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Functional and Taxonomic Dysbiosis of the Gut, Urine, and Semen Microbiomes in Male Infertility - Beyond the Abstract

From its initial description by Leeuwenhoek1 over three centuries ago to the discovery of its necessity for egg fertilization a hundred years later;2 the spermatozoon is now appreciated as a crucial but incompletely understood component of mammalian reproduction. Serendipitously, the Italian physiologist who first described fertilization with sperm and egg3 – Lazzaro Spallanzani – also performed instrumental experiments that helped form the genesis of germ theory and paved the way for future microbiology work by Louis Pasteur.4 Despite this serendipitous historical confluence, the notion that semen was sterile remained dogma for over two hundred years.



With the advent of next-generation sequencing, it is now increasingly clear that few – if any – human tissues and fluids (including semen) are truly sterile, and the presence of the microbiome may play roles in both symbiosis and dysbiosis throughout the human body and specifically including the testicle. In the current study, we explored the relationship between the genitourinary and gastrointestinal microbiome as they relate to male reproductive health. Despite the recent completion of the Human Microbiome Project in 2016,5 seminal fluid was not included as a sample source, and no comprehensive evaluation of the semen, urine, and gut microbiome has yet been reported.

To address this, we sought to explore this relationship in young men of reproductive age. We identified similarities between the urinary and seminal microbiomes, which as expected differ significantly in composition when compared to the gut microbiome. Our data also identified significant differences in both the genitourinary and gastrointestinal taxonomic makeup of the infertile microbiome, as well as key metabolic pathways such as the S-adenosyl-L-methionine cycle that may be driving a causal relationship with infertility.

These findings undoubtedly raise more questions than answers. How can the gut microbiome remotely influence spermatogenesis, which occurs behind a tight blood-testis barrier? Are the striking increases in anaerobes in men with varicocele clinically relevant, and do they contribute to the subfertility seen in some, but not all, men with a varicocele? How can these preliminary findings be leveraged to improve clinical care for infertile men? Much like Leeuwenhoek peering into the microscope and for the first time to catch a glimpse of the minuscule world that lies within, this first glimpse into the world of the male reproductive microbiome will require far more study to understand and perhaps one day manipulate for the benefit of our patients.

Written by: Scott Lundy, MD, PhD, Resident Physician, Urology, Glickman Urological & Kidney Institute, Clinical Instructor of Surgery, Lerner College of Medicine, Cleveland Clinic Foundation, Cleveland, OH

References:

  1. Howards, S. S. Antoine van Leeuwenhoek and the discovery of sperm. Fertil. Steril. 67, 16–17 (1997).
  2. Wade, W. Unculturable bacteria - The uncharacterized organisms that cause oral infections. J. R. Soc. Med. 95, 81–83 (2002).
  3. De Felici, M. & Dolci, S. From testis to teratomas: A brief history of male germ cells in mammals. Int. J. Dev. Biol. 57, 115–121 (2013).
  4. Ariatti, A. & Mandrioli, P. Lazzaro spallanzani: A blow against spontaneous generation. Aerobiologia (Bologna). 9, 101–107 (1993).
  5. Langille, M. G. I. et al. Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences. Nat. Biotechnol. 31, 814–821 (2013).

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