Fetal microbiome and exosomes, developing immune system and health in children

Project Leader

Terhi Tapiainen, M.D., Ph.D., Docent, Pediatrician, Pediatric Infectious Diseases Specialist
E-mail: terhi.tapiainen (at) oulu.fi

Affiliation

Department of Children and Adolescents, Oulu University Hospital, PEDEGO Research Unit, and Biocenter Oulu, University of Oulu, Finland

Mailing address

P.O. Box 5000, PEDEGO Research Unit, Department of Children and Adolescents, FIN-90014 University of Oulu, Finland

Street address

Department of Children and Adolescents, Kajaanintie 50, 90220 Oulu

About the project

We aim to find a link between maternal living environment, fetal microbiome, the development of immune system and subsequent allergic and autoimmune diseases in childhood using a cohort of 500 newborn infants with samples from the first stool after birth, amniotic fluid and placenta. We start collecting samples already at delivery room and follow up the children until the age of three years. Our idea is that the microbiome of the first stool, amniotic fluid, and placenta reflects the fetal microbiome, which modifies developing immune system during pregnancy and affect subsequent health in children.

Our projects relates to the recent paradigm shift: Fetus is not sterile. Culture-independent methods, such as next generation sequencing of bacterial 16S rDNA have shown bacterial DNA of various bacterial species present in amniotic fluid and umbilical cord. Microbiome of human placenta has been shown to consist of immunologically active and beneficial bacteria such as Lactobacilli and Bifidobacteria. The first stool after birth contains many different species of commensal bacteria in several small studies of hospitalized preterm infants. Maternal bacteria may thus colonize fetal gut before birth.  In animal studies, intestinal colonization can induce significant changes on developing immune system. Commensal microbes and their metabolites can induce T regulatory cells needed for mucosal tolerance. Fetus is immunologically active in utero. For example, T-cells, including CD4 and CD8 T cells are present in the fetal ileum by the end of the first trimester, 12 weeks of gestational age. Interestingly, in humans, the numbers of maternal mononuclear cells that harbor whole bacteria or bacterial antigens are frequently detected during pregnancy.

We have previously shown the diverse microbiome in a population-based cohort of 212 newborn infants using their first-pass meconium. The microbiome of the first stool, characterized using bacterial 16S gene sequencing, was not affected by the delivery mode or the sampling time (Tapiainen T. et al. 2018). Interestingly, the biodiversity of maternal living environment during pregnancy and maternal antibiotics changed the microbiome of the first stool implying that the first stool reflects the maternal influence on the fetal microbiome during pregnancy before birth.

Our hypothesis is that materno-fetal microbial contacts are crucial in the development of immune system during pregnancy and subsequent health of children. Specifically, materno-fetal microbial contacts could be mediated by either whole viable bacterial, or alternatively, by bacterial exosomes that are able to cross biological barriers and release their cargo of bacterial DNA, RNA and proteins in the fetus via amniotic fluid that fetus drinks during normal pregnancy.

We will first characterize the fetal microbiome in placenta, amniotic fluid, and the first stool including 16S next generation sequencing and metagenomics including whole bacterial genome sequencing and transcriptomics. Furthermore, we will evaluate the maternal influence on the fetal microbiome and will analyze immunological properties of cord blood in relation to fetal microbiome. In the clinical arm of the research project, we will follow up children and their health using web-based questionnaires and by reviewing both medical records and obtaining data from national registries at the age of 6 months, 18 months, and 36 months.

Selected Publications

Tapiainen T, Paalanne N, Tejesvi MV et al. Maternal influence on the fetal microbiome in a population-based study of the first-pass meconium. Pediatr Res 2018.

Tapiainen T, Ylitalo S, Eerola E, Uhari M. Dynamics of gut colonization and source of intestinal flora in healthy newborn infants. APMIS 2006.

Tapiainen T, Aittoniemi J, Immonen J et al. Finnish guidelines for the treatment of laryngitis, wheezing bronchitis and bronchiolitis in children. Acta Paediatr 2016.

Dunder T, Tapiainen T, Pokka T, Uhari M. Infections in child day care centers and later development of asthma, allergic rhinitis, and atopic dermatitis: prospective follow-up survey 12 years after controlled randomized hygiene intervention. Arch Pediatr Adolesc Med 2007.

Tapiainen T, Dunder T, Mottonen M, Pokka T, Uhari M. Adolescents with asthma or atopic eczema have more febrile days in early childhood: a possible explanation for the connection between paracetamol and asthma? J Allergy Clin Immunol 2010.

Research Group Members

Docent Justus Reunanen Group, Biocenter Oulu, will perform exosome studies for the project.

Niko Paalanne, MD, PhD, Pediatrician, Resident in Pediatric Infectious Diseases, Post-doc Investigator. Responsible for the clinical arm of the study.

Katja Korpela, Medical student (MD graduation in 2018), PhD student in the project. Responsible for the clinical microbiome papers based on the first cohort (212 newborns).

Tytti Pokka, B.Sc., Biostatistician. Responsible for data set and conversions and multi-modeling.

Leena Okkonen, Master’s degree in Public Health, Registered nurse. Responsible for recruiting the families and sample flow from delivery rooms and wards until storage.

Mysore Tejesvi, PhD, Docent. Responsible for the performance of 16SrRNA analyses, bioinformatics, PiCRUST analysis, metagenomics and quality of work in the research laboratory.

Anna Maria Pirttilä, PhD, Docent, Adjunct Professor. Responsible of supervising and planning microbiome analyses.

Virpi Glumoff, PhD, Docent, Adjunct Professor of Microbiology and Immunology. Responsible for clinical immunological laboratory at University of Oulu. Expertise in flow cytometry, inflammation, and innate immunity.

International Collaborators

Karen E. Nelson, PhD. President of the J. Craig Venter Institute (JCVI), Rockville, Maryland and La Jolla, California, USA.

Lauren Brinkac (Leone), Staff scientist in the Informatics department at the JCVI since 2001. Extensive experience of genome annotation and tool development for genome analysis.

Reference List

  1. Tapiainen T, Paalanne N, Tejesvi MV et al. Maternal influence on the fetal microbiome in a population-based study of the first-pass meconium. Pediatr Res 2018.
  2. Tapiainen T, Ylitalo S, Eerola E, Uhari M. Dynamics of gut colonization and source of intestinal flora in healthy newborn infants. APMIS 2006;114(11):812-817.
  3. Tapiainen T, Aittoniemi J, Immonen J et al. Finnish guidelines for the treatment of laryngitis, wheezing bronchitis and bronchiolitis in children. Acta Paediatr 2016;105(1):44-49.
  4. Dunder T, Tapiainen T, Pokka T, Uhari M. Infections in child day care centers and later development of asthma, allergic rhinitis, and atopic dermatitis: prospective follow-up survey 12 years after controlled randomized hygiene intervention. Arch Pediatr Adolesc Med 2007;161(10):972-977.
  5.  Tapiainen T, Dunder T, Mottonen M, Pokka T, Uhari M. Adolescents with asthma or atopic eczema have more febrile days in early childhood: a possible explanation for the connection between paracetamol and asthma? J Allergy Clin Immunol 2010;125(3):751-752.

Last updated: 4.5.2018