Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, and is characterized by a high mortality of up to 30-40%. Treatment of sepsis was revolutionized by two steps that significantly decreased mortality: antibiotics and the intensive care units. It has been hoped that a third revolution, immunotherapy, would further improve outcome of sepsis, but this hope did not materialize. This was due to the incompletely understood pathophysiology, and the heterogeneity of the immune status in different sepsis patients. We propose that while both overinflammation and immunoparalysis are important, they are present in individual sepsis patients.The mission of the present project is to design and perform a proof-of-concept clinical trial of personalized immunotherapy in sepsis, and within this clinical trial, to develop a next-generation theranostics platform for the design of future personalized immunotherapy trials in sepsis. This theranostics platform would be based on an integrated, multidimensional systems biology analysis of omics-based datasets, to identify biomarkers, clinical endotypes, and therapeutic targets for precision medicine approaches. In order to achieve the mission proposed, several complementary aims will be pursued: Aim 1: To design and perform a large personalized immunotherapy trial in sepsis patients, that can provide a clinical answer towards the usefulness of currently employed immunotherapies for sepsis. Aim 2: To chart host genome, epigenome, transcriptome, metabolome and microbiome in at least 180 sepsis patients enrolled in Aim 1 over a defined time course. Aim 3: To use a theranostics approach based on the data provided by Aim 2 to design novel personalized immunotherapeutic strategies. Aim 4: To integrate the clinical and psychological aspects involved when introducing novel immunotherapies for infections in the health care systems of European countries, building bridges with the patient community.

In Europe, the population is aging. The age-associated decline in cognitive functions represents a serious social and medical problem. Recent studies show that changes in lifestyle such as physical activity and nutritional interventions – even late in life –are beneficial for cognition. The microbiome in the gut is a central effector in the maintenance of brain plasticity and therefore represents a promising target as well as sensor for interventions that aim to improve cognitive ability in the elderly. Detailed and concise scientific investigations of gut-brain interactions, in particular in the elderly, are limited. Such studies require a multidisciplinary approach and a combination of experts from various fields. The aim of our network is to train a new generation of young scientists within a multidisciplinary consortium. The ESRs will engage in individual and well defined, jointly supervised research projects, securing excellent career perspectives and employability. By enabling ESRs to design and conduct studies in this economically and socially important field, SmartAge will elucidate the role of the microbiome-gut-brain axis in aging and its impact on cognition. SmartAge will apply a translational approach combining animal and human studies, nutritional and life style interventions, cognitive tests, brain imaging, cutting edge OMICS and systems biology as well as fecal transfer as proof of principle to identify key regulators of gut-brain communication with the aim to develop microbiome-based therapies. An expert team of scientists from both academia and industry such as clinicians, psychologists, nutritionists, biotechnologists and bioinformaticians will closely collaborate to strengthen microbiome research in aging which will have a direct impact on cognitive health in Europe. Specialists for public communication outreach will ensure effective and efficient transfer of outcomes to policy makers and into the everyday life of the European population.