The conference discussed the concept of a "neonatal window of opportunity", a critical time frame in the newborn life, during which of environmental factors exert a lasting effect on the host determining the susceptibility to allergies and certain lifestyle diseases in adult life.
Birth is undoubtedly the first most dramatic experience in life. When the neonate leaves the protective environment of the mother's womb for the first time it faces direct exposure to the external microbial environment. Increasingly, scientific evidence reveals that the neonatal organism is particularly susceptible to environmental influences. More importantly, they appear to exert a lasting influence that sets the course for the organism's susceptibility to diseases later in life. "The investigation of the time window of enhanced susceptibility, the underlying molecular mechanisms and primed effector functions could therefore be the key to understanding how long-term negative health consequences can be prevented at an early stage," said Henrike Hartmann, Head of Funding at the Volkswagen Foundation in her introduction.
John Penders (Maastricht University, The Netherlands) highlighted a number of actors including antibiotic treatment that influence the establishment of a diverse community of commensal bacteria in the neonate's body. He also pointed out that influences during birth, such as delivery by cesarian section, can delay the establishment of a stable and diverse bacterial community in the new-born.
A mother's womb is thought to be a sterile environment. However, Kathy McCoy (University of Bern, Switzerland) demonstrated that the immune sys-tem of young mice is affected by the maternal microbiota: Compared to mice born to microbe-free mothers, pups born to mothers that had been colonized only during pregnancy harboured more innate lymphoid and mononuclear cells in their intestines. When mice born to microbe-free mothers were colonized later in life they showed an increased inflammatory response compared to mice that were born from gestationally colonized mothers, suggesting that exposure to molecules originating from the maternal microbiota helps to prepare the new-born to face colonization with its own microbiota.
Benjamin Marsland (University Hospital of Lausanne, Switzerland) made similar observations when challenging the immune tolerance of neonatal mice. He was able to demonstrate that germ-free mice elicit a strong allergic reaction towards house dust mite allergens, while neonatal mice colonized with bacteria tolerated this immune challenge. "Colonizing previously germ-free mice as adults didn't change their susceptibility which indicates a critical phase in the neonate in which an immune tolerance can be established," Marsland concluded.
During weaning, the immune system has to learn to tolerate food-derived antigens. Agnes Wold (University of Gothenburg, Sweden) presented research data suggesting that early oral contact to food allergens can prevent children from developing hypersensitivity against these proteins. In contrast, Valerie Verhasselt (University of Nice-Sophia Antipolis, France) showed that neonatal oral exposure to certain allergens present in breastmilk such as allergen from house dust mites can increase the risk for development of hypersensitivity in later life.
Erika von Mutius (Dr. von Hauner Children's Hospital, Ludwig Maximilians University Munich, Germany) presented epidemiological studies showing a strong correlation between early exposure to microbes and reduced risk of asthma and allergies later in life. Comparing children who grew up on a farm with those living in rural, but not farming environments shows that contact with farm animals in the barn and the consumption of unprocessed cow's milk significantly protects against asthma and allergies later in life.
"Asthma should be regarded as a developmental disease," Harald Renz (University of Marburg, Germany) concluded. This illustrates the role of microbial exposition in the training of a lifelong immune tolerance. Renz also pointed out that the diversity and duration of microbial exposure early in life is important for the development of an immune function.
Despite growing evidence that the maturation of immune function is an important step early in life, the underlying mechanisms shaping this event still remain unclear. Several speakers presented unpublished data that provide new insights into the molecular processes that set the scene for immune function early in life.
Richard Blumberg (Harvard University, USA) illustrated that natural killer T cells (NKT cells) regulate the microbiota and at the same time are regulated by them. This regulation of NKT cells by the microbiota was shown by his group, using germ-free mice, to occur at a critical time period of early life when the microbiota determine the influx and proliferation of these immune cells. In the absence of this early life regulation by the microbiota, Richard Blumberg showed that NKT cells accumulate in certain mucosal tissues such as the colon and are hypersensitive to newly described environmental triggers. Exposure to these agents might disturb the crosstalk between the microbiota and epithelial cells which in turn could influence the integrity of the intestinal barrier, Blumberg concluded.
Duane Wesemann (Harvard University, Brigham and Womens's Hospital, USA) showed that symbiotic bacteria control the selection processes that determine the antibody repertoire of naive B cells in neonatal mice. Interestingly, this training event appears to be particularly influential during a narrow window of opportunity after birth as commensal bacteria exposure of adult germ-free mice showed no effect on the positive selection events that appear to be active in weaning mice. Donna Farber (Columbia University Medical Center, USA) highlighted the role of tissue specific memory T-cells as mediators of protective immunity. Her analysis of human tissue from organ donors revealed that T-cells do not mediate their responses through rapid migration and surveillance through tissues but instead are established as non-circulating memory T cells that are resident in tissue sites.
After birth, every organism has to resolve a trade-off: It has to allow the establishment of a symbiotic microbiota while avoiding the entrance of pathogens at the same time. "The striking susceptibility yet resilience of human neonates towards infectious disease might illustrate this narrow trade-off period," Peter Ghazal (The University of Edinburgh, Scotland) summarized. Becky Adkins (University of Miami, USA) demonstrated that cytotoxic T cells also appear to contribute to protective immunity against certain extracellular bacteria in neonates. In contrast, adaptive immune responses to other extracellular bacteria are poor, leading to exquisite susceptibility of infant mice to these pathogens. Current data indicate that a strong, early antimicrobial innate response may rapidly eliminate the bacteria and, therefore, adaptive immunity fails to develop.
Jeffrey Weiser (New York University School of Medicine, USA) looked at the bacterium Streptococcus pneumoniae, a leading cause of acquired respiratory diseases. He demonstrated how acquisition of this pathogen follows from the acquisition of very few organisms that quickly proliferate and dominate the niche in the upper respiratory tract. This work provides a paradigm for understanding the initial establishment of the colonizing microbiota in new-borns.
Mathias Hornef (RWTH Aachen University, Germany) demonstrated using in vivo models that the low expression of the innate immune receptor toll-like receptor (Tlr)3 in the neonates intestinal epithelium is responsible for the enhanced susceptibility of the neonate to viral infection. He also showed that age-dependent epithelial innate immune receptor expression provides a time window to influence the enteric microbial composition with lasting effects into adulthood. "This also illustrates that the host is actively influencing the establishment of the enteric microbiota," Hornef concludes.
This is underlined by David Hackam's (Johns Hopkins Children's Center, Baltimore, USA) research data. In mice, Hackam could show that the toll-like receptor (Tlr) 4 acts like a "switch", which detects bacteria in the intestine and then releases chemicals to call the immune system to attack. This "switcher" could play a crucial role in the establishment of the microbiome in neonatal mice, according to Hackam. "Directly after birth, Tlr4 is down-regulated, suggesting a window of opportunity in neonatal life where the presence of bacteria doesn't activate this switch." Xin Sun (University of Wisconsin-Madison, USA) emphasized the function of pulmonary neuroendocrine cells (PNECs). She demonstrated that these cells act like sensors in the epithelial layer of the lungs of neonate mice where they regulate the immune response by releasing neuropeptides into the bloodstream.
During the conference, 30 young scholars were given the opportunity to present their research projects in short Lightning Talks and poster sessions. Martijn van Herwijnen's (Utrecht University, The Netherlands) presentation about "the influence of milk-derived extracellular vesicles on immunity and barrier function" captured the audience. He did not only win the first price for the best Lightning Talk but also for the best poster.
"I think the conference illustrate the nature of a neonatal window of opportunity in early life", Mathias Hornef concluded at the end of the conference. He pointed out that current research data suggest that there might actually exist several different priming periods that affect the host organism's maturation and determine the susceptibility towards certain diseases throughout life. Harald Renz highlighted the importance of further research on the underlying mechanisms. "Most knowledge is based on animal models and it is therefore important to concentrate on translational science to be able to give answers to interventional questions."
All academic titles have been omitted.
Christine Westerhaus, Science reporter
Volkswagen Foundation in collaboration with Prof. Mathias Hornef, Uniklinik RWTH Aachen, Germany, and Prof. Harald Renz, Universitätsklinikum Gießen und Marburg (UKGM), Germany
Speakers and Chairs
Rebecca Adkins, University of Miami, USA, Richard Blumberg, Harvard University, USA, Donna Faber, Columbia University Medical Center, USA, Johan Garssen, University of Utrecht, Netherlands, Peter Ghazal, The University of Edinburgh, Scotland, David Hackam, Johns Hopkins Children's Center Baltimore, USA, Gesine Hansen, Hannover Medical School, Germany, Mathias Hornef, Uniklinik RWTH Aachen, Germany, Arnaud Marchant, Université libre de Bruxelles, Belgium, Benjamin Marsland, University Hospital of Lausanne, Switzerland, Kathy McCoy, University of Bern, Switzerland, John Penders, Maastricht University, Netherlands, Immo Prinz, Hannover Medical School, Germany, Harald Renz, Universitätsklinikum Gießen und Marburg (UKGM), Germany, Xin Sun, University of California, USA, Sina Bartfeld, University of Würzburg, Germany, Valérie Verhasselt, University of Nice-Sophia Antipolis, France, Erika von Mutius, Ludwig-Maximilians-University (LMU) Munich, Germany, Jeffrey Weiser, University of Pennsylvania, USA, Duane Wesemann, Harvard University, USA, Agnes Wold, University of Gothenburg, Sweden