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1 Endometrial Microbiota Composition Is Associated with Reproductive Outcome in Infertile 2 Patients. 3 Authors medRxiv preprint doi: https://doi.org/10.1101/2021.02.05.21251207; this version posted February 8, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. 1 Title: 2 Endometrial microbiota composition is associated with reproductive outcome in infertile 3 patients. 4 Authors: 5 Inmaculada Moreno1,2‡, Iolanda Garcia-Grau1,3‡, David Perez-Villaroya2, Marta Gonzalez- 6 Monfort1,2, Mustafa Bahçeci4, Marcelo J. Barrionuevo5, Sagiri Taguchi6, Elena Puente7, 7 Michael Dimattina8, Mei Wei Lim9, Georgina Meneghini10, Mira Aubuchon11, Mark 8 Leondires12, Alexandra Izquierdo13,¥, Martina Perez-Olgiati14, Alejandro Chavez15, Ken 9 Seethram16, Davide Bau2, Carlos Gomez2, Diana Valbuena2, Felipe Vilella1, Carlos 10 Simon1,2,3,17,18,*. 11 Affiliations: 12 1 Igenomix Foundation, INCLIVA Health Research Institute, Valencia, Spain. 13 2 Igenomix R&D, Valencia, Spain. 14 3 Department of Obstetrics & Gynecology, University of Valencia, Valencia, Spain. 15 4 Bahçeci Group, Istanbul, Turkey. 16 5 IVF Florida. Margate, Florida, USA. 17 6 Oak Clinic Sumiyoshi, Osaka, Osaka Prefecture, Japan. 18 7 Clinica Fertia, Fuengirola, Malaga. Spain. 19 8 Dominion Fertility, Arlington, Washington, USA. 20 9 Alpha IVF & Women’s Specialists Centre, Petaling Jaya, Selangor, Malaysia 21 10 Gestanza Medicina Reproductiva, Rosario, Santa Fe, Argentina. 22 11 Missouri Center for Reproductive Medicine, Chesterfield, Missouri, USA. 23 12 RMA Connecticut, Norwalk, Connecticut, USA. 24 13 ProcreaTec, Madrid, Spain. 25 14 Pregna Medicina Reproductiva, Buenos Aires, Argentina. NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2021.02.05.21251207; this version posted February 8, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. 26 15 New Hope Fertility Center, Mexico City, Mexico. 27 16 Pacific Centre for Reproductive Medicine, Burnaby, British Columbia, Canada. 28 17 Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Harvard 29 Medical School, Boston, Massachusetts, USA. 30 18 Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, 31 USA. 32 ‡ Equal contribution 33 ¥ Present address: Médipôle Lyon-Villeurbanne, Villeurbanne, France. 34 *Correspondence: [email protected] 35 36 ABSTRACT 37 Background: Previous evidence indicates associations between the female reproductive tract 38 microbiome composition and reproductive outcome in infertile patients undergoing assisted 39 reproduction. We aimed to determine whether the endometrial microbiota composition is 40 associated with reproductive outcomes of live birth, biochemical pregnancy, clinical 41 miscarriage, or no pregnancy. 42 Methods: Here we present a multicentre prospective observational study using 16S rRNA 43 gene sequencing to analyse endometrial fluid and biopsy samples before embryo transfer in a 44 cohort of 342 infertile patients asymptomatic for infection undergoing assisted reproductive 45 treatments. 46 Results: A dysbiotic endometrial microbiota profile composed of Atopobium, 47 Bifidobacterium, Chryseobacterium, Gardnerella, Haemophilus, Klebsiella, Neisseria, 48 Staphylococcus and Streptococcus was associated with unsuccessful outcomes. In contrast, 49 Lactobacillus was consistently enriched in patients with live birth outcomes. 50 Conclusions: Our findings indicate that endometrial microbiota composition before embryo 51 transfer is a useful biomarker to predict reproductive outcome, offering an opportunity to 52 further improve diagnosis and treatment strategies. 53 medRxiv preprint doi: https://doi.org/10.1101/2021.02.05.21251207; this version posted February 8, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. 54 INTRODUCTION 55 Humans have co-evolved as holobionts with microbial companions including bacteria, 56 viruses, fungi, yeast and archaea (Simon et al. 2019). These microbes and their genetic 57 information (the microbiome) are now well-characterised; the Human Microbiome Project 58 has revealed that approximately 9% of the total human microbiome is found in the female 59 reproductive tract (Peterson et al. 2009). Historically, all microbes were believed to inhabit 60 only the lower portion of the tract; the cervix was considered a perfect barrier between the 61 vagina and the upper genital tract that maintained sterility of the uterine cavity (Tissier 1900). 62 However, accumulating evidence demonstrates that this tract is an open system with a 63 microbiota continuum that gradually changes from the outer to the inner organs, with 64 decreasing bacterial abundance and increasing bacterial diversity from the vagina to the 65 ovaries (Walther-António et al. 2016; Miles, Hardy, and Merrell 2017; C. Chen et al. 2017; 66 Koedooder, Mackens, et al. 2019; Peric et al. 2019). There are reportedly 102–104 fewer 67 bacteria in the uterine cavity than in the vaginal microbiota (Mitchell et al. 2015; C. Chen et 68 al. 2017). Thus, the uterine cavity contains a low-abundance bacterial community, also 69 known as a low-biomass microbiota. 70 The presence of different microorganisms in the female and male reproductive tracts might 71 influence reproductive function (Franasiak and Scott 2015; Koedooder, Mackens, et al. 2019; 72 Ravel, Moreno, and Simón 2020). Recent studies indicate that the chance of becoming 73 pregnant before the start of an in vitro fertilisation (IVF) treatment is stratified based on the 74 vaginal microbiota composition, as women with a low percentage of Lactobacillus in their 75 vaginal sample are less likely to have a successful embryo implantation (Koedooder, Singer, 76 et al. 2019). Analyses by 16S ribosomal RNA (16S rRNA) gene sequencing of endometrial 77 samples suggest that this microbiome impacts reproductive outcomes in infertile patients. 78 Having a Lactobacillus-dominated microbiota, defined as ≥90% or ≥80% Lactobacillus spp., 79 is associated with significantly increased implantation, pregnancy, ongoing pregnancy, and 80 live birth rates (Moreno et al. 2016; Kyono et al. 2019). Lately, 16S rRNA and whole 81 metagenomics sequencing have been used to investigate the endometrial microbiome (EM) in 82 cases of spontaneous clinical miscarriage (Moreno et al. 2020), recurrent miscarriage 83 (Garcia-Grau et al. 2019), and at 4 weeks gestation in a pregnancy resulting in a live birth 84 (Moreno et al. 2020). Interestingly, the EM during early successful pregnancy exhibited no 85 bacterial diversity and higher Lactobacillus abundance (Moreno et al. 2020). medRxiv preprint doi: https://doi.org/10.1101/2021.02.05.21251207; this version posted February 8, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. 86 In this prospective multicentre observational study, we investigated the EM composition in 87 342 infertile patients undergoing assisted reproductive technology (ART) in 13 different 88 centres on 3 continents by analysing endometrial fluid (EF) and endometrial biopsy (EB) 89 samples using 16S rRNA sequencing. The objective of the study was to determine whether 90 EM composition is associated with reproductive outcomes: live birth (LB), biochemical 91 pregnancy (BP), clinical miscarriage (CM), or no pregnancy (NP). Lactobacillus was 92 consistently more abundant than dysbiotic or pathogenic bacteria in women that achieved a 93 pregnancy with a LB. Lactobacillus spp. depletion and increased abundance of specific taxa 94 including Gardnerella, Haemophilus, Klebsiella, Neisseria, Staphylococcus, Streptococcus, 95 Atopobium, Bifidobacterium, and Chryseobacterium were associated with NP or CM. The 96 microbiota composition in EF did not fully reflect that in EB, although their association with 97 clinical outcome was consistent. 98 METHODS 99 Study design and sample size calculation 100 This was a multicentre prospective observational study analysing the EM of infertile patients 101 with maternal age ≤40 years undergoing IVF or ≤50 years undergoing ovum donation. The 102 EM was analysed in the same endometrial sample in which endometrial receptivity analysis 103 (ERA) was conducted in a cycle prior to embryo transfer of frozen blastocyst stage embryos 104 (day 5/6). Patients were all assessed in a hormone replacement therapy cycle after 120 h of 105 progesterone administration. The EF sample was aspirated before EB collection for EM 106 analysis by 16S rRNA sequencing. The EB was divided into two pieces for the study of 107 endometrial receptivity and EM analysis. Patients were treated following the standard 108 protocols in each clinic and the embryo was transferred on the day recommended by the ERA 109 test result using the same hormonal protocol as for the diagnostic cycle. 110 The main objectives of this prospective study were to validate our pilot study of
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