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

doi:10.1038/s41586-022-05546-8

Review

. 2023 Jan;613(7945):639-649.

doi: 10.1038/s41586-022-05546-8. Epub 2023 Jan 25.

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

Katherine M Kennedy^#^{1

2}, Marcus C de Goffau^#^{3

4

5}, Maria Elisa Perez-Muñoz⁶, Marie-Claire Arrieta⁷, Fredrik Bäckhed^{8

9

10}, Peer Bork^{11

12

13

14}, Thorsten Braun¹⁵, Frederic D Bushman¹⁶, Joel Dore¹⁷, Willem M de Vos^{18

19}, Ashlee M Earl²⁰, Jonathan A Eisen^{21

22

23}, Michal A Elovitz²⁴, Stephanie C Ganal-Vonarburg^{25

26}, Michael G Gänzle⁶, Wendy S Garrett^{27

28

29

30}, Lindsay J Hall^{31

32

33}, Mathias W Hornef³⁴, Curtis Huttenhower^{27

30

35}, Liza Konnikova³⁶, Sarah Lebeer³⁷, Andrew J Macpherson²⁶, Ruth C Massey^{38

39}, Alice Carolyn McHardy^{40

41

42}, Omry Koren⁴³, Trevor D Lawley⁴, Ruth E Ley⁴⁴, Liam O'Mahony^{38

39

45}, Paul W O'Toole^{38

39}, Eric G Pamer⁴⁶, Julian Parkhill⁴⁷, Jeroen Raes^{48

49}, Thomas Rattei⁵⁰, Anne Salonen¹⁸, Eran Segal⁵¹, Nicola Segata^{52

53}, Fergus Shanahan^{38

45}, Deborah M Sloboda^{1

2

54

55}, Gordon C S Smith^{56

57}, Harry Sokol^{58

59

60}, Tim D Spector⁶¹, Michael G Surette^{1

2

62}, Gerald W Tannock⁶³, Alan W Walker⁶⁴, Moran Yassour^{65

66}, Jens Walter^{67

68

69}

Affiliations

¹ Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
² Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
³ Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
⁴ Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
⁵ Wellcome Sanger Institute, Cambridge, UK.
⁶ Department of Agriculture, Food and Nutrition Sciences, University of Alberta, Edmonton, Alberta, Canada.
⁷ International Microbiome Center, University of Calgary, Calgary, Alberta, Canada.
⁸ The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
⁹ Department of Clinical Physiology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden.
¹⁰ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
¹¹ Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
¹² Max Delbrück Centre for Molecular Medicine, Berlin, Germany.
¹³ Yonsei Frontier Lab (YFL), Yonsei University, Seoul, South Korea.
¹⁴ Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany.
¹⁵ Department of Obstetrics and Experimental Obstetrics, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
¹⁶ Department of Microbiology Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁷ Université Paris-Saclay, INRAE, MetaGenoPolis, AgroParisTech, MICALIS, Jouy-en-Josas, France.
¹⁸ Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
¹⁹ Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands.
²⁰ Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Boston, MA, USA.
²¹ Department of Evolution and Ecology, University of California, Davis, Davis, CA, USA.
²² Department of Medical Microbiology and Immunology, University of California, Davis, Davis, CA, USA.
²³ UC Davis Genome Center, University of California, Davis, Davis, CA, USA.
²⁴ Maternal and Child Health Research Center, Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
²⁵ Universitätsklinik für Viszerale Chirurgie und Medizin, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
²⁶ Department for Biomedical Research (DBMR), University of Bern, Bern, Switzerland.
²⁷ Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
²⁸ Harvard T.H. Chan Microbiome in Public Health Center, Boston, MA, USA.
²⁹ Department of Medicine and Division of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
³⁰ Broad Institute of Harvard and MIT, Cambridge, MA, USA.
³¹ Quadram Institute Bioscience, Norwich Research Park, Norwich, UK.
³² Norwich Medical School, University of East Anglia, Norwich, UK.
³³ Chair of Intestinal Microbiome, ZIEL-Institute for Food and Health, School of Life Sciences, Technical University of Munich, Freising, Germany.
³⁴ Institute of Medical Microbiology, RWTH University Hospital, Aachen, Germany.
³⁵ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
³⁶ Departments of Pediatrics and Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
³⁷ Department of Bioscience Engineering, University of Antwerp, Antwerp, Belgium.
³⁸ APC Microbiome Ireland, University College Cork, Cork, Ireland.
³⁹ School of Microbiology, University College Cork, Cork, Ireland.
⁴⁰ Computational Biology of Infection Research, Helmholtz Centre for Infection Research, Braunschweig, Germany.
⁴¹ German Center for Infection Research (DZIF), Hannover Braunschweig site, Braunschweig, Germany.
⁴² Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität Braunschweig, Braunschweig, Germany.
⁴³ Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
⁴⁴ Department of Microbiome Science, Max Planck Institute for Developmental Biology, Tübingen, Germany.
⁴⁵ Department of Medicine, University College Cork, Cork, Ireland.
⁴⁶ Duchossois Family Institute, University of Chicago, Chicago, IL, USA.
⁴⁷ Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
⁴⁸ VIB Center for Microbiology, Leuven, Belgium.
⁴⁹ Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium.
⁵⁰ Centre for Microbiology and Environmental Systems Science, University of Vienna, Vienna, Austria.
⁵¹ Weizmann Institute of Science, Rehovot, Israel.
⁵² Department CIBIO, University of Trento, Trento, Italy.
⁵³ European Institute of Oncology (IEO), IRCCS, Milan, Italy.
⁵⁴ Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
⁵⁵ Department of Obstetrics and Gynecology, McMaster University, Hamilton, Ontario, Canada.
⁵⁶ Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, UK.
⁵⁷ NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
⁵⁸ Gastroenterology Department, AP-HP, Saint Antoine Hospital, Centre de Recherche Saint-Antoine, CRSA, INSERM and Sorbonne Université, Paris, France.
⁵⁹ Paris Center for Microbiome Medicine (PaCeMM), Fédération Hospitalo-Universitaire, Paris, France.
⁶⁰ Micalis Institute, INRAE, AgroParisTech, Université Paris-Saclay, Jouy en Josas, France.
⁶¹ Department of Twin Research, King's College London, London, UK.
⁶² Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
⁶³ Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.
⁶⁴ Gut Health Group, Rowett Institute, University of Aberdeen, Aberdeen, UK.
⁶⁵ School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel.
⁶⁶ Department of Microbiology and Molecular Genetics, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
⁶⁷ APC Microbiome Ireland, University College Cork, Cork, Ireland. jenswalter@ucc.ie.
⁶⁸ School of Microbiology, University College Cork, Cork, Ireland. jenswalter@ucc.ie.
⁶⁹ Department of Medicine, University College Cork, Cork, Ireland. jenswalter@ucc.ie.

^# Contributed equally.

PMID: 36697862
PMCID: PMC11333990
DOI: 10.1038/s41586-022-05546-8

Review

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

Katherine M Kennedy et al. Nature. 2023 Jan.

. 2023 Jan;613(7945):639-649.

doi: 10.1038/s41586-022-05546-8. Epub 2023 Jan 25.

Authors

Affiliations

¹ Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
² Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
³ Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
⁴ Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
⁵ Wellcome Sanger Institute, Cambridge, UK.
⁶ Department of Agriculture, Food and Nutrition Sciences, University of Alberta, Edmonton, Alberta, Canada.
⁷ International Microbiome Center, University of Calgary, Calgary, Alberta, Canada.
⁸ The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
⁹ Department of Clinical Physiology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden.
¹⁰ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
¹¹ Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
¹² Max Delbrück Centre for Molecular Medicine, Berlin, Germany.
¹³ Yonsei Frontier Lab (YFL), Yonsei University, Seoul, South Korea.
¹⁴ Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany.
¹⁵ Department of Obstetrics and Experimental Obstetrics, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
¹⁶ Department of Microbiology Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁷ Université Paris-Saclay, INRAE, MetaGenoPolis, AgroParisTech, MICALIS, Jouy-en-Josas, France.
¹⁸ Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
¹⁹ Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands.
²⁰ Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Boston, MA, USA.
²¹ Department of Evolution and Ecology, University of California, Davis, Davis, CA, USA.
²² Department of Medical Microbiology and Immunology, University of California, Davis, Davis, CA, USA.
²³ UC Davis Genome Center, University of California, Davis, Davis, CA, USA.
²⁴ Maternal and Child Health Research Center, Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
²⁵ Universitätsklinik für Viszerale Chirurgie und Medizin, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
²⁶ Department for Biomedical Research (DBMR), University of Bern, Bern, Switzerland.
²⁷ Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
²⁸ Harvard T.H. Chan Microbiome in Public Health Center, Boston, MA, USA.
²⁹ Department of Medicine and Division of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
³⁰ Broad Institute of Harvard and MIT, Cambridge, MA, USA.
³¹ Quadram Institute Bioscience, Norwich Research Park, Norwich, UK.
³² Norwich Medical School, University of East Anglia, Norwich, UK.
³³ Chair of Intestinal Microbiome, ZIEL-Institute for Food and Health, School of Life Sciences, Technical University of Munich, Freising, Germany.
³⁴ Institute of Medical Microbiology, RWTH University Hospital, Aachen, Germany.
³⁵ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
³⁶ Departments of Pediatrics and Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
³⁷ Department of Bioscience Engineering, University of Antwerp, Antwerp, Belgium.
³⁸ APC Microbiome Ireland, University College Cork, Cork, Ireland.
³⁹ School of Microbiology, University College Cork, Cork, Ireland.
⁴⁰ Computational Biology of Infection Research, Helmholtz Centre for Infection Research, Braunschweig, Germany.
⁴¹ German Center for Infection Research (DZIF), Hannover Braunschweig site, Braunschweig, Germany.
⁴² Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität Braunschweig, Braunschweig, Germany.
⁴³ Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
⁴⁴ Department of Microbiome Science, Max Planck Institute for Developmental Biology, Tübingen, Germany.
⁴⁵ Department of Medicine, University College Cork, Cork, Ireland.
⁴⁶ Duchossois Family Institute, University of Chicago, Chicago, IL, USA.
⁴⁷ Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
⁴⁸ VIB Center for Microbiology, Leuven, Belgium.
⁴⁹ Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium.
⁵⁰ Centre for Microbiology and Environmental Systems Science, University of Vienna, Vienna, Austria.
⁵¹ Weizmann Institute of Science, Rehovot, Israel.
⁵² Department CIBIO, University of Trento, Trento, Italy.
⁵³ European Institute of Oncology (IEO), IRCCS, Milan, Italy.
⁵⁴ Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
⁵⁵ Department of Obstetrics and Gynecology, McMaster University, Hamilton, Ontario, Canada.
⁵⁶ Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, UK.
⁵⁷ NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
⁵⁸ Gastroenterology Department, AP-HP, Saint Antoine Hospital, Centre de Recherche Saint-Antoine, CRSA, INSERM and Sorbonne Université, Paris, France.
⁵⁹ Paris Center for Microbiome Medicine (PaCeMM), Fédération Hospitalo-Universitaire, Paris, France.
⁶⁰ Micalis Institute, INRAE, AgroParisTech, Université Paris-Saclay, Jouy en Josas, France.
⁶¹ Department of Twin Research, King's College London, London, UK.
⁶² Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
⁶³ Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.
⁶⁴ Gut Health Group, Rowett Institute, University of Aberdeen, Aberdeen, UK.
⁶⁵ School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel.
⁶⁶ Department of Microbiology and Molecular Genetics, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
⁶⁷ APC Microbiome Ireland, University College Cork, Cork, Ireland. jenswalter@ucc.ie.
⁶⁸ School of Microbiology, University College Cork, Cork, Ireland. jenswalter@ucc.ie.
⁶⁹ Department of Medicine, University College Cork, Cork, Ireland. jenswalter@ucc.ie.

^# Contributed equally.

PMID: 36697862
PMCID: PMC11333990
DOI: 10.1038/s41586-022-05546-8

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.

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Figures

**Fig. 1 |. Relative abundance of bacterial taxa from three recent fetal studies.**
Distribution and mean relative abundance (%) of taxa present In fetal samples from three recent studies^,, investigating the fetal microbiome, and their corresponding abundance in control samples. Taxa were selected on the basis of the following criteria: genera that were cultured from or detected as enriched in fetal samples as described by Mishra et al. (indicated by ^) or by Rackaityte et al. (indicated by *, including the family Micrococcaceae); all genera detected in fetal samples from Kennedy et al. and the PBS-enriched genus *Ralstonia*. Taxa were grouped by potential source of contamination in agreement with the likely origin of genera (for skin microorganisms) and previous studies that characterized sources of contamination^-. Publicly available unfiltered relative abundance microbiota profiling data associated with each publication were merged into a single phyloseq object (RRID:SCR_01380). Amplicon sequence variants (ASVs) were grouped at the genus or family level (for Micrococcaceae). The mean relative abundance of each taxon was calculated for each sample type within each study and plotted in R (tidyverse, ggplot2; RRID:SCR_014601). Dot size corresponds to the mean relative abundance by sample type and study (mean relative abundances of less than 0.0001% were excluded). Dots are coloured by sample type: reagent controls in grey (Mishra: PBS n = 42, reagent n = 23; Rackaityte: buffer n = 11; Kennedy: reagent n = 2), sampling negatives in aqua (Kennedy: swab n = 1; Rackaityte: air swab n = 19; procedural swab n = 16; moistened swab n = 17) and environmental negatives in sky blue (Mishra: environment n = 47, operator n = 12), internal controls in indigo (Mishra: thymus n = 27, spleen n = 12; Rackaityte: kidney n = 16), fetal lung in pink (Mishra: n = 25), fetal gut in purple (Kennedy: n = 20; Mishra: n = 44; Rackaityte: proximal n = 41, mid n = 45, distal n = 42), and external tissues in red (Mishra: skin n = 35, placenta n = 16).

**Fig. 2 |. Reagent contamination in meconium samples from extremely premature infants.**
a, Representation of the percentage of reagent contamination (% of total sequence reads) in the first meconium of extremely premature infants collected in a previous study in relation to the day of procurement of said samples (day 1–3 or day 4–6) or in regard to the mode of delivery (C-section or vaginal). Colours indicate the percentage of sequence reads assigned to reagent contamination (legend on top). The day of procurement is significantly correlated with the percentage of reagent contamination reads (P = 0.005 by Mann–Whitney U test or P = 0.01 by Spearman rho test) and the mode of delivery shows a trend (P = 0.07 by Mann–Whitney U test). The number of samples (n) is noted below each category. b, Top, list of reagent contaminants shown together in a. Bottom, list of the most abundant sample-associated-signals and their association (or lack thereof owing to limited size of cohort) with vaginal (V) or C-section (C) delivery.

**Fig. 3 |. Relative abundance of bacterial taxa in samples from Rackaityte et al.**
Distribution and mean relative abundance (%) of taxa present In fetal and control samples from Rackaityte et al. by batch as defined by Rackaityte et al.. Dominant taxa were selected as described in Fig. 1. Publicly available unfiltered relative abundance microbiota data associated with each publication were merged into a single phyloseq object (RRID:SCR_01380). ASVs were grouped at the genus or family (for Micrococcaceae) level. The mean relative abundance of each taxon was calculated for each sample type within each batch and plotted in R (tidyverse, ggplot2; RRID:SCR_014601). Dot size corresponds to the mean relative abundance by sample type and batch. Dots are coloured by sample type: reagent controls in grey (buffer), sampling negative controls in aqua, internal controls in indigo (kidney) and fetal gut samples in purple.

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References

1. Macpherson AJ, de Aguero MG & Ganal-Vonarburg SC How nutrition and the maternal microbiota shape the neonatal immune system. Nat. Rev. Immunol 17, 508–517 (2017). - PubMed
1. Kalbermatter C, Fernandez Trigo N, Christensen S & Ganal-Vonarburg SC Maternal microbiota, early life colonization and breast milk drive immune development in the newborn. Front. Immunol 12, 683022 (2021). - PMC - PubMed
1. Gensollen T, Iyer SS, Kasper DL & Blumberg RS How colonization by microbiota in early life shapes the immune system. Science 352, 539–544 (2016). - PMC - PubMed
1. Jain N The early life education of the immune system: moms, microbes and (missed) opportunities. Gut Microbes 12, 1824564 (2020). - PMC - PubMed
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[1] Macpherson AJ, de Aguero MG & Ganal-Vonarburg SC How nutrition and the maternal microbiota shape the neonatal immune system. Nat. Rev. Immunol 17, 508–517 (2017). - PubMed

[2] Macpherson AJ, de Aguero MG & Ganal-Vonarburg SC How nutrition and the maternal microbiota shape the neonatal immune system. Nat. Rev. Immunol 17, 508–517 (2017). - PubMed

[3] Kalbermatter C, Fernandez Trigo N, Christensen S & Ganal-Vonarburg SC Maternal microbiota, early life colonization and breast milk drive immune development in the newborn. Front. Immunol 12, 683022 (2021). - PMC - PubMed

[4] Kalbermatter C, Fernandez Trigo N, Christensen S & Ganal-Vonarburg SC Maternal microbiota, early life colonization and breast milk drive immune development in the newborn. Front. Immunol 12, 683022 (2021). - PMC - PubMed

[5] Gensollen T, Iyer SS, Kasper DL & Blumberg RS How colonization by microbiota in early life shapes the immune system. Science 352, 539–544 (2016). - PMC - PubMed

[6] Gensollen T, Iyer SS, Kasper DL & Blumberg RS How colonization by microbiota in early life shapes the immune system. Science 352, 539–544 (2016). - PMC - PubMed

[7] Jain N The early life education of the immune system: moms, microbes and (missed) opportunities. Gut Microbes 12, 1824564 (2020). - PMC - PubMed

[8] Jain N The early life education of the immune system: moms, microbes and (missed) opportunities. Gut Microbes 12, 1824564 (2020). - PMC - PubMed

[9] Hornef MW & Torow N ‘Layered immunity’ and the ‘neonatal window of opportunity’ — timed succession of non-redundant phases to establish mucosal host–microbial homeostasis after birth. Immunology 159, 15–25 (2020). - PMC - PubMed

[10] Hornef MW & Torow N ‘Layered immunity’ and the ‘neonatal window of opportunity’ — timed succession of non-redundant phases to establish mucosal host–microbial homeostasis after birth. Immunology 159, 15–25 (2020). - PMC - PubMed

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

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

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