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

Katherine M. Kennedy, Marcus C. de Goffau, Maria Elisa Perez-Muñoz, Marie-Claire Arrieta, Fredrik Bӓckhed, Peer Bork, Thorsten Braun, Frederic D Bushman, Joel Dore, Willem M de Vos, Ashlee M. Earl, Jonathan A. Eisen, Michal A. Elovitz, Stephanie C. Ganal-Vonarburg, Michael G. Gӓnzle, Wendy S Garrett, Lindsay J. Hall, Mathias W. Hornef, Curtis Huttenhower, Liza KonnikovaSarah 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 Walker, Moran Yassour, Jens Walter* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

74 Citations (Scopus)


Whether the human fetus and the prenatal intrauterine environment (amniotic fluid, placenta) are stably colonized by microbes in a healthy pregnancy remains the subject of debate. Here, we evaluate recent studies that characterized microbial populations in human fetuses from the perspectives of reproductive biology, microbiology, bioinformatics, immunology, clinical microbiology, and gnotobiology, and assess possible mechanisms by which the fetus might
interact with microbes. Our analysis indicates that the detected microbial signals are likely the result of contamination during the clinical procedures to obtain fetal samples, DNA extraction, and DNA sequencing. Further, 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 also 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, also incorporating biological, ecological, and mechanistic concepts.
Original languageEnglish
Pages (from-to)639–649
Number of pages11
Early online date25 Jan 2023
Publication statusPublished - 26 Jan 2023

Bibliographical note

Acknowledgements. T.B. receives funding from the Deutsche Forschungsgemeinschaft (German Research Foundation No. BR2925 10-1 & PL241 16-1). J.D. acknowledges funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant agreement ERC-2017-AdG No. 788191 - Homo.symbiosus). W.M.dV. and A.S. are supported by the Academy of Finland (grants 1308255 and 1325103). A.M.E. is funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Department of Health and Human Services, under Grant Number U19AI110818 to the Broad Institute. F.D.B. is funded by AI045008, AI120489, R33HL137063, CA219871, AI139240, and the PennCHOP Microbiome Program. M.A.E. is
funded through grants R01HD102318, R01HD098867 and R01NR014784. S.C.G.V. was funded through a Peter Hans Hofschneider Professorship provided by the Stiftung Molekulare Biomedizin. M.G.G. and D.M.S are funded by the Canada Research Chairs Program. L.J.H. is supported by Wellcome Trust Investigator Awards 100974/C/13/Z and 220876/Z/20/Z; the Biotechnology and Biological Sciences Research Council (BBSRC), Institute Strategic Programme Gut Microbes and Health BB/R012490/1, and its constituent projects BBS/E/F/000PR10353 and BBS/E/F/000PR10356. M.W.H. has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant agreement No. 101019157). S.L. has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant agreement 852600 Lacto-Be). A.J.M. receives funding from ERCAd HHMM-Neonates and Swiss National Science Sinergia. Work in P.W.O., L.O’M., and J.W.
1162 laboratories is supported by Science Foundation Ireland (SFI) through a Centre award (APC/SFI/12/RC/2273_P2) to APC Microbiome Ireland. J.W. acknowledges support through an SFI Professorship (19/RP/6853) and thanks Victoria McMahon for coordination of this review and Ryan O'Callaghan for encouragement. J.R. acknowledges funding from the Interuniversity Special Research Fund (iBOF) Flanders [FLEXIGUT R-11423], the Rega Institute, VIB and KU Leuven. N.S. receives funding from the European Research Council (ERC-STG project MetaPG1168 716575). F.S. is supported in part by Science Foundation Ireland. G.C.S.S. acknowledges funding from Medical Research Council (UK; MR/K021133/1) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (Women’s Health theme). D.M.S. is funded by the Canadian Institute for Health Research and the Canada Research Chairs Program.
A.W.W. receives core funding support from the Scottish Government’s Rural and Environment Science and Analytical Services (RESAS). M.Y. is supported by the Azrieli Faculty Fellowship.


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