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Infants born to mothers with IBD present with altered gut microbiome that transfers abnormalities of the adaptive immune system to germ-free mice
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  1. Joana Torres1,2,
  2. Jianzhong Hu3,
  3. Akihiro Seki4,
  4. Caroline Eisele3,
  5. Nilendra Nair3,
  6. Ruiqi Huang5,
  7. Leonid Tarassishin3,
  8. Bindia Jharap6,
  9. Justin Cote-Daigneault7,
  10. Qixing Mao3,8,
  11. Ilaria Mogno3,
  12. Graham J Britton3,9,
  13. Mathieu Uzzan4,
  14. Ching-Lynn Chen10,
  15. Asher Kornbluth11,
  16. James George1,
  17. Peter Legnani1,
  18. Elana Maser1,
  19. Holly Loudon10,
  20. Joanne Stone10,
  21. Marla Dubinsky12,
  22. Jeremiah J Faith3,4,
  23. Jose C Clemente3,4,
  24. Saurabh Mehandru1,4,
  25. Jean-Frederic Colombel1,
  26. Inga Peter3
  1. 1 Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
  2. 2 Department of Gastroenterology, Hospital Beatriz Angelo, Loures, Portugal
  3. 3 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
  4. 4 The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
  5. 5 Department of Health Evidence and Policy, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
  6. 6 Department of Gastroenterology and Hepatology, Meander Medical Center, Amersfoort, The Netherlands
  7. 7 Department of Gastroenterology, Centre Hospitalier de L’Universite de Montreal, Montreal, Quebec, Canada
  8. 8 Department of Thoracic Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Naijing, China
  9. 9 The Precision Immunology Institute Icahn School of Medicine at Mount Sinai, New York City, New York, USA
  10. 10 Department of Obstetrics, Gynecology and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
  11. 11 Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
  12. 12 Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
  1. Correspondence to Dr Inga Peter, Mt Sinai School of Medicine, New York, NY 10029, USA; inga.peter{at}mssm.edu

Abstract

Background and aims Prenatal and early life bacterial colonisation is thought to play a major role in shaping the immune system. Furthermore, accumulating evidence links early life exposures to the risk of developing IBD later in life. We aimed to assess the effect of maternal IBD on the composition of the microbiome during pregnancy and on the offspring’s microbiome.

Methods We prospectively examined the diversity and taxonomy of the microbiome of pregnant women with and without IBD and their babies at multiple time points. We evaluated the role of maternal IBD diagnosis, the mode of delivery, antibiotic use and feeding behaviour on the microbiome composition during early life. To assess the effects of IBD-associated maternal and infant microbiota on the enteric immune system, we inoculated germ-free mice (GFM) with the respective stool and profiled adaptive and innate immune cell populations in the murine intestines.

Results Pregnant women with IBD and their offspring presented with lower bacterial diversity and altered bacterial composition compared with control women and their babies. Maternal IBD was the main predictor of the microbiota diversity in the infant gut at 7, 14, 30, 60 and 90 days of life. Babies born to mothers with IBD demonstrated enrichment in Gammaproteobacteria and depletion in Bifidobacteria. Finally, GFM inoculated with third trimester IBD mother and 90-day infant stools showed significantly reduced microbial diversity and fewer class-switched memory B cells and regulatory T cells in the colon.

Conclusion Aberrant gut microbiota composition persists during pregnancy with IBD and alters the bacterial diversity and abundance in the infant stool. The dysbiotic microbiota triggered abnormal imprinting of the intestinal immune system in GFM.

  • inflammatory bowel disease
  • pregnancy
  • early life microbiome
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Footnotes

  • Contributors JT and JH contributed equally. JT, J-FC, IP, JH and BJ conceived and designed the study. CE, NN, LT, QM, EM, C-LC, AK, JG, PL, HL, JS, JC-D and MD managed subject recruitment, data and sample collection and sample processing. GB, IM, JF, LT and AS designed and conducted germ-free mice (GFM) experiments. AS, MU and SM designed and conducted immune profiling experiments. JH, JT, JCC, AS and RH generated and analysed data. JT, J-FC, IP, SM and JH wrote the manuscript. All authors read the manuscript and provided critical comments.

  • Funding This work was funded by the International Organization for the Study of Inflammatory Bowel Disease (to IP and J-FC.), The Crohn’s and Colitis Foundation (to IP, JT, JCC and J-FC), and the Kenneth Rainin Foundation (to IP, J-FC, JF and SM). We would like to express our gratitude for Dr Jixin Dai and Ms Yi Liu’s generosity in supporting the MECONIUM study.

  • Competing interests JT received lecture fees from Takeda and Abbvie. JJF is a consultant for Janssen Research & Development and a member of the Scientific Advisory Board of Vedanta Biosciences. JFC reports receiving research grants from AbbVie, Janssen Pharmaceuticals and Takeda; receiving payment for lectures from AbbVie, Amgen, Allergan, Inc. Ferring Pharmaceuticals, Shire, and Takeda; receiving consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene Corporation, Celltrion, Eli Lilly, Enterome, Ferring Pharmaceuticals, Genentech, Janssen Pharmaceuticals, Landos, Ipsen, Medimmune, Merck,Novartis, Pfizer, Shire, Takeda, Tigenix and holding stock options in Intestinal Biotech Development and Genfit.

  • Ethics approval All experiments were performed using protocols approved by the local animal ethics committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Patient consent for publication Parental/guardian consent obtained

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