Background and current state of research
The mammalian intestinal tract is colonized by an indigenous diverse microbial community that remains highly stable throughout the individual’s life. Over 1000 different bacterial species are estimated to be present in the human gastrointestinal tract1, with a density of 1011 bacterial cells per gram wet weight in the distal large bowel contents, outnumbering eukaryotic cells by an order of magnitude. The “normal” intestinal microflora represents a complex equilibrium of microbial populations and builds the first line of defense against enteric pathogenic infections and toxic or otherwise noxious agents (e.g. from food)2. It is becoming increasingly clear that the close symbiotic relationship between hosts and a resilient microbiota is a vital part of the homeostasis of intestinal physiology. The microbial communities are crucially involved in diverse processes such as the production of short chain fatty acids, metabolism of nutrients and organic substrates, the development of intestinal epithelium, protection against foreign pathogens and importantly, the maturation and development of the immune system3,4 Intestinal infections, such as acute infectious diarrhea, or antibiotic treatment are typical conditions leading to “dysbiosis”, a state characterized by the destruction of the sensitive intestinal microbial balance. Physiologically, the gut microflora shows a tendency to self-regeneration (so-called resilience phenomenon) resulting in a more or less exact reconstitution of the microbial composition observable before the dysbiosis event5.
The stable host-microbe association of an individual is established during the first months of life. The transition from a sterile prenatal intestine to the adult gut – harboring region-specific complex microbial communities – is accompanied by a distinct change in host cellular responses and programs. The transition is influenced by both host genetic factors and environmental influences (e.g. vertical and horizontal transmission). We hypothesize that epigenetic marks (i.e. DNA methylation and histone modification) are important biological master switches that contribute to the stability of the physiological host-flora association6.
The selected doctoral researcher will build a genome-wide map of the dynamic epigenetic marks (DNA methylation, selected histone marks) during the establishment of the stable host-microbe association in the murine gut. S/He will further assess the stability of selected marks during experimental dysbiosis events. Finally, the doctoral researcher will address the functional relevance of epigenetic events on the development of the murine intestinal microflora using cellular and molecular methodologies.
 Eckburg PB, et al. (2005) Diversity of the human intestinal microbial flora. Science 308(5728):1635-1638.
 Flint HJ, et al. (2007) Interactions and competition within the microbial community of the human colon: links between diet and health. Environ Microbiol 9(5):1101-1111.
 Round JL & Mazmanian SK (2009) The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 9(5):313-323.
 Tatsuo H, Rosenstiel P et al. (2012) ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature in press
 Hooper LV & Gordon JI (2001) Commensal host-bacterial relationships in the gut. Science 292(5519):1115-1118.
 Häsler, R., Rosenstiel P et al. A functional methylome map of ulcerative colitis. Genome Research in press
 Franke, A. et al. (2010) Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nature genetics 42:1118-25. Link.