The gut microbiota plays a key role in pulmonary defense against infection. It can distally, through metabolites and cell wall components, arm immune cells to fight infection. Elderly adults are especially vulnerable to respiratory tract infections. We hypothesize that an alteration in the gut-lung axis - caused by gut dysbiosis - is involved in this high susceptibility. Our research has shown that an old microbiota can remotely transfer susceptibility to respiratory infection. In a murine model, we will first seek to identify microbial candidates and bacterially produced metabolites involved in the age-dependent control of pulmonary defences against bacterial infections (Pneumococcus) and viral infections (influenza). This approach will be based on faecal transfer experiments, microbiota sequencing, metabolomics analyses and biostatistical and correlative analyses. For translational perspectives, potential candidates will be also identified in human samples. In recipient mice, we will determine the mechanisms underlying microbiota-mediated pulmonary immune (dys)function. Later, microbial and metabolite candidates will be used to manipulate the gut microbiota and thus better control respiratory infections in older animals. The GUTSY program is of biomedical importance.

Aging is a progressive physiological decline that predisposes individuals to age-related pathologies such as cardiometabolic diseases, leading causes of death in Europe. Loss of adaptation to various stresses, including metabolic stresses, emerged as both a hallmark and a driver of the aging process. However, the implication of glucocorticoids (GCs)—central players in the response to metabolic stresses—in organismal aging has never been studied, and yet would be critical. Indeed, prolonged exposure to GCs induce age-related cardiometabolic disorders suggesting that GCs contribute to premature aging. GLUCAge aims at characterizing the impact of GCs and the glucocorticoid receptor (GR) on the aging process and healthspan. Especially, GLUCAge will (1) characterize the impact of supraphysiologic GC treatment on the premature aging in Human and on the dysfunction of insulin-sensitive tissues such as the adipose tissue (AT); (2) dissect the pro-senescent signals induced by GC/GR in primary adipose stem cells and fibroblasts deleted or not for the GR and induced to cellular senescence; (3) address how disrupting GR signaling within AT can extend the healthspan and lifespan, paving the way for tailored tissue-specific medicine to improve healthspan. In parallel, the impact of age itself on the resistance to GCs will be studied. To this end, (4) we will establish a mathematical model describing the age-dependent loss in the adaptive response to GCs in order to describe dynamics of activation of GR-downstream targets during cellular senescence in old and young mice. In fine, GLUCAge will help understand not only how GC signaling is affected during the aging process, but also how modulating GC signaling itself may lead to novel therapeutic strategies to delay cardiometabolic disorders and extend healthspan.

Microbes residing in the gastro-intestinal tract (GIT), among which bacteria and their viruses (phages) are the most abundant, are associated to human health. However, little is known about the causes and consequences of alterations of the population of intestinal phages, and in particular the induction of prophages on healthy and inflamed GIT, the latter having strong impact on the metabolism of bile acids. The DynaProGIT project aims to characterize prophage dynamics in healthy and inflamed GIT, including the role of secondary bile acids, and to assess the impact of induced prophages on opportunistic pathogens. DynaProGIT will use an isobiotic murine line (OMM12), in which resident bacteria and prophages can be tracked. This murine model is also permissive to additional bacteria that provide specific metabolic pathways (bile acids modifications), making it as flexible as suitable for these studies. Having shown that two enteric pathogens, Citrobacter rodentium and Clostridiodes difficile colonize the GIT of OMM12 mice and induce a GIT inflammation, we will investigate the putative role of resident prophages in this process. Moreover, we will introduce in OMM12 mice the intestinal bacteria able to produce in the GIT specific secondary bile acids, amongst which we showed that one lowers inflammation in vitro. We will then assess the in vivo impact of bile acids on prophage induction and on the GIT colonization of the two intestinal pathogens. We will particularly focus on the mechanism of the transition step from infection to colonization that is still poorly understood for these pathogens. In addition, we will evaluate the potential of viral transfer to lower GIT inflammation By providing a mechanistic investigation on the dynamics of intestinal prophages, the DynaProGIT project will uncover the role played by these resident viruses in the intestinal microbiota and GIT health.

The OPAID project proposes the development of an original extended microscopy solution for reading blood smears and classifying circulating cells (white blood cells / WBC). The challenge is to overcome the limits of current solutions and avoid any return to manual reading under a microscope. The proposed solution is based on a Fourier ptychography approach which produces an Optical Twin, a digital clone of the specimen that can be manipulated in a computational manner. The images produced are natively multimodal (intensity and phase) and have a resolution that exceeds the limits of conventional optics. The sharpness plane can be chosen a posteriori by calculation. Based on initial preparatory work (TAMIS 2020-2023), the innovation concerns the equipment for data production and processing (UV source, etc.). The perspective aims for a major development for the detection and classification of peripheral blood WBCs on both coloured smears and uncoloured smears (label-free). The validation of the label-free will resolve the stability and survivorship problems of the reagents and will open up the possibility of reusing the slides for other explorations such as Raman spectrometry or immunocytochemistry. Artificial Intelligence tools occupy a central place in the project and are applied both to the reconstruction of the images produced and to the various classification processes. OPAID is supported by a well-established collaborative partnership between teams of biologists (APHP, Sorbonne University) specialists in haematological medical issues, the multi-disciplinary of Télécom SudParis combining mastery of Physical Optics and the exploitation of Artificial Intelligence, both for the reconstruction of computational imagery, the improvement of image quality and classification, and the company TRIBVN which has experience in both the development and deployment of imaging solutions diagnostic microscopy.