NOSE study cohort
Premature infants are highly susceptible to viral infections in early life, which is associated with higher
morbidity and mortality. Although established preventive measures such as passive and active
immunization are available, the majority of respiratory illnesses in premature infants are caused by viruses
(e.g. rhinovirus, metapneumovirus) with non-existing preventive strategies. Recently, the nasal microbiome
of healthy term-newborns has been linked to the severity of viral respiratory illnesses, accompanied by
heightened risk for asthma development. However, systemic data from premature infants is currently
missing, but novel prophylactic and therapeutic options are urgently needed in this high-risk patient cohort.
Establishing the NOSE cohort study (Nasal Cross-Omics Signatures to Decipher Viral Susceptibility in Early
Childhood), the overarching aim of this study is to decipher host-virus-microbiome-interactions in the nasal
airway of premature infants unraveling so-far unknown mechanisms of viral susceptibility leading to novel
treatment options. These goals will be achieved via holistic and integrative systems-biology-based
approaches incorporating state-of-the-art cross-omics and modern cell culture techniques. Therefore,
combating viral susceptibility with this precision medicine approach opens up the opportunity to improve the
long-term outcome and quality of life of premature infants.
The premature gut microbiome and the influence on neonatal immunity, brain development and white matter injury study
Recent advances in neonatal intensive care have dramatically increased the survival rate of extremely premature infants but the number of survivors with severe morbidity and lifelong neurodevelopmental impairment remains high. Perinatal white matter injury is the predominant form of brain injury in premature infants, often leading to adverse outcome. Hypoxic-ischemic events as well as intrauterine and neonatal infection and inflammation have been identified as major risk factors of neonatal brain injury. The fragile gut microbiome of premature infants seems to play an important role in health and disease as distortions of the microbiome occur prior to sepsis and necrotizing enterocolitis. Furthermore, the close link of the gut microbiome to psychiatric and neurological diseases suggests that the microbiome may even influence infant development. Recent studies have underlined the importance of regulatory T cells as well as γδ T cells in brain injury, which can be directly influenced by the gut microbiome. It is therefore likely that an underdeveloped or distorted gut microbiome affects host immune response and may be a risk factor for neurodevelopmental disabilities in extremely premature infants. Therefore, the overarching aim of the PreMiBraIn study is to elucidate the role of the gut-immune-brain axis on neonatal brain injury and its impact on long-term neurodevelopmental outcome of extremely premature infants. This goal will be achieved by state-of-the-art techniques using 16s rRNA gene sequencing of the gut microbiome, holistic analysis of T cell biology using flow cytometry, whole transcriptome analysis and proteomics as well as neurophysiological measurements (aEEG, NIRS, VEP) and cranial MRI of extremely premature infants. Short- and long-term neurological outcome will be investigated using Bayley Scales of Infant Development, Third Edition (BSID-III) at one and two years corrected age, and Kaufmann-Assessment Battery for Children (K-ABC) at five years of age. The prospects of precision medicine targeting the gut-immune-brain axis in extremely premature infants hold the opportunity to improve the overall outcome of these high-risk patients.
Trained immunity mechanisms seems to positively influence the immune response against important bacterial antigens. Thus, we aim to investigate trained immunity in extreme premature and term infants to unravel novel mechanisms in infection control in this high-risk patient cohort.
A main mechanism of action proposed for probiotics is immunomodulation, which is expected to impart health benefits in the host by influencing immune and inflammatory factors. Consequently, host immunity can be positively modulated by the symbiotic relationship between microbiota and host immunity. To date, research supporting the use of probiotics in healthy adults has been limited and inconsistent. Additionally, data concerning immunological mechanisms and reproducible positive effects on probiotic supplementation of especially multi-strain formulations in a large healthy cohort is currently missing. For this reason, the aim of this study is to explore the potential effects of probiotic supplementation on immune responses as well as the gut microbial composition and metabolic activity of healthy adult volunteers. The study will be conducted as patient-blinded, placebo-controlled, randomized trial involving three different study arms: ProPrems® (3-strain Probiotic), 2-strain Probiotic with Lactobacillus acidophilus & Bifidobacterium lactis, and placebo (maltodextrin). Each study arm consists of 30 patients with an equal distribution of gender. Overall, the participants are enrolled over a study period of 36 weeks consisting of four different phases: PRE-Phase (observational period of 8 weeks), PRO-Phase (intervention period of 8 weeks), POST-Phase (observational period of 8 weeks), and LATE-Phase (control visit 12 weeks after POST-Phase). Blood, urine, and stool samples will be collected at 6 different timepoints (0, 8, 12, 16, 24, 36 weeks) and analyzed for selected immune responses as well as gut microbial composition and metabolic activity. This will be achieved by investigating serum immunoglobulins, blood immune cell populations, and the production of inflammatory markers by whole blood cultures. To decipher relevant microbial effects, metagenomic and metabolomic analysis will be conducted. Additionally, fecal water analysis and T cell co-culture systems will be used to identify direct microbial and metabolic effects on host immune cells. Gut microbiome data will be evaluated at gene, pathway, taxonomic, and diversity levels and analyzed together with clinical, immunological, and metabolomic data generated in the project.