The future challenge in animal production will be to provide food to a growing human population by respecting a balance between quality products, consumer acceptance and safety, as well as animal welfare. In a perspective of safe and sustainable food systems, reducing the use of antibiotics in livestock is a major concern. In fact, antibiotic resistance is one of the major medical challenges of the 21st century. The transfer of genes conferring resistance through the environment and the food chain, the potential for development of resistant bacteria and the appearance of therapeutic failures in human medicine, notably due to zoonotic bacteria, constitute major health issues for livestock farming sectors. In the pig breeding industry, the weaning period is often accompanied by a decreased growth rate caused by disparate food intake and diarrhoea due to digestive disorders that might be associated with bacterial population disequilibrium (i.e. dysbiosis) and/or opportunistic intestinal infections. Alarmingly, during this transition period the prophylactic use of antibiotics is still very frequent in order to limit piglet morbidity and mortality. Thus, reducing the prophylactic use of antibiotics in weaning pigs is a main issue and there is a strong need for alternatives. In this context, we have built a public-private partnership that gathers INRA scientists and industries from economic sectors of both animal feeding and pig breeding. PigletBiota is a precompetitive project that will study the physiological and genetic bases of the piglet sensitivity at weaning, as a prerequisite to identify innovative actions to adapt animals and pig production systems to a reduction of antibiotic use. The global aim of the PIGLETBIOTA project is to develop research that will contribute to adapt pig production systems to a reduction of antibiotics. The project proposes an integrative biology approach to determine the main factors influencing the variability of the individual’s robustness at weaning. We will monitor piglets for health, immune, stress and zootechnical traits and will characterize the intestinal microbiota diversity and composition as well as the contribution of host’s genotypes. The experimental design will combine various environments, including experimental and commercial farms, and ages at weaning and all animals will be fed without antibiotics. Animals (n~1000) will be clinically surveyed, measured for various traits related to production, immunity and stress, and genotyped with high-density SNP chips. The genetic parameters of the sensitivity at weaning will be estimated and genetic association studies performed. Faecal samples before and after the weaning date will be collected for characterizing the dynamics of the gut microbiota and studying its influence on the individual sensitivity at weaning. Animal and microbiota data will be vertically integrated in order to better understand the interplay between the these two levels of this biological system, and to develop robust indicators of weaning sensitivity. Finally, a functional screening using INRA platforms dedicated to human studies will be performed in order to detect active molecules to be tested in vivo and by using an axenic pigs model. The PigletBiota public-private consortium will favor translational research and innovation.

The severity of the global COVID-19 pandemic poses an urgent need for the development of efficient therapeutic strategies. To complete the available therapeutic arsenal, targeting the SARS-CoV-2 genome by antisense RNA therapy should be deeply investigated. We designed in silico antisense oligonucleotides (ASO) targeting viral genome to block the viral replication and transcription. The objective of the project is to validate the best ASO firstly by in vitro experiments on infected Vero E6 cultures, and secondly to test the best oligonucleotides antisense in vivo on infected animal model to perform a preclinical trial.

The worldwide prevalence of Gestational Diabetes Mellitus (GDM) has increased steadily over the last decade, affecting up to 10.8 % of the pregnancies in France, mainly due to the rising proportion of women with pre-pregnancy overweight, sedentary lifestyle and advanced maternal age at birth. GDM fuels the type 2 diabetes (T2D) epidemic in the next generation. Whether nutritional interventions during critical time windows in early life, such as breastfeeding could mitigate this risk remains to be explored. Indeed, despite emerging evidence of the infant-health benefit of breastfeeding in GDM, there is still a paucity of data concerning GDM-breast milk (BM) composition in regard with consensual key regulators of energy homeostasis and insulin sensitivity. In original studies, GDM-MILK consortium reported adaptations of BM composition in link with maternal diet or physiological status in human cohorts and in a cross-fostering rodent model of programming. Interestingly, in a pilot study conducted on GDM mothers, using comprehensive human BM (HBM) metabolomics/lipidomics analyses, we evidenced a specific GDM-HBM signature. Based on these preliminary data, GDM-MILK plans to (i) achieve the identification and validation of BM bioactive compounds associated with maternal glycaemia in existing human cohorts and integrate compositional and clinical data, (ii) validate the HBM bioactive components in a pre-clinical rodent model of GDM and explore the mechanisms of adaptations of key maternal organs (pancreas-placenta-mammary gland) impacting GDM-milk composition, and (iii) in vivo using cross-fostering, evaluate the functional impact of a cocktail of milk components previously selected by in vitro studies, on the sensitivity/secretion of insulin in the male and female offspring. This project will provide a major breakthrough in the understanding of lactation period as a sustainable intervention that may curb the T2D pandemic in the next generations and also yield the scientific basis for nutritional recommendations for mothers with GDM and their infants. Therefore, GDM-MILK perfectly fits the research axis Translational Health Research.

The aim of the Path2Bos project is to reconstruct the evolutionary path of cattle from its domestication starting about 10,000 years ago in Anatolia, during its later spread into Europe and Africa and up to now, through a paleogenomic analysis of fossils, the direct witnesses of evolution. The goal is to identify genomic regions that were selected at the early stages of domestication, corresponding to basic phenotypes that should be preserved in ongoing genetic selection schemes. The project is based on a previous paleogenetic characterization of a large number (~ 700) of 9,000- to 1,000-year-old archaeological bones of ancient domesticated cattle and their wild ancestors, the aurochs. We have genotyped the mitochondrial genomes and sequenced the hypervariable regions of almost 200 of these ancient bones, allowing us to assign reliably their mitochondrial haplogroups and to follow the evolution of populations from their initial domestication in Anatolia during the Neolithic as well as their spread and evolution in Europe and North Africa until the Middle Ages. Using sequence capture, we obtained complete mitogenomes from 40 of these samples representing the various clades, reconstructed the evolution and timing of radiation of aurochs’ populations, and untangled the impacts on population diversity of both climate changes during the Pleistocene-Holocene transition and initial domestication. We have sequenced the genome of a 9,000-year-old aurochs from the domestication centre in Anatolia that will serve as a reference genome to follow the genomic changes and selective sweeps during the domestication process. We propose to sequence about 30 of these ancient genomes and to compare them with genomes and phenotypic records from modern domestic animals to reconstruct many aspects of the selection pressure exerted during different prehistoric and historic periods. We will also sequence several individuals from modern hardy breeds to generate reference genetic data from breeds that have escaped recent selection schemes or that were selected for alternative phenotypes. Our data will be used in combination with modern genomic data from the 1,000 Bull Genomes consortium in various complementary ways to identify and to date signatures of selection during the cattle domestication process. We will screen for selection events that are either recent or old, complete or ongoing, acting on new variants or on standing variation. Using powerful tools to detect selective sweeps in genomes, ancient genomic data will provide the ability to date the various selection events, to identify the population(s) of origins onto which selection was exerted and to explore the validity of the various demographic models used to detect selective sweeps from modern genomic data. We will also use extensive GWAS data, produced by one of us using modern cattle, to reconstruct the past evolution of complex multigenic traits. Path2Bos will (1) improve the power and accuracy of the identification of genomic regions under selection, (2) estimate the strength of selection and date the origin of the corresponding selective events, (3) identify variants that were selected in the past and that have been lost in modern selection schemes, thereby pinpointing the genetic bases of phenotypic traits that might be useful to preserve for the long-term sustainability of cattle husbandry. Thus, it will provide an original and very useful cattle genome annotation data source to complement the genomic characterization efforts of modern cattle breeds and enrich the current selection strategies. A strong point of Path2Bos is the complementarity of the expertise and resources, including preliminary data, of the consortium partners, in particular paleogenomics and a large collection of characterized archeological samples, involvement in the 1000 Bull Genomes consortium and GWAS, selective sweep method developments and analyses of genomes and a high-throughput sequencing facility.

Chronic Wasting Disease (CWD) is a prion disease that affects wild and farmed cervids. CWD is a highly contagious: over the last 15 years the disease has spread across the whole United States of America and Canada. The CWD epidemics reached a stage where it now threatens the long term survival of cervid populations. Beside the ecological disaster it represents, major concerns exist with regard to the risk that CWD prions might represent for human (zoonosis) and other animal species (propagation in farmed ruminants) During three decades Europe was considered to be free of CWD. However, CWD cases have now been identified in three European countries. The goals of this project are: • to provide the necessary elements for an in depth assessment of the public health risks that are associated with the emergence of CWD prions in Europe. • to identify allele that would be associated with genetic resistance/ susceptibility to the disease in the cervid populations.