Questioning the fetal microbiome illustrates pitfalls of low-biomass microbial studies

Katherine M. Kennedy, Marcus C. Goffau, Maria Elisa Perez-Muñoz, Marie-Claire Arrieta, Fredrik Bäckhed, Peer Bork, Thorsten Braun, Frederic D. Bushman, Joel Dore, Willem M. Vos, Ashlee M. Earl, Jonathan A. Eisen, Michal A. Elovitz, Stephanie C. Ganal-Vonarburg, Michael G. Gänzle, Wendy S. Garrett, Lindsay J. Hall, Mathias W. Hornef, Curtis Huttenhower, Liza Konnikova, Sarah Lebeer, Andrew J. Macpherson, Ruth C. Massey, Alice Carolyn McHardy, Omry Koren, Trevor D. Lawley, Ruth E. Ley, Liam O’Mahony, Paul W. O’Toole, Eric G. Pamer, Julian Parkhill, Jeroen Raes, Thomas Rattei, Anne Salonen, Eran Segal, Nicola Segata, Fergus Shanahan, Deborah M. Sloboda, Gordon C. S. Smith, Harry Sokol, Tim D. Spector, Michael G. Surette, Gerald W. Tannock, Alan W. Walker, Moran Yassour and Jens Walter ()
Additional contact information
Katherine M. Kennedy: McMaster University
Marcus C. Goffau: Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers
Maria Elisa Perez-Muñoz: University of Alberta
Marie-Claire Arrieta: University of Calgary
Fredrik Bäckhed: University of Gothenburg
Peer Bork: European Molecular Biology Laboratory
Thorsten Braun: Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Frederic D. Bushman: University of Pennsylvania
Joel Dore: Université Paris-Saclay, INRAE, MetaGenoPolis, AgroParisTech, MICALIS
Willem M. Vos: University of Helsinki
Ashlee M. Earl: Broad Institute of MIT and Harvard
Jonathan A. Eisen: University of California, Davis
Michal A. Elovitz: University of Pennsylvania Perelman School of Medicine
Stephanie C. Ganal-Vonarburg: Bern University Hospital, University of Bern
Michael G. Gänzle: University of Alberta
Wendy S. Garrett: Harvard T.H. Chan School of Public Health
Lindsay J. Hall: Norwich Research Park
Mathias W. Hornef: RWTH University Hospital
Curtis Huttenhower: Harvard T.H. Chan School of Public Health
Liza Konnikova: Yale School of Medicine
Sarah Lebeer: University of Antwerp
Andrew J. Macpherson: University of Bern
Ruth C. Massey: University College Cork
Alice Carolyn McHardy: Helmholtz Centre for Infection Research
Omry Koren: Bar-Ilan University
Trevor D. Lawley: University of Amsterdam
Ruth E. Ley: Max Planck Institute for Developmental Biology
Liam O’Mahony: University College Cork
Paul W. O’Toole: University College Cork
Eric G. Pamer: University of Chicago
Julian Parkhill: University of Cambridge
Jeroen Raes: VIB Center for Microbiology
Thomas Rattei: University of Vienna
Anne Salonen: University of Helsinki
Eran Segal: Weizmann Institute of Science
Nicola Segata: University of Trento
Fergus Shanahan: University College Cork
Deborah M. Sloboda: McMaster University
Gordon C. S. Smith: University of Cambridge
Harry Sokol: AP-HP, Saint Antoine Hospital, Centre de Recherche Saint-Antoine, CRSA, INSERM and Sorbonne Université
Tim D. Spector: King’s College London
Michael G. Surette: McMaster University
Gerald W. Tannock: University of Otago
Alan W. Walker: University of Aberdeen
Moran Yassour: The Hebrew University of Jerusalem
Jens Walter: University College Cork

Nature, 2023, vol. 613, issue 7945, 639-649

Abstract: Abstract Whether the human fetus and the prenatal intrauterine environment (amniotic fluid and placenta) are stably colonized by microbial communities in a healthy pregnancy remains a subject of debate. Here we evaluate recent studies that characterized microbial populations in human fetuses from the perspectives of reproductive biology, microbial ecology, bioinformatics, immunology, clinical microbiology and gnotobiology, and assess possible mechanisms by which the fetus might interact with microorganisms. Our analysis indicates that the detected microbial signals are likely the result of contamination during the clinical procedures to obtain fetal samples or during DNA extraction and DNA sequencing. Furthermore, the existence of live and replicating microbial populations in healthy fetal tissues is not compatible with fundamental concepts of immunology, clinical microbiology and the derivation of germ-free mammals. These conclusions are important to our understanding of human immune development and illustrate common pitfalls in the microbial analyses of many other low-biomass environments. The pursuit of a fetal microbiome serves as a cautionary example of the challenges of sequence-based microbiome studies when biomass is low or absent, and emphasizes the need for a trans-disciplinary approach that goes beyond contamination controls by also incorporating biological, ecological and mechanistic concepts.

Date: 2023
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DOI: 10.1038/s41586-022-05546-8

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