title: Mode of delivery shapes gut colonization pattern and modulates regulatory immunity in mice.
abstract: Delivery mode has been associated with long-term changes in gut microbiota composition and more recently also with changes in the immune system. This has further been suggested to link Cesarean section (C-section) with an increased risk for development of immune-mediated diseases such as type 1 diabetes. In this study, we demonstrate that both C-section and cross-fostering with a genetically distinct strain influence the gut microbiota composition and immune key markers in mice. Gut microbiota profiling by denaturing gradient gel electrophoresis and 454/FLX-based 16S rRNA gene amplicon sequencing revealed that mice born by C-section had a distinct bacterial profile at weaning characterized by higher abundance of Bacteroides and Lachnospiraceae, and less Rikenellaceae and Ruminococcus. No clustering according to delivery method as determined by principal component analysis of denaturing gradient gel electrophoresis profiles was evident in adult mice. However, the adult C-section-born mice had lower proportions of Foxp3(+) regulatory T cells, tolerogenic CD103(+) dendritic cells, and less Il10 gene expression in mesenteric lymph nodes and spleens. This demonstrates long-term systemic effect on the regulatory immune system that was also evident in NOD mice, a model of type 1 diabetes, born by C-section. However, no effect of delivery mode was seen on diabetes incidence or insulitis development. In conclusion, the first exposure to microorganisms seems to be crucial for the early life gut microbiota and priming of regulatory immune system in mice, and mode of delivery strongly influences this.
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg C, Denmark; camfriis@sund.ku.dk.
authors.forename: Camilla H F
authors.initials: CH
authors.lastname: Hansen
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg C, Denmark;
authors.forename: Line S F
authors.initials: LS
authors.lastname: Andersen
authors.affiliation: Department of Food Science, Faculty of Science, University of Copenhagen, 1958 Frederiksberg C, Denmark;
authors.forename: Lukasz
authors.initials: L
authors.lastname: Krych
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg C, Denmark;
authors.forename: Stine B
authors.initials: SB
authors.lastname: Metzdorff
authors.affiliation: Department of Pathology, Rigshospitalet, 2100 Copenhagen, Denmark;
authors.forename: Jane P
authors.initials: JP
authors.lastname: Hasselby
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg C, Denmark;
authors.forename: Søren
authors.initials: S
authors.lastname: Skov
authors.affiliation: Department of Food Science, Faculty of Science, University of Copenhagen, 1958 Frederiksberg C, Denmark;
authors.forename: Dennis S
authors.initials: DS
authors.lastname: Nielsen
authors.affiliation: Bartholin Institute, Rigshospitalet, 2100 Copenhagen, Denmark;
authors.forename: Karsten
authors.initials: K
authors.lastname: Buschard
authors.affiliation: Department of Biology, Faculty of Science, University of Copenhagen, 1307 Copenhagen, Denmark; and Department of Environmental Science, Faculty of Science and Technology, Aarhus University, 4000 Roskilde, Denmark.
authors.forename: Lars H
authors.initials: LH
authors.lastname: Hansen
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg C, Denmark;
authors.forename: Axel K
authors.initials: AK
authors.lastname: Hansen
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001439:Bacteroides / Q000276:immunology / Q000302:isolation & purification; D002585:Cesarean Section / Q000379:methods; D003013:Clostridium / Q000276:immunology / Q000302:isolation & purification; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D005260:Female; D007422:Intestines / Q000166:cytology / Q000276:immunology* / Q000382:microbiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D064307:Microbiota / Q000276:immunology*; D009092:Mucous Membrane / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D045857:Ruminococcus / Q000276:immunology / Q000302:isolation & purification; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000382:microbiology*