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Bifidobacteria-mediated immune system imprinting early in life

Bethany M. Henrick, Lucie Rodriguez, Tadepally Lakshmikanth, Christian Pou, Ewa Henckel, Axel Olin, Jun Wang, Jaromir Mikes, Ziyang Tan, Yang Chen, Amy M. Ehrlich, Anna Karin Bernhardsson, Constantin Habimana Mugabo, Ylva Ambrosiani, Anna Gustafsson, Stephanie Chew, Heather K. Brown, Johann Prambs, Kajsa Bohlin, Ryan D. Mitchell, Mark A. Underwood, Jennifer T. Smilowitz, J. Bruce German, Steven A. Frese, View ORCID ProfilePetter Brodin
doi: https://doi.org/10.1101/2020.10.24.353250
Bethany M. Henrick
1Evolve Biosystems, Inc, 95618, Davis, CA, USA
2Department of Food Science and Technology, University of Nebraska, 68588-6205, Lincoln, NE, USA
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  • For correspondence: petter.brodin@ki.se
Lucie Rodriguez
3Science for Life Laboratory, Dept. of Women’s and Children’s Health, Karolinska Institutet, 17121, Solna, Sweden
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Tadepally Lakshmikanth
3Science for Life Laboratory, Dept. of Women’s and Children’s Health, Karolinska Institutet, 17121, Solna, Sweden
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Christian Pou
3Science for Life Laboratory, Dept. of Women’s and Children’s Health, Karolinska Institutet, 17121, Solna, Sweden
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Ewa Henckel
3Science for Life Laboratory, Dept. of Women’s and Children’s Health, Karolinska Institutet, 17121, Solna, Sweden
4Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 14152, Stockholm, Sweden
5Department of Neonatology, Karolinska University Hospital, 141 86, Stockholm Sweden
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Axel Olin
3Science for Life Laboratory, Dept. of Women’s and Children’s Health, Karolinska Institutet, 17121, Solna, Sweden
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Jun Wang
3Science for Life Laboratory, Dept. of Women’s and Children’s Health, Karolinska Institutet, 17121, Solna, Sweden
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Jaromir Mikes
3Science for Life Laboratory, Dept. of Women’s and Children’s Health, Karolinska Institutet, 17121, Solna, Sweden
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Ziyang Tan
3Science for Life Laboratory, Dept. of Women’s and Children’s Health, Karolinska Institutet, 17121, Solna, Sweden
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Yang Chen
3Science for Life Laboratory, Dept. of Women’s and Children’s Health, Karolinska Institutet, 17121, Solna, Sweden
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Amy M. Ehrlich
1Evolve Biosystems, Inc, 95618, Davis, CA, USA
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Anna Karin Bernhardsson
3Science for Life Laboratory, Dept. of Women’s and Children’s Health, Karolinska Institutet, 17121, Solna, Sweden
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Constantin Habimana Mugabo
3Science for Life Laboratory, Dept. of Women’s and Children’s Health, Karolinska Institutet, 17121, Solna, Sweden
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Ylva Ambrosiani
4Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 14152, Stockholm, Sweden
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Anna Gustafsson
4Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 14152, Stockholm, Sweden
5Department of Neonatology, Karolinska University Hospital, 141 86, Stockholm Sweden
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Stephanie Chew
1Evolve Biosystems, Inc, 95618, Davis, CA, USA
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Heather K. Brown
1Evolve Biosystems, Inc, 95618, Davis, CA, USA
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Johann Prambs
1Evolve Biosystems, Inc, 95618, Davis, CA, USA
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Kajsa Bohlin
4Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 14152, Stockholm, Sweden
5Department of Neonatology, Karolinska University Hospital, 141 86, Stockholm Sweden
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Ryan D. Mitchell
1Evolve Biosystems, Inc, 95618, Davis, CA, USA
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Mark A. Underwood
7Foods for Health Institute, University of California Davis, 95616, Davis, CA, USA
8Department of Pediatrics, University of California Davis Children’s Hospital, 95817, Sacramento, CA, USA
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Jennifer T. Smilowitz
7Foods for Health Institute, University of California Davis, 95616, Davis, CA, USA
9Department of Food Science and Technology, University of California Davis, 95616, Davis, CA, USA
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J. Bruce German
7Foods for Health Institute, University of California Davis, 95616, Davis, CA, USA
9Department of Food Science and Technology, University of California Davis, 95616, Davis, CA, USA
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Steven A. Frese
1Evolve Biosystems, Inc, 95618, Davis, CA, USA
2Department of Food Science and Technology, University of Nebraska, 68588-6205, Lincoln, NE, USA
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Petter Brodin
3Science for Life Laboratory, Dept. of Women’s and Children’s Health, Karolinska Institutet, 17121, Solna, Sweden
10Pediatric Rheumatology, Karolinska University Hospital, 17176, Solna, Sweden
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  • ORCID record for Petter Brodin
  • For correspondence: petter.brodin@ki.se
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SUMMARY

Immune-microbe interactions early in life influence an individual’s risk of developing allergies, asthma and some autoimmune disorders. Breastfeeding helps guide the development of healthy immune-microbe relationships, in part by providing nutrients to specialized microbes that in turn benefit the host and its developing immune system. Such bacteria having co-evolved with humans are associated with reduced risks of immune mediated diseases but are increasingly rare in modern societies. Here we map an immunological sequence of events, triggered by microbial colonization that distinguish children with different gut bacterial composition. Lack of bifidobacterial species is associated with elevated markers of intestinal inflammation and immune dysregulation and in a randomized trial of breastfed infants, the infant-adapted Bifidobacterium infantis EVC001 silenced intestinal Th2 and Th17 immune responses, while inducing IFNβ, and its metabolites skew T-cell polarization in vitro, from Th2 towards Th1, suggesting a healthier immune imprinting during the first critical months of life.

HIGHLIGHTS An ordered sequence of immune changes after birth, driven by microbial interactions

Low gut Bifidobacterium abundance is associated with markers of intestinal inflammation

Feeding B. infantis EVC001 silenced intestinal Th2 and Th17 but upregulates IFNβ

B. infantis EVC001 metabolites and/or enteric cytokines skew naïve T-cell polarization towards Th1 and away from Th2

Competing Interest Statement

PB, JM and TL are founders and shareholders of Cytodelics AB (Stockholm, Sweden). PB is an advisor to Scailyte AG (Zurich, Switzerland). RDM, SC, JP, HKB, SAF, and BMH are employees of Evolve BioSystems, a company focused on restoring the infant microbiome. JTS received funding to conduct the IMPRINT trial and AME received funding to assist in writing the manuscript. JBG is a co-founder of Evolve BioSystems. SAF and BMH serve as Adjunct Assistant Professors in Food Science & Technology Department, University of Nebraska Lincoln.

Footnotes

  • ↵12 Lead contact

  • https://brodinlab.com/data-repository/

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Bifidobacteria-mediated immune system imprinting early in life
Bethany M. Henrick, Lucie Rodriguez, Tadepally Lakshmikanth, Christian Pou, Ewa Henckel, Axel Olin, Jun Wang, Jaromir Mikes, Ziyang Tan, Yang Chen, Amy M. Ehrlich, Anna Karin Bernhardsson, Constantin Habimana Mugabo, Ylva Ambrosiani, Anna Gustafsson, Stephanie Chew, Heather K. Brown, Johann Prambs, Kajsa Bohlin, Ryan D. Mitchell, Mark A. Underwood, Jennifer T. Smilowitz, J. Bruce German, Steven A. Frese, Petter Brodin
bioRxiv 2020.10.24.353250; doi: https://doi.org/10.1101/2020.10.24.353250
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Bifidobacteria-mediated immune system imprinting early in life
Bethany M. Henrick, Lucie Rodriguez, Tadepally Lakshmikanth, Christian Pou, Ewa Henckel, Axel Olin, Jun Wang, Jaromir Mikes, Ziyang Tan, Yang Chen, Amy M. Ehrlich, Anna Karin Bernhardsson, Constantin Habimana Mugabo, Ylva Ambrosiani, Anna Gustafsson, Stephanie Chew, Heather K. Brown, Johann Prambs, Kajsa Bohlin, Ryan D. Mitchell, Mark A. Underwood, Jennifer T. Smilowitz, J. Bruce German, Steven A. Frese, Petter Brodin
bioRxiv 2020.10.24.353250; doi: https://doi.org/10.1101/2020.10.24.353250

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