ERKEK İNFERTİLİTESİNDE SEMEN MİKROBİYOM DİSBİYOZU

Year 2025, Volume: 26 Issue: 2, 179 - 189, 28.04.2025

Hatice Nur Şeflek , Fatma Zehra Erbayram , Semih Tokak

https://doi.org/10.18229/kocatepetip.1123730

Abstract

İnfertilite, önemli bir sağlık sorunudur ve dünya çapında giderek artmaktadır. Her iki partnerin de ilk çocuk sahibi olma yaşının ileri yaşlara kayması ve yaşam tarzındaki değişiklikler, infertilite insidansının artışına katkıda bulunmuştur. Çiftlerde infertilite durumunun %50’si erkek infertilitesine bağlıdır. İn vitro çalışmalar, bakterilerin sperm fonksiyonunu olumsuz etkileyebileceğini göstermektedir. Bakterilerin; hareketli spermlerin aglütinasyonu, apopitoz indüksiyonu, immobilizasyon faktörlerinin üretimi ve akrozom reaksiyonunun bozulması da dahil olmak üzere, sperm fonksiyonunu etkileyen birçok mekanizmada önemli rolü olduğu ortaya konulmuştur. Azoospermik hastalarda biyolojik çeşitlilikte de genel bir azalma olduğu gösterilmiştir. Kültüre dayalı çalışmalar ile, semen örneklerinde geniş bir bakteri spektrumu saptanmış, bununla beraber semen mikrobiyomunun sperm fonksiyonu ve infertilite üzerindeki etkisine ilişkin kanıtlar çelişkili olmaya devam etmektedir. Daha önce yapılan çalışmalarda semende birkaç bakteri türü erkek infertilitesi ile ilişkilendirilmiştir. Anaerococcus varlığı ile düşük sperm kalitesi, Prevotella varlığı ile anormal sperm hareketliliği, Lactobacillus varlığıyla normal sperm morfolojisinin ilişkili olduğu bildirilmiştir. Yeni nesil dizileme (NGS) tekniklerinin kullanılması, insan mikrobiyomunun daha iyi anlaşılmasını sağlamış ve disbiyozun insan sağlığını etkilediği kanıtlanmıştır. Yakın zamana kadar infertil erkeklerdeki mikrobiyom çalışmalarının birçoğu polimeraz zincir reaksiyon (PCR) tabanlı ya da kültür yöntemine dayalı çalışmalar iken seminal mikrobiyomun infertilite üzerindeki etkisini karakterize etmek için yeni nesil dizileme tekniklerini kullanan sınırlı sayıda yayınlanmış veri bulunmaktadır. Bu derlemede amaç, infertil erkeklerin semendeki bakteri kompozisyonunu, yeni nesil dizileme teknikleriyle araştıran güncel çalışmalara odaklanarak mikrobiyota ile semen kalitesi arasındaki ilişkinin kapsamlı analizine katkıda bulunmaktır. Bu konuda yapılacak çalışmalar, seminal mikrobiyotanın infertil erkeklerdeki rolünün daha iyi anlaşılmasına olanak sağlayacaktır.

Keywords

Erkek infertilitesi, Semen, Metagenomik, Mikrobiyota, NGS.

SEMEN MICROBIOME DYSBIOSIS IN MALE INFERTILITY

Abstract

Infertility is a significant health issue that is increasing globally. The shift in the age at which both partners have their first child to older ages, combined with lifestyle changes, has contributed to the rise in infertility rates. Approximately 50% of infertility cases in couples are attributed to male infertility. In vitro studies have shown that bacteria can negatively affect sperm function. Bacteria play a crucial role in various mechanisms that influence sperm function, including the agglutination of motile sperm, induction of apoptosis, production of immobilization factors, and disruption of the acrosome response. A general decrease in biodiversity has also been demonstrated in azoospermic patients. Culture-based studies have identified a wide range of bacteria in semen samples, but evidence regarding the effects of the semen microbiome on sperm function and infertility remains inconclusive. Previous studies have linked certain types of bacteria in semen to male infertility. It has been reported that the presence of Anaerococcus is associated with low sperm quality, the presence of Prevotella with abnormal sperm motility, and the presence of Lactobacillus with normal sperm morphology. The use of next-generation sequencing (NGS) techniques has provided a better understanding of the human microbiome and has shown that dysbiosis (microbial imbalance) affects human health. Until recently, most microbiome studies in infertile men were based on polymerase chain reaction (PCR) or culture-based methods. However, limited published data have used next-generation sequencing techniques to characterize the effect of the seminal microbiome on infertility. This review aims to contribute to the comprehensive analysis of the relationship between the microbiota and semen quality by focusing on recent studies that investigate the bacterial composition in the semen of infertile men using next-generation sequencing techniques. Future studies on this topic will enhance our understanding of the role of the seminal microbiota in male infertility.

Keywords

Male infertility, Semen, Metagenomics, Microbiota, NGS

References

• 1. Zegers-Hochschild F, Adamson GD, Dyer S, et al. The International Glossary on Infertility and Fertility Care. Hum Reprod. 2017;32(9):1786-801.
• 2. Ombelet W, Cooke I, Dyer S, Serour G, Devroey P. Infertility and the provision of infertility medical services in developing countries. Hum Reprod Update. 2008;14(6):605-21.
• 3. Cariati F, D’Argenio V, and Tomaiuolo R. The evolving role of genetic tests in reproductive medicine. Journal of translational medicine. 2019;17(1):1-33.
• 4. WHO, WHO, Manual for the StandardisedInvestigation and Diagnosis of the Infertile Couple. 2000.
• 5. Keck C, Gerber-Schäfer C, Clad A, Wilhelm C, Breckwoldt M. Seminal tract infections: impact on male fertility and treatment options. Human Reproduction Update. 1998;4(6):891-903.
• 6. Villegas J, Schulz M, Soto L, Sanchez R. Bacteria induce expression of apoptosis in human spermatozoa. Apoptosis. 2005;10(1):105-10.
• 7. Kaur S. and V. Prabha. Receptor mediated amelioration of the detrimental effects of sperm agglutinating factor on sperm parameters. Andrology. 2013;1(4):624-31.
• 8. Núñez-Calonge R, Caballero P, Redondo C, Baquero F, Martínez-Ferrer M, Meseguer MA. Ureaplasma urealyticum reduces motility and induces membrane alterations in human spermatozoa. Hum Reprod. 1998;13(10):2756-61.
• 9. Boguen R, Treulen F, Uribe P, Villegas JV. Ability of Escherichia coli to produce hemolysis leads to a greater pathogenic effect on human sperm. Fertil Steril. 2015;103(5):1155-61.
• 10. Ma XP. and XQ. Gao. The effect of Ureaplasma urealyticum on the level of P34H expression, the activity of hyaluronidase, and DNA fragmentation in human spermatozoa. Am J Reprod Immunol. 2017;77(1):e12600.
• 11. Jungwirth A, Diemer T, Kopa Z, Krausz C, Minhas S, Tournaye H. Male Infertility, in European Association of Urology. http://uroweb.org/guide lines/ compi latio ns-of-all-guide lines/. 20.04.2022.
• 12. Henkel R. R. Leukocytes and oxidative stress: dilemma for sperm function and male fertility. Asian Journal of Andrology. 2011;13(1): 43.
• 13. Ochsendorf F. Infections in the male genital tract and reactive oxygen species. Human Reproduction Update. 1999;5(5):399-420.
• 14. Simon L, Castillo J, Oliva R, Lewis SE. Relationships between human sperm protamines, DNA damage and assisted reproduction outcomes. Reprod Biomed Online. 2011;23(6):724-34.
• 15. Simon L, Murphy K, Shamsi MB, et al. Paternal influence of sperm DNA integrity on early embryonic development. Hum Reprod. 2014;29(11):2402-12.
• 16. Lewis SE and RJ Aitken. DNA damage to spermatozoa has impacts on fertilization and pregnancy. Cell Tissue Res. 2005;322(1):33-41.
• 17. Koedooder R, Mackens S, Budding A, et al. Identification and evaluation of the microbiome in the female and male reproductive tracts. Hum Reprod Update. 2019;25(3):298-325.
• 18. Jordan JA and MB Durso, Real-time polymerase chain reaction for detecting bacterial DNA directly from blood of neonates being evaluated for sepsis. J Mol Diagn. 2005;7(5):575-81.
• 19. Clarridge JE. 3rd, Impact of 16S rRNA gene sequence analysis for identification of bacteria on clinical microbiology and infectious diseases. Clin Microbiol Rev. 2004;17(4):840-62.
• 20. Woese CR and GE Fox, Phylogenetic structure of the prokaryotic domain: the primary kingdoms. Proc Natl Acad Sci U S A. 1977;74(11):5088-90.
• 21. Woo PC, Lau SK, Teng JL, Tse H, Yuen KY. Then and now: use of 16S rDNA gene sequencing for bacterial identification and discovery of novel bacteria in clinical microbiology laboratories. Clin Microbiol Infect. 2008;14(10):908-34.
• 22. Consortium THMP. A framework for human microbiome research. Nature. 2012;486(7402):215-21.
• 23. Witkin SS. The vaginal microbiome, vaginal anti-microbial defence mechanisms and the clinical challenge of reducing infection-related preterm birth. Bjog. 2015;122(2):213-8.
• 24. García-Velasco JA, Menabrito M, and Catalán IB. What fertility specialists should know about the vaginal microbiome: a review. Reprod Biomed Online. 2017;35(1):103-12.
• 25. Champer M, Wong AM, Champer J, et al. The role of the vaginal microbiome in gynaecological cancer. Bjog. 2018;125(3):309-15.
• 26. Freitas AC, Chaban B, Bocking A, Rocco M, Yang S, Hill JE, Money DM. The vaginal microbiome of pregnant women is less rich and diverse, with lower prevalence of Mollicutes, compared to non-pregnant women. Sci Rep. 2017;7(1):9212.
• 27. Stout MJ, Zhou Y, Wylie KM, Tarr PI, Macones GA, Tuuli MG. Early pregnancy vaginal microbiome trends and preterm birth. Am J Obstet Gynecol. 2017;217(3):356-57.
• 28. Mändar R, Punab M, Borovkova N, et al. Complementary seminovaginal microbiome in couples. Res Microbiol. 2015;166(5):440-7.
• 29. Castillo J, Jodar M, and Oliva R, The contribution of human sperm proteins to the development and epigenome of the preimplantation embryo. Human Reproduction Update.2018;24(5):535-55.
• 30. Altmäe S, Franasiak JM, and Mändar R. The seminal microbiome in health and disease. Nature Reviews Urology. 2019;16(12):703-21.
• 31. Jodar M, Sendler E, and Krawetz SA. The protein and transcript profiles of human semen. Cell and tissue research.2016;363(1):85-96.
• 32. Javurek AB, Spollen WG, Ali AMM, et al. Discovery of a novel seminal fluid microbiome and influence of estrogen receptor alpha genetic status. Scientific reports. 2016;6(1):1-14.
• 33. Mändar R. Microbiota of male genital tract: impact on the health of man and his partner. Pharmacological research. 2013;69(1):32-41.
• 34. Weng SL, Chiu CM, Lin FM, et al. Bacterial communities in semen from men of infertile couples: metagenomic sequencing reveals relationships of seminal microbiota to semen quality. PloS one. 2014;9(10):e110152.
• 35. Monteiro C, Marques PI, Cavadas B, et al. Characterization of microbiota in male infertility cases uncovers differences in seminal hyperviscosity and oligoasthenoteratozoospermia possibly correlated with increased prevalence of infectious bacteria. American Journal of Reproductive Immunology. 2018;79(6):12838.
• 36. Hou D, Zhou X, Zhong X, et al. Microbiota of the seminal fluid from healthy and infertile men. Fertility and sterility. 2013;100(5):1261-9.
• 37. Baud D, Pattaroni C, Vulliemoz N, Castella V, Marsland BJ, Stojanov M. Sperm microbiota and its impact on semen parameters. Frontiers in Microbiology. 2019;10:234.
• 38. Alfano M, Ferrarese R, Locatelli I, et al. Testicular microbiome in azoospermic men-first evidence of the impact of an altered microenvironment. Human Reproduction. 2018; 33(7):1212-7.
• 39. Cavarretta I, Ferrarese R, Cazzaniga W, et al. The microbiome of the prostate tumor microenvironment. European urology. 2017;72(4):625-31.
• 40. Chen H, Luo T, Chen T, Wang G. Seminal bacterial composition in patients with obstructive and non‑obstructive azoospermia. Experimental and therapeutic medicine. 2018;15(3):2884-90.
• 41. Baker JM, Chase DM, and Herbst-Kralovetz MM. Uterine microbiota: residents, tourists, or invaders? Frontiers in Immunology. 2018;9:208.
• 42. Jeon SJ, Cunha F, Vieira-Neto A. Blood as a route of transmission of uterine pathogens from the gut to the uterus in cows. Microbiome. 2017;5(1):1-13.
• 43. Türk S, Mazzoli S, Štšepetova J, Kuznetsova J, Mändar R. Coryneform bacteria in human semen: inter-assay variability in species composition detection and biofilm production ability. Microbial ecology in health and Disease.2014;25(1):22701.
• 44. Magri V, Boltri M, Cai T, et al. Multidisciplinary approach to prostatitis. Archivio Italiano di Urologia e Andrologia. 2018;90(4):227-48.
• 45. Cai T, Tessarolo F, Caola I, et al. Prostate calcifications: A case series supporting the microbial biofilm theory. Investigative and Clinical Urology. 2018;59(3):187-93.
• 46. Bartoletti R, Cai T, Nesi G, et al. The impact of biofilm-producing bacteria on chronic bacterial prostatitis treatment: results from a longitudinal cohort study. World journal of urology. 2014;32(3):737-42.
• 47. Willeén M, Hoist E, Myhre EB, Olsson AM. The bacterial flora of the genitourinary tract in healthy fertile men. Scandinavian journal of urology and nephrology. 1996;30(5): 387-93.
• 48. Ivanov IB, Kuzmin MD, and Gritsenko VA, Microflora of the seminal fluid of healthy men and men suffering from chronic prostatitis syndrome. International journal of andrology. 2009;32(5):462-7.
• 49. Kermes K, Punab M, Lõivukene K, Mändar R. Anaerobic seminal fluid micro-flora in chronic prostatitis/chronic pelvic pain syndrome patients. Anaerobe. 2003;9(3):117-23.
• 50. Punab M, Lõivukene K, Kermes K, Mändar R. The limit of leucocytospermia from the microbiological viewpoint. Andrologia. 2003;35(5):271-8.
• 51. Korrovits P, Punab M, Türk S, Mändar R. Seminal microflora in asymptomatic inflammatory (NIH IV category) prostatitis. European urology. 2006;50(6):1338-46.
• 52. Türk S, Korrovits P, Punab M, Mändar R. Coryneform bacteria in semen of chronic prostatitis patients. international journal of andrology. 2007;30(2):123-8.
• 53. Petrova MI, Lievens E, Malik S, Imholz N, Lebeer S. Lactobacillus species as biomarkers and agents that can promote various aspects of vaginal health. Frontiers in Physiology. 2015;6: 81.
• 54. Barbonetti A, Cinque B, Vassallo MRC, et al. Effect of vaginal probiotic lactobacilli on in vitro–induced sperm lipid peroxidation and its impact on sperm motility and viability. Fertility and Sterility. 2011;95(8):2485-8.
• 55. Rehewy M, Hafez E, Thomas A, Brown W. Aerobic and anaerobic bacterial flora in semen from fertile and infertile groups of men. Archives of Andrology. 1979;2(3):263-8.
• 56. Balmelli T, Stamm J, Dolina‐Giudici M, et al. Bacteroides ureolyticus in men consulting for infertility. Andrologia. 1994;26(1):35-8.
• 57. Vandamme P, Debruyne L, De Brandt E, Falsen E. Reclassification of Bacteroides ureolyticus as Campylobacter ureolyticus comb. nov., and emended description of the genus Campylobacter. Int J Syst Evol Microbiol. 2010; 60(9):2016-22.
• 58. Kiessling AA, Desmarais BM, Yin HZ, Loverde J, Eyre RC. Detection and identification of bacterial DNA in semen. Fertility and Sterility. 2008;90(5):1744-56.
• 59. Jarvi K, Lacroix JM, Jain A, Dumitru I, Heritz D, Mittelman MW. Polymerase chain reaction-based detection of bacteria in semen. Fertility and sterility. 1996;66(3):463-7.
• 60. Liu CM, Osborne BJ, Hungate BA. The semen microbiome and its relationship with local immunology and viral load in HIV infection. PLoS pathogens. 2014;10(7):e1004262.
• 61. Mändar R, Punab M, Korrovits P, et al. Seminal microbiome in men with and without prostatitis. International Journal of Urology. 2017;24(3):211-6.
• 62. Monteiro C, Marques PI, Cavadas B, et al. Characterization of microbiota in male infertility cases uncovers differences in seminal hyperviscosity and oligoasthenoteratozoospermia possibly correlated with increased prevalence of infectious bacteria. Am J Reprod Immunol. 2018;79(6):12838.
• 63. Chen H, Luo T, Chen T, Wang G. Seminal bacterial composition in patients with obstructive and non- obstructive azoospermia. Exp Ther Med. 2018;15(3):2884-90.