How Early Infections Influence Neonatal Gut Development
We spoke with Prof. Dr. Mathias Hornef about the ERC-funded EarlyLife project, which investigates how early-life infections impact the gut epithelium, microbiome, and immune system development in neonates. Using advanced techniques and mouse models, the project aims to uncover the influence of these infections on long-term health and disease susceptibility.
The immediate postnatal period is a critical period for the development and maturation of the immune system. A timed succession of non-redundant phases allow the establishment of mucosal hostmicrobial homeostasis after birth. The enteric microbiota, mucosal immune system, and epithelial barrier are key factors that together facilitate a balanced relationship between the host and microbes in the intestine. The enteric microbiota consists of a diverse community of mainly bacterial microorganisms that colonize the gut. The mucosal immune system represents a defense mechanism that is able to recognize and respond to pathogenic threats while maintaining tolerance to commensal bacteria. The epithelial barrier, formed by a variety of highly specialized cells lining the gut surface, facilitates nutrient digesting and absorption but restricts commensal microorganisms to the gut lumen and prevents enteropathogens from entering sterile host tissues. Early-life infections significantly impact all three components, which may reduce the host’s fitness during the course of the infection and influence the outcome but also lead to long-term consequences.
The ERC-funded EarlyLife project investigates the dynamic changes in the gut epithelium of neonates during early-
life infections. The study seeks to create a comprehensive map of postnatal epithelial cell type differentiation and analyze the impact of early-life bacterial, viral, and parasitic infections on cell differentiation and function. The main long-term goal is to understand how early-life infections influence the development of the epithelium, the immune system, and the establishment of the microbiome, and thereby the risk for inflammatory, immune-mediated, and metabolic diseases later in life.
Uncovering differences in the gut epithelium of neonates
The gut epithelium forms the luminal surface of the intestine and comes into direct contact with the enteric microbiome and potentially pathogenic microorganisms. It is composed of a variety of different cell types with highly specialized function and plays a critical role in maintaining a balance between the host and its microbiota. Traditionally, the gut epithelium was considered to largely represent a passive physical barrier between the sterile host tissue and the microbially colonized gut lumen. However, research during the last decades has shown that epithelial cells actively participate in establishing hostmicrobial homeostasis. Additionally, these
cells trigger an early immune response and communicate intensively with the underlying immune system when the host is exposed to enteropathogenic microorganisms. This interaction is particularly significant in neonates, who transition from a sterile inutero environment to a microbiota-rich external world immediately after birth and mature their tissue and immune system during the postnatal period. Upon birth, neonates undergo rapid colonization by environmental and maternal bacteria. This sudden exposure requires a delicate balance between immune tolerance of beneficial commensal bacteria and activation against potential pathogenic threats. The gut epithelium plays a vital role in this process.
Colonization happens very quickly, reaching adult levels in the small intestine within hours to days. The baby’s body must support and tolerate this rapid bacterial growth. Additionally, neonates are most susceptible to infections during early life, so at the same time, they have to react to infections and try to defeat pathogens. All this happens while they are massively limited by energy supplies because the maternal energy supply via the umbilic cord is suddenly interrupted and they need to establish uptake of breast milk and enteral feeding. The severity of this energetic
bottleneck is illustrated by the fact that neonates often lose weight during the early transition period. This temporal energy deficit may, in turn, explain why neonates react to different to infection.
“Neonates are very different from adults. They are not just small adults; they have unique physiological and immunological needs. Our group works on understanding these differences, particularly in adaptive immune development, infectious diseases, and microbiota establishment, using neonatal infection models in mice. This type of research is difficult in humans because we can’t get tissue samples from healthy newborns” explains Prof. Hornef. His research team aims to understand how neonates are different from adults in terms of energy constraints, tissue maturation, and the balance between immune tolerance and antimicrobial host responses.
“Infections
adult host. Whereas the adult host releases invaded epithelial cells into the gut lumen in a process called exfoliation to prevent pathogen translocation, infected epithelial cells in the neonate are engulfed by neighboring cells and subjected to lysosomal degradation.
Prof. Hornef and his research team are additionally exploring the innate immune recognition in the gut epithelium. Innate immune receptors in the gut help recognize and respond to microbial threats. When these receptors bind to microbes, they trigger the release of immune mediators that recruit immune cells and produce antimicrobial molecules to eliminate invaders. However, uncontrolled activation can lead to inflammation and tissue damage. In the lab, the researchers are studying the molecular basis and regulation of these receptors in intestinal epithelial cells.
in early life not only impact immediate health but can also prime the immune system in ways that affect long-term disease susceptibility.”
“We are addressing the link between infection and the gut epithelium. The gut epithelium consists of several cell types, such as goblet cells, Paneth cells, stem cells, tuft cells, M cells, enteroendocrine cells, and enteroabsorptive cells that fulfill different functions. It has a complex structure with crypts and villi and undergoes continuous proliferation. In neonates, many aspects are different. For example, newborn mice lack certain cell types, like Paneth cells, which produce antimicrobial peptides crucial for maintaining the barrier against microbial exposure. Understanding these differences and how infections impact them is critical” says Prof. Hornef.
The EarlyLife project employs advanced techniques such as single-cell RNA sequencing, spatial transcriptomics, and epigenetic profiling to study the gut epithelium. By using mice models, Dr. Hornef and his team have discovered that the emergence of M cells, that transfer luminal particulate antigen to the Peyer’s patch, the site of immune activation, determines the maturation of the early adaptive immune system. Interestingly, certain microbial stimuli present during infection can accelerate the emergence of M cells and thus lead to earlier immune maturation and immune responses. This may be advantageous during infection but may still come with unwanted consequences in respect to the control of inappropriate responses. Also, they found that the fate of intestinal epithelial cells invaded by the enteropathogen Salmonella differs markedly between the neonate and
EarlyLife
Gut epithelial dynamics and function at the nexus of early life infection and longterm health
Project Objectives
The Long-term Impact of Early Infections
The main question for the EarlyLife project is how early-life infections affect longterm health. Preliminary findings suggest that neonatal infections can have lasting effects on the gut epithelium, microbiome composition, and immune function. This concept is supported by observations in humans. Children in developing countries with frequent infections often exhibit stunted growth and altered immune responses.
“Infections in early life not only impact immediate health but can also prime the immune system in ways that affect long-term disease susceptibility. Understanding these processes is crucial for developing targeted interventions” concludes Prof. Hornef. By translating EarlyLife’s findings from mice models to human health, and identifying key molecular and cellular changes in the neonatal gut epithelium during infections, researchers hope to develop new strategies to prevent and treat infections in newborns and reduce childhood mortality worldwide. This includes potential therapies designed to modulate the gut microbiome and enhance immune responses in vulnerable neonates. Additionally, the project explores the concept of neonatal “priming,” where early life exposures shape immune and epithelial cell functions. These insights could lead to novel approaches for preventing chronic diseases that originate from a dysregulated early immune system maturation.
Infections of the gastrointestinal tract cause significant childhood mortality and morbidity worldwide. EarlyLife aims to map postnatal intestinal epithelial cell and tissue differentiation. It studies age-dependent differences that explain the enhanced susceptibility of the neonate host to infection and investigates the impact of early life infection on long-term gut health. Using advanced analytical methods and innovative models, it explores how early life infections influence enteric function in the neonate host but also immune development and long-term disease susceptibility, focusing on the gut microbiota, mucosal immune system, and epithelial barrier.
Project Funding
This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant agreement No. 101019157).
Project Collaborators
ERC Work Program • Martin von Bergen, Helmholtz Centre for Environmental Research, Germany • Thomas Clavel, RWTH Aachen University, Germany • Ivan Costa, RWTH Aachen University, Germany Research Group • Ivan Costa • Thomas Clavel • Oliver Pabst • Michael Hensel • Martin von Bergen • Geraldine ZimmerBensch • Jochen Hühn • Lars Küpfer • Frank Tacke • Tim Hand • Jens Walter • Marc Burian
Contact Details
Dr. rer. nat. Christin Meier
Administrative Coordinator Universitätsklinikum Aachen (UKA) Pauwelsstraße 30, D 52074 Aachen
T: +49 241 80-37694
E: cmeier@ukaachen.de W: https://www.ukaachen.de/
Mathias Hornef studied medicine in Tübingen, Lübeck, New York, and Lausanne. He has held positions at the Max von Pettenkofer Institute in Munich, the Karolinska Institute in Stockholm, and the University of Freiburg and Hannover Medical School. Now as a director of the Institute of Medical Microbiology at University Hospital RWTH Aachen, his research focuses on interactions between bacteria, viruses, and parasites, the intestinal epithelium and the mucosal immune system in the neonatal host.
