins. However, plant proteins quality could be improved by combining different plant sources, as legume and cereals, to achieve a more favorable amino acid profile. Moreover, not only protein but also plant food matrix could contribute to maintain muscle health in seniors as dietary fibres or polyunsaturated fatty acids. However, effects of plant-based diet on muscle metabolism in the elderly remain to be studied and clinical studies are needed. The main objective of the present project is to determine how increase in the share of plant foods in the diet impacts skeletal muscle mass, function and protein metabolism, as well as the main metabolic markers in elderly. A clinical study will be conducted to compare the effects of diets containing different proportions of plant foods on skeletal muscle mass and function and protein metabolism in healthy older men and women. Subsequently, omics analyses will identify molecular mechanisms and potential muscle biomarkers that could reflect metabolic changes of skeletal muscle associated to plant-based diet. Thus, our MYOVEG project will provide information about the consequences of a switch towards more plant foods on muscle health in elderly and will participate to recommendations for maintenance of muscle and global health in older men and women.

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.

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.

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 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.