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Microbiota y reproducción: ¿más allá de la vulva y la vagina?

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Juan Antonio García Velasco

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Microbiota y reproducción: ¿más allá de la vulva y la vagina?

  1. 1. Microbiota y reproducción: ¿más allá de la vulva y la vagina? Dr. Juan A Garcia-Velasco IVI Madrid
  2. 2. The Endometrial Factor
  3. 3. E 17 18 19 20 21 22 23 P P+4 P+5 P+6 P+7 P+8 P+9 P+10 Endometrial receptivity Embryos attach ONLY under optimal conditions
  4. 4. The Puzzle of the Endometrial Factor Omics Visuals Ultrasound Kasius et al., 2014 Histology Noyes al., 1950 Coutifaris et al., 2004 Murray et al., 2007 Secretomics Van der Gaast et al., 2002, 2009 Vilella et al., 2013 Transcriptomics Riesewijk et al., 2003 Simon et al., 2005 Diaz-Gimeno et al., 2011, 2013 Aghajanova et al., 2012 Microbes Microbiota Franasiak et al., 2015 Moreno et al., 2016 Doppler Kupesick et al., 2001 Omics Hysteroscopy Rambouts et al., 2016 Immunohistochemistry Lessey et al., 1995 Kliman et al., 2006
  5. 5.  Dosage for COS (AMH, AFC, BMI, age)  Type of protocol  IVF vs ICSI  Embryo number and quality  ……… Personalized Medicine However: endometrial status at ET is treated equally neglected customized approach lack of knowledge? Embryo transfer TIMING can be personalized
  6. 6. Technology helps
  7. 7. Transcriptome Proteome Metabolome The age of –OMICS Different subtypes of disease TRANSCRIPTION TRANSDUCTION Transcription regulation Alternative splicing Transduction regulation DNA RNA mRNA Protein METABOLITES
  8. 8. The Human Microbiome Project • The human body contains 10-fold more microbial cells than human cells – Accounts for 1-3% of total body mass – Some estimate as much as 2-6 lbs • Termed the “second human genome” – Linked in health & disease: diabetes, reumathoid artritis, muscular dystrophy, multiple sclerosis, fibromyalgia, and cancer HMP, PLoS 2012 Wu, Nature Medicine 2009
  9. 9. hoy
  10. 10. Google: 6.900.000 hitsPubMed : 46,000 hits 2017
  11. 11. Techniques to study microbiota Garcia-Velasco et al. RBMO 2017
  12. 12. P Principal coordinate - 1 Principalcoordinate-2 Principal Coordinate Analysis
  13. 13. Human microbiome projectMicrobiota and disease • Diabetes, CV…..
  14. 14. • Un microbioma saludable presenta baja diversidad de bacterias, siendo rico fundamentalmente en lactobacilli. • El paper de los Lactobacilli es proteger el epitelio vaginal fabricando una capa gruesa que proteja la vagina de la infección por patógenos (pH ~4.5) Microbioma vaginal
  15. 15. Healthy women have a low diverse vaginal microbiota (few microbial species present), mainly lactobacilli Women with unhealthy vagina shows dysbiosis (high number of diverse microbial species) Vaginal Microbiota
  16. 16. Vínculo entre microbiota vaginal y fertilidad 1.- Live birth Shannon Diversity Index (SDI). Hyman et al J. Assist Reprod Genet 2012;29:105–115 2.- Moore DE et al. Fertil Steril 2000;74:1118–1124 3.- Sirota et al. Semin Reprod Med 2014;32:35–42 • Un microbioma rico en Lactobacilli y baja diversidad de otras bacterias se asocia con buenos resultados en FIV 1,2 • Los lactobacillus que producen H2O2 tienen un impacto positivo en la tasa de recién nacido vivo (88% vs 37%)2 • Durante un ciclo de FIV, 76% de la microbiota del tracto reproductivo de las pacientes varía por los cambios hormonales inducidos por el tratameinto
  17. 17. Vagina con microbiota saludable rico en Lactobacilli Disbiosis puede estar cuasada por presencia de otras especies Esto tiene un impacto en fertilidad
  18. 18. Human microbiome projectVaginal microbiome of healthy women Ravel J et al. PNAS 2011; 108 (suppl 1): 4680-7 394 women Heatmap of log 10-transformed microbial taxa found in vaginal bacterial communities of 394 women of reproductive age
  19. 19. Human microbiome projectVaginal microbiome of healthy women Ravel J et al. PNAS 2011; 108 (suppl 1): 4680-7 Bacterial community groups – ethnic variations
  20. 20. Human microbiome projectLow lactobacilli and risk of infection • 5x higher risk of Chlamydia infection • 3x higher risk of HPV • 3x higher risk of HIV Tamarelle J et al. Clin Microbiol Infect 2018; van de Wijgert J. Sex Transm Dis 2009
  21. 21. Human microbiome projectUteri is not sterile Mitchell CM et al. Am J Obstet Gynecol 2015 UGT Vagina L. inners 45% 61% Prevotella spp 33% 76% L. crispatus 33% 56%
  22. 22. Human microbiome projectUteri is not sterile Mitchell CM et al. Am J Obstet Gynecol 2015
  23. 23. Human microbiome projectThe continuum of microbiota along the female reproductive tract Chen C et al. Nature Comm 2017
  24. 24. The stability of VAGINAL microbiota Kroon et al. Fertil Steril 2018
  25. 25. Endometrial Microbiome Haahr et al. Hum Reprod 2016 Abnormal vaginal microbiota is associated with poor reproductive outcome
  26. 26. The relevance of UTERINE microbiota Simon C. Fertil Steril 2018
  27. 27. 35 INFERTILE PATIENTS UNDERGOING ART IVF PATIENTS Endometrial fluid MICROBIOTA Healthy Altered Endometrial biopsy Receptive Non-receptive ERA TEST ENDOMETRIAL MICROBIOTA & RECEPTIVITY EMBRYO TRANSFER YES NO PREGNANCY OUTCOME PREGNANT Non-pregnant ENDOMETRIAL MICROBIOTA & IMPLANTATION ONGOING PREGNANCY YES NO ENDOMETRIAL MICROBIOTA & PREGNANCY OUTCOME Moreno et al. Am J Obstet Gynecol 2016 Endometrial Microbiome
  28. 28. COMPARISON OF THE AVERAGE BACTERIAL COMMUNITIES IN ENDOMETRIUM AND VAGINA MICROBIOTA OF FERTILE SUBJECTS Only found in endometrial samples of these women EF= endometrial fluid VA= vaginal aspirate 11 Endometrial Microbiome Moreno et al. Am J Obstet Gynecol 2016
  29. 29. 1.00 0.00 0.75 0.50 0.25 Live birth No PregnantMiscarriage LOW ABUNDANCE OF Lactobacillus IN ENDOMETRIAL MICROBIOTA IS ASSOCIATED WITH POOR REPRODUCTIVE OUTCOMES IN IVF PATIENTS Moreno et al., AJOG 2016 29 Moreno et al. Am J Obstet Gynecol 2016
  30. 30. Characteristics and Outcomes LDM (n=17) NLDM (n=15) p-value Age (y) 40.06±3.47 39.00±5.09 0.49 BMI (kg/m2 ) 24.18±5.18 22.45±4.02 0.30 Previous pregnancies (n) 1.71±2.44 1.53±2.32 0.84 Previous miscarriages (n) 1.53±2.21 1.14±1.56 0.58 Metaphase II oocytes per cycle (n) 11.94±4.27 10.20±4.81 0.28 Fertilization rate per cycle 157/203 (77.34%) 118/153 (77.12%) 0.62 Transferred embryos per cycle (n) 1.65±0.49 1.73±0.59 0.65 Months between EF and transfer (n) 2.82±2.55 1.80±1.08 0.16 Pregnancy rate per transfer 12/17 (70.6%) 5/15 (33.3%) 0.03* Implantation rate per transfer 17/28 (60.7%) 6/26 (23.1%) 0.02* Ongoing pregnancy per transfer 10/17 (58.5%) 2/15 (13.3%) 0.02* Miscarriage rates (%) 2/10 (16.7%) 3/5 (60.0%) 0.07 Live birth rate per transfer 10/17 (58.8%) 1§ /15 (6.7%) 0.002* BMI: body mass index; LDM: Lactobacillus-dominated microbiota; NLDM: non-Lactobacillus-dominated microbiota; *Chi Square (χ² test) and Student’s t-test were performed; *p-value<0.05; §: Voluntary termination of pregnancy. LOW ABUNDANCE OF Lactobacillus IN ENDOMETRIAL MICROBIOTA IS ASSOCIATED WITH POOR REPRODUCTIVE OUTCOMES IN IVF PATIENTS 31 Moreno et al. Am J Obstet Gynecol 2016
  31. 31. ¿Qué nos falta? CONCLUSIONS: First time to asses the effect of a well documented probiotic strain on vaginal microbioma and as well as its variations during an OC cycle. L. rhamnosus CECT 8800 vaginal colonization and safety are shown: it is well-tolerated, increases significantly Lactobacilli presence and has an influence in vaginal microbiota evolving it into healthier vaginotypes. All this may be useful in IVF cycles. Garcia-Velasco et al . ASRM 2018
  32. 32. Results Microbiome evaluation by sequencing 16S rRNA • Higher presence of L. rhamnosus after probiotic vs placebo Garcia-Velasco et al . ASRM 2018
  33. 33. Results • Probiotic microbiome at T3 & T4 clearly different from placebo: probiotic affects vaginal microbiome T3 (end of COS) T4 (3/4 after OPU) Microbiome evaluation by sequencing 16S rRNA Garcia-Velasco et al . ASRM 2018
  34. 34.  El factor endometrial es responsible del 10-20% de los casos de fallo de implantación  La microbiota vaginal y endometrial tiene una relevancia hasta ahora desconocida en reproducción  El porcentaje de Lactobacillus junto con patógenos específicos pueden ayudar a predecir el resultado de un ciclo  La valoración del factor endometrial puede expandirse de la morfología al estudio molecular y/o microbiologia Conclusiones
  35. 35. Gracias juan.garcia.velasco@ivi.es

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