Which influence do intestinal bacteria have on the early development of the immune system and thus on susceptibility to infection?
What is this research project about?
Click to enlarge!
What is this research project about?
Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. The most important threats are infections. About a quarter of all infants born < 32 weeks of gestation develop a serious infection during infancy. Our knowledge is fragmented regarding how immune programming at preterm birth differs from that of term infants and adults. There is increasing evidence that the developing gut microbiome is both an important source
of postnatal microbial challenges and a critical site of postnatal maturation of the immune system. In humans detailed information is not yet available on how age-related programming and microbiota-dependent imprinting influence the individual’s immune status and life-long susceptibility towards infectious diseases.
What’s the current status?
Currently, we cannot predict what baby is at heightened risk of infections. This diagnostic dilemma frequently leads to a preemptive exposure of preterm newborn infants to antibiotics. We neither know what immunomodulatory strategy could aid in immune maturation and prevent severe infections. Epidemiologic and animal studies suggest that reciprocal host-microbiota interactions particularly at the neonatal phase are crucial for the postnatal maturation of the immune system and development of life-long immune homeostasis. However, the host factors and the specific combination of commensal bacteria that are required for promoting host resistance and immune-mediated protection remain largely elusive.
How do we get there?
In the recent past, RG Viemann and RG Hansen contributed to the paradigm shift that a specific inflammatory programming of systemic innate immunity at birth does not reflect infection but actually is a protective S100-alarmin-mediated state (Austermann et al., 2014; Heinemann et al., 2017; Ulas et al., 2017; Pirr et al., 2017; Bickes et al., 2019). Therefore, traditionally used biomarkers and risk criteria need to be scrutinized when evaluating preterm infants. Moreover, RG Viemann and others showed in preterm babies that gut dysbiosis precedes late-onset sepsis and necrotizing enterocolitis (Graspeuntner et al., 2018). RG Hühn demonstrated that the neonatal phase is critical for the stable imprinting of tolerogenic properties in mesenteric lymph node stromal cells by microbiota (Pezoldt et al. 2018). RG Strowig focused on the composition of microbiota and revealed that specific microbial communities can initiate inflammation and modulate the host’s ability to produce anti-bacterial effector cytokines (Thiemann et al., 2017; Roy et al., 2017). Within RESIST we combine our expertise and jointly continue the work on how the newly developing microbiota in preterm infants contributes to the age-dependent programming of innate and adaptive immunity and related susceptibility towards sepsis and respiratory infections. For this purpose we use amongst others data from the “Priming Immunity at the beginning of Life” (PRIMAL) cohort.
Large amounts of S100 alarmines are produced in the intestine of the healthy newborn. These prevent excessive inflammatory reactions when the newborn adapts to the new environment and promote the development of a healthy intestinal microbiome. (Click to enlarge!)
