The influence of postnatal infectious challenge on enteric tissue development and epithelial cell differentiation

Schlößer, Stefan; Hornef, Mathias (Thesis advisor); Pradel, Gabriele (Thesis advisor); Zimmer-Bensch, Geraldine Marion (Thesis advisor)

Aachen : RWTH Aachen University (2021)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2021


Infections with enteropathogenic microorganisms remain a major health burden worldwide, especially in neonates and young infants, who exhibit a higher mortality and a more severe disease progression compared to adults. While research in the past has provided a good understanding of the pathogenesis of various pathogenic agents in adults, little is known about the effect of gastrointestinal infection on the antimicrobial host defence and tissue development in the neonatal intestine. In this work, I sought to decipher the influence of enteropathogenic infections on small intestinal tissue development and epithelial cell differentiation during the early postnatal period using the recently established murine neonatal Salmonella Typhimurium (S. Typhimurium) infection model. S. Typhimurium infection on the first day of life was shown to induce drastic changes within the intestinal epithelium. In addition to the previously described increased expression of genes important for epithelial developmental, cell lineage fate and the antimicrobial host response, I found an enhanced proliferative activity and a dysregulated expression of metabolic genes upon perinatal S. Typhimurium challenge. In fact, expression of lactase, an enzyme crucial for postnatal nutrition, was strongly reduced, while expression of metabolic genes typically expressed in older animals (i.e. sucrase isomaltase) was induced in infected neonatal mice. Overall, neonatal epithelial expression level of antimicrobial peptide-related, developmental and metabolic genes (with the exception of lactase) were reminiscent of those observed in more mature animals. Mechanistic investigations using specific knockout animals identified these infection-induced changes to be strongly dependent on immune signalling via the mediator MYD88 in haematopoietic cells. Finally, inflammatory cytokines, such as IL-4, IL-6, IL-13, IL-22 and TNF, known to be produced in vivo upon S. Typhimurium infection, were shown to directly influence the expression of selected target genes using a neonatal small intestinal organoid model. Taken together, my results suggest that a complex interplay of haematopoietic cell-derived cytokines produced upon early postnatal S. Typhimurium infection leads to drastic changes in intestinal epithelial cell proliferation, development and the expression of metabolic genes. This infection-induced phenotype of accelerated tissue maturation shifts the neonatal small intestinal epithelium towards a more adult-like profile. This might add an additional disease burden to the host, for example by the expression of inappropriate metabolic enzymes leading to malnutrition and an aggravated course of the disease. Thus, the results presented in this thesis contribute to a better understanding of the increased severity of enteropathogenic infections in newborns and identify new therapeutic strategies to improve the clinical outcome of infected children in the future.