Characterisation and comparison of semen microbiota and bacterial load in men with infertility, recurrent miscarriage, or proven fertility

Mean sperm counts reported within clinical studies have reduced annually by 2.6% since 2000 (Levine et al., 2017). Male factor accounts for approximately half of all cases of infertility, yet there are limited available interventions to improve sperm quality. Understanding the pathogenesis of male infertility may reveal novel therapeutic approaches for treating affected couples.

Symptomatic genitourinary infection is an established cause of male infertility, which may be detected by semen culture and treated with antibiotics (Eini et al., 2021; Jung et al., 2016). The current European Association of Urology guidance states that whilst antibiotics may improve overall semen quality, there is no evidence of increased pregnancy rates after antibiotic treatment of the male partner (Brunner et al., 2019; Jung et al., 2016). Seminal leucocytes release bactericidal reactive oxygen species (ROS) in response to infection; however, paradoxically, this may damage sperm DNA and impair semen quality (Aitken et al., 2022). We and others have reported that asymptomatic men affected by recurrent pregnancy loss (RPL), infertility, or impaired preimplantation embryo development have increased risks of high seminal ROS and sperm DNA fragmentation (Benchaib et al., 2007; Jayasena et al., 2019; Aitken and Bakos, 2021; De Iuliis et al., 2009; Vorilhon et al., 2018; Agarwal et al., 2006). It is therefore plausible that asymptomatic seminal infections may be associated with impaired reproductive function in some men. Since semen culture has a limited scope for studying the seminal microbiota due to its inability to identify all present microbiota, next-generation sequencing (NGS) approaches have been reported recently by a growing number of investigators (Hou et al., 2013; Weng et al., 2014; Monteiro et al., 2018; Baud et al., 2019; Lundy et al., 2021; Garcia-Segura et al., 2022; Yang et al., 2020). These studies, with varying methodologies, have produced inconsistent and conflicting results. As such, the composition of semen microbiota and its associations with clinical and molecular markers of male reproduction remain understudied. Elucidation of an association would have wide clinical application with therapeutic potential coupled with reproductive disorders (Altmäe et al., 2019).

We hypothesised that semen microbiota composition associates with functional semen parameters, including ROS levels and sperm DNA fragmentation. To test this, we explored relationships between metataxonomic profiles of bacteria, bacterial copy number, and key parameters of sperm function and quality in semen samples collected from 223 men, including those diagnosed with male factor infertility (MFI), unexplained infertility (UI), partners affected by recurrent miscarriage, and paternity-proven controls.

We report the largest study to date investigating the seminal microbiota from patients suffering a range of adverse reproductive outcomes, including UI, MFI, and RPL. Moreover, we provide a detailed assessment of the relationship between semen microbial diversity, load, and compositional structure with both molecular and classical seminal parameters. We identified three main clusters present in all study groups. Whilst overall bacterial composition was not associated with aberrations in semen analysis, ROS, and DNA fragmentation, men with unidentified Flavobacterium species were more likely to have abnormal semen quality or sperm morphology.

Several recent studies have indicated the existence of a semen microbiota; however, these studies have been limited to small sample sizes and have failed to reach consensus on the compositional structure of the microbiota or its biological relevance, particularly in the context of sperm function and quality (Hou et al., 2013; Weng et al., 2014; Baud et al., 2019; Lundy et al., 2021; Garcia-Segura et al., 2022; Yang et al., 2020; Veneruso et al., 2023). By analysing the samples of 233 men with various reproductive disorders, we offer not only a robust assessment of association between the microbiota and classical seminal parameters, but also key functional parameters including seminal ROS and sperm DNA damage. We incorporated stringent negative controls to permit removal of sequences likely originating from extraction kits and reagents known to contaminate low biomass samples such as semen (Weng et al., 2014; Baud et al., 2019; Veneruso et al., 2023). Molina et al. report that 50–70% of detected bacterial reads may be environmental contaminants in a sample from extracted testicular spermatozoa (Molina et al., 2021); with the addition of passage along the urethra, it is likely that contamination of ejaculated semen would be much higher.

Mapping of genera-level relative abundance data enabled semen samples to be categorised into three major clusters characterised by differing relative abundance of Streptococcus, Prevotella, Lactobacillus, and Gardnerella. Unlike previous studies, we used an objective statistical approach (i.e. silhouette methods) to determine the optimal number of microbial clusters supported by the data. These findings are largely consistent with earlier semen metataxonomic profiling studies, reporting clusters enriched for Streptococcus, Lactobacillus, and Prevotella (Hou et al., 2013; Weng et al., 2014; Baud et al., 2019). Moreover, Baud et al. reported increased bacterial richness in the Prevotella-enriched cluster, which we also observed (Baud et al., 2019). This may suggest that certain compositional characteristics of seminal microbiota are conserved across populations. However, similar modelling of species-level data failed to identify statistically robust clusters. This contrasts with other niches such as the vagina where reproducible clusters based on species-level metataxonomic profiles have been demonstrated, reflecting mutualistic relationships between specific species and the host, which have co-evolved over long periods of time (Pruski et al., 2021; France et al., 2020). It is possible, therefore, that our findings indicate that microbiota detected in semen are likely the result of transient colonisation events. Consistent with this, several species known to be commensal to the penile skin including Streptococcus, Corynebacterium, and Staphylococcus, or the female genital tract including Gardnerella and Lactobacillus, were observed in semen samples (Byrd et al., 2018). This is in keeping with data suggesting microbiota transference during sexual intercourse (Ma, 2022). It remains possible that a proportion of bacteria detected in semen reflects contamination of the sample acquired during the collection procedure. Studies undertaking assessment of female partner microbiota profiles as well as temporal profiling of semen microbiota would improve understanding of potential dynamic restructuring of semen microbiota compositions. This has been done in part by Baud et al. by studying the subfertile couple as a unit to establish if there is a ‘couple microbiota’ (Baud et al., 2023). They took samples from 65 couples with a range of pathologies including idiopathic infertility. From each woman, they took vaginal swabs and follicular fluid samples. From each man, they took semen samples and penile swabs. They undertook extensive negative control series and stringent in silico elimination of possible contaminants. They found the male microbiota to be much more diverse than the female, with 90% of female samples being Lactobacillus-dominant. Intra-personal male samples, i.e., semen and penile swabs from the same man, bore more similarity to each other than inter-personal samples of the same sample type, i.e., semen or penile swab comparisons between men (Baud et al., 2023). They identified that the male microbiota had very little impact on the microbiota of the female sexual partner (Baud et al., 2023). Lack of information regarding the sexual activity of the enrolled couples limits this study somewhat.

Several previous studies have described semen microbiota composition to genera level, and some have reported associations between specific genera and parameters of semen quality and function (Hou et al., 2013; Weng et al., 2014; Baud et al., 2019; Lundy et al., 2021; Garcia-Segura et al., 2022; Yang et al., 2020; Veneruso et al., 2023). However, in many cases, these studies have failed to consider multiple comparisons testing, likely leading to the reporting of spurious associations. We did not observe any significant associations between bacterial clusters, richness, diversity or load with traditional seminal parameters, sperm DNA fragmentation, or semen ROS. This is in contrast with Veneruso et al., who reported that in infertile patients, semen bacterial diversity and richness was decreased, whereas Lundy et al. reported that diversity was increased in infertile patients (Lundy et al., 2021; Veneruso et al., 2023). Further, Lundy et al. reported Prevotella abundance to be inversely associated with sperm concentration; this was not replicated in our study (Lundy et al., 2021). There are several possible reasons accounting for the high heterogeneity in results, including differences in methodology used to assess the microbial component of semen as well as differences in study design (Farahani et al., 2021). For example, time of sexual abstinence prior to sample production as well as sample processing time often differs between studies, which has been shown to impact microbiological composition of semen (Yao et al., 2020).

The only association between bacterial taxa and semen parameters to withstand false detection rate testing for multiple comparisons detected in our study was between Flavobacterium and abnormal semen quality and sperm morphology (q=0.02). The Flavobacterium genus taxon we identified as significantly associated with abnormal semen quality and sperm morphology was present in 36.28% of the samples, with a mean relative abundance of 1.15% in those samples. This information and the mention of previous findings of Flavobacterium in contamination studies have been added to the discussion. Flavobacterium are gram-negative physiologically diverse aerobes, some of which are pathogenic (Waskiewicz A, 2014). Flavobacterium was recently identified as a dominant genus in immature sperm cells retrieved from testicular biopsies of infertile men in a study by Molina et al., 2021. However, in contrast to these findings, a recent smaller study investigating semen collected from 14 sperm donors and 42 infertile idiopathic patients reported an association between Flavobacterium and increased sperm motility but a negative correlation with sperm DNA fragmentation (Garcia-Segura et al., 2022). The genus Flavobacterium was defined in 1923 to encompass gram-negative, non-spore-forming rods of yellow pigment (Holmes and McMeekin, 1923). The inclusiveness of this definition resulted in a collective of heterogeneous species. By 1984, the genus had been restricted to those that were also non-motile and non-gliding (Holmes and McMeekin, 1923). More recently, with an increase in genomic profiling, many species previously considered to be of genus Flavobacterium have been reclassified to genera Chryseobacterium, Cytophaga, and Weeksella (Bernardet et al., 1996). Increasing numbers of Flavobacterium species are being discovered, such as gondwanense, collinsii, branchiarum, branchiicola, salegens, and scophthalmum (Dobson et al., 1993; Mudarris et al., 1994; Zamora et al., 2013). The allocation of Flavobacterium aquatile to this genus remains controversial due to its motility (Sheu et al., 2013). Flavobacterium species are widely distributed in the environment, including soil, freshwater, and saltwater habitats (Loch and Faisal, 2015; Vela et al., 2007). There are many reports of pathogenic infections of Flavobacterium species in fish; however, human infections are rare (Zamora et al., 2013). A handful of case reports have described opportunistic infections, including pneumonia, urinary tract infection, peritonitis, and meningitis (Sung et al., 2015; Tian et al., 2011; Park and Ryoo, 2016; Mosayebi et al., 2011). Flavobacterium lindanitolerans and Flavobacterium ceti have been isolated as causative agents in some (Zurbuchen et al., 2023; Park and Ryoo, 2016). Case reports also describe Flavobacterium odoratum as a causative agent in urinary tract infection, most often in the immunocompromised or those with indwelling devices (Benedetti et al., 2011; Chauhan et al., 2020; Verma et al., 2018). However, this was one of many species previously of genus Flavobacterium reclassified, in this case to genus Myroides (Vancanneyt et al., 1996). Notably, in our sample, participants were asymptomatic of urinary tract infection.

Though notwithstanding multiple corrections, we did observe several other associations between specific bacterial taxa and semen parameters. For example, samples enriched with Lactobacillus had lower incidence of elevated seminal ROS, a relationship which could largely be accounted for by L. iners, a common member of the cervicovaginal niche (MacIntyre et al., 2017). Various studies have also found Lactobacillus enrichment in semen to associate with normal seminal parameters, especially morphology (Weng et al., 2014; Baud et al., 2019), where Lactobacillus is predominant (Weng et al., 2014). However, an association between samples enriched with Lactobacillus and asthenospermia or oligoasthenospermia has also been described (Yang et al., 2020). We also observed an association between increased sperm DNA fragmentation and samples enriched with Varibaculum, which is consistent with previous reports of increased relative abundance of Varibaculum in semen of infertile men (Veneruso et al., 2023).

A limitation of this and other similar studies is that it was a single institutional study with limited ethnic diversity and potential geographical changes induced by environment or dietary habit. Gut microflora is known to display geographical variability; we cannot exclude that similar geographical variability exists for the seminal microbiota (Suzuki and Worobey, 2014). The universal primers used during NGS may not be universal and may anneal variably to specific bacteria, resulting in over-detection, under-detection, or indeed non-detection of some taxa (Forney et al., 2004; Wintzingerode et al., 1997). A further limitation of this study, and others, is the lack of reciprocal genital tract microbiota testing of the female partners, or paired seminal and urinary samples from male participants. Additionally, we did not have other covariables such as smoking status with which to include in further analyses.

In summary, our study confirms that compositionally, the semen microbiota can be broadly classified into three major groups based upon relative abundance of key bacterial genera. Despite different methodological approaches, a number of studies, including our own, indicate a Prevotella-dominated or Lactobacillus-dominated seminal microbiota, perhaps suggesting a stable microbiota at genera level. Our species-level data, however, failed to show similar clusters, perhaps instead suggesting transient colonisation. Longitudinal studies are required to ascertain the stability of the seminal microbiota. We provide evidence for an association between Lactobacillus abundance and normal seminal parameters. However, our results indicate that no specific semen bacterial composition can robustly differentiate between fertile and infertile men, although a small subset of bacteria may be associated with changes in seminal parameters. Our finding that an unidentified species of Flavobacterium impairs seminal parameters warrants further exploration and may offer the potential for targeted therapies. Larger, multicentred studies as well as mechanistic investigations are required to establish causal links between the semen microbiota and male fertility.

Ethical approval was granted by the West London and Gene Therapy Advisory Committee (GTAC) Research Ethics Committee (approval identifier: 14/LO/1038) and by the Internal Review Board at the Centre for Reproductive and Genetic Health (CRGH) (approval identifier: IRB-0003C07.10.19). Participants were recruited following informed consent from clinics in Imperial College London NHS Trust and the CRGH. No individually identifiable data is presented, so separate consent to publish from participants was not required. Further detailed information on methods used in this study is included in the Supplementary Material.

Semen samples were produced by means of masturbation after 3–7 days abstinence. All semen samples were collected into sterile containers after cleaning of the penis using a sterile wipe. Samples were incubated at 37°C for a minimum of 20 min prior to analysis. An aliquot was collected in a sterile cryovial and stored at –80°C.

Diagnostic semen analysis was carried out according to WHO 2010 guidelines and UK NEQAS accreditation (World Health Organization, 2021; Scheme UNRS, 2023). Seminal analysis was performed in the Andrology Departments of Hammersmith Hospital and CRGH. Microscopic and macroscopic semen qualities were assessed within 60 min of sample production. Semen volume, sperm concentration, total sperm count, progressive motility and total motility count, morphological assessment, anti-sperm antibodies, and leucocyte count were established.

ROS analysis was performed using an in-house developed chemiluminescence assay validated by Vessey et al., 2014. Results are therefore reported as ‘relative light units per second per million sperm’. The upper limit of optimal ROS was internally determined at 3.77 RLU/s/10⁶ sperm (95% CI) (Sergerie et al., 2005).

Sperm DNA fragmentation assessment performed by terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling (TUNEL) assay defined elevated sperm DNA fragmentation as >20% (Sharma et al., 2021). Samples for the Comet assay were sent to the Examen Lab (Belfast, UK) for analysis with elevated sperm DNA fragmentation defined as >27% (Hughes et al., 1996).

DNA extraction was performed on 200 μl of semen using enzymatic lysis and mechanical disruption. Bacterial load was estimated by determining the total number of 16S rRNA gene copies per sample using the BactQuant assay (Liu et al., 2012).

Metataxonomic profiling of semen microbiota was performed using MiSeq sequencing of bacterial V1-V2 hypervariable regions of 16S rRNA genes using a mixed forward primer set 28F-YM GAGTTTGATYMTGGCTCAG, 28F-Borrelia GAGTTTGATCCTGGCTTAG, 28F-Chloroflex GAATTTGATCTTGGTTCAG, and 28F-Bifdo GGGTTCGATTCTGGCTCAG at a ratio of 4:1:1:1 with 388R reverse primers. Sequencing was performed on the Illumina MiSeq platform (Illumina, Inc, San Diego, CA, USA). Following primer trimming and assessment of read quality, amplicon sequence variant (ASV) counts per sample were calculated and denoised using the QIIME2 pipeline (Bolyen et al., 2019) and the DADA2 algorithm (Callahan et al., 2016). ASVs were taxonomically classified to species level using a naive Bayes classifier trained on all sequences from the V1-V2 region of the bacterial 16S rRNA gene present in the SILVA reference database (release 138.1) (Quast et al., 2013; Davis et al., 2018).

Further methodological details can be found in Appendix 3.

Data and material availability statement: The 16S rRNA metataxonomic dataset and the data analysis scripts are publicly available at the European Nucleotide Archive (project accession PRJEB57401) and GitHub (repository link https://github.com/Gscorreia89/semen-microbiota-infertility, copy archived at Zenodo: Correia, 2025) respectively.

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Author details

1. Shahriar Mowla

   Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom

   Contribution

   Data curation, Formal analysis, Investigation, Methodology, Project administration, Writing – review and editing

   Contributed equally with

   Linda Farahani, David A MacIntyre and Channa N Jayasena

   Competing interests

   No competing interests declared

2. Linda Farahani

   1. Wolfson Fertility Unit, Department of Gynaecology, St. Mary’s Hospital, Imperial College NHS Trust, London, United Kingdom
   2. Section of Endocrinology & Investigative Medicine, Imperial College London, London, United Kingdom

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Writing – review and editing

   Contributed equally with

   Shahriar Mowla, David A MacIntyre and Channa N Jayasena

   Competing interests

   No competing interests declared

3. Tharu Tharakan

   1. Section of Endocrinology & Investigative Medicine, Imperial College London, London, United Kingdom
   2. Department of Urology, Charing Cross Hospital, Imperial College NHS Trus, London, United Kingdom

   Contribution

   Data curation, Formal analysis, Investigation, Methodology, Project administration

   Competing interests

   No competing interests declared

4. Rhianna Davies

   Section of Endocrinology & Investigative Medicine, Imperial College London, London, United Kingdom

   Contribution

   Formal analysis, Writing – original draft

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-6922-4553

5. Goncalo DS Correia

   1. Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom
   2. March of Dimes European Prematurity Research Centre, Imperial College London, London, United Kingdom

   Contribution

   Data curation, Formal analysis, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8271-9294

6. Yun S Lee

   1. Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom
   2. March of Dimes European Prematurity Research Centre, Imperial College London, London, United Kingdom

   Contribution

   Writing – review and editing

   Competing interests

   No competing interests declared

7. Samit Kundu

   1. Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom
   2. March of Dimes European Prematurity Research Centre, Imperial College London, London, United Kingdom

   Contribution

   Conceptualization, Writing – review and editing

   Competing interests

   No competing interests declared

8. Shirin Khanjani

   Department of Gynaecology, University College London Hospital, London, United Kingdom

   Contribution

   Conceptualization, Writing – review and editing

   Competing interests

   No competing interests declared

9. Emad Sindi

   Section of Endocrinology & Investigative Medicine, Imperial College London, London, United Kingdom

   Contribution

   Investigation, Project administration

   Competing interests

   No competing interests declared

10. Raj Rai

    Wolfson Fertility Unit, Department of Gynaecology, St. Mary’s Hospital, Imperial College NHS Trust, London, United Kingdom

    Contribution

    Conceptualization, Supervision, Investigation, Writing – review and editing

    Competing interests

    No competing interests declared

11. Lesley Regan

    1. Wolfson Fertility Unit, Department of Gynaecology, St. Mary’s Hospital, Imperial College NHS Trust, London, United Kingdom
    2. Tommy's National Centre for Miscarriage Research, Imperial College London, London, United Kingdom

    Contribution

    Conceptualization, Investigation, Writing – review and editing

    Competing interests

    No competing interests declared

12. Dalia Khalifa

    Department of Andrology, Hammersmith Hospital, Imperial College NHS Trust, London, United Kingdom

    Contribution

    Data curation, Investigation, Project administration

    Competing interests

    No competing interests declared

13. Ralf Henkel

    1. Section of Endocrinology & Investigative Medicine, Imperial College London, London, United Kingdom
    2. LogixX Pharma, Theale, Berkshire, United Kingdom
    3. Department of Medical Bioscience, University of the Western Cape, Bellville, South Africa

    Contribution

    Conceptualization, Methodology

    Competing interests

    No competing interests declared

14. Suks Minhas

    Department of Urology, Charing Cross Hospital, Imperial College NHS Trus, London, United Kingdom

    Contribution

    Supervision, Writing – review and editing

    Competing interests

    No competing interests declared

15. Waljit S Dhillo

    Section of Endocrinology & Investigative Medicine, Imperial College London, London, United Kingdom

    Contribution

    Conceptualization, Supervision, Writing – review and editing

    Competing interests

    No competing interests declared

16. Jara Ben Nagi

    Centre for Reproductive and Genetic Health (CRGH), London, United Kingdom

    Contribution

    Conceptualization, Writing – review and editing

    Competing interests

    No competing interests declared

17. Phillip Bennett

    1. Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom
    2. March of Dimes European Prematurity Research Centre, Imperial College London, London, United Kingdom
    3. Tommy's National Centre for Miscarriage Research, Imperial College London, London, United Kingdom

    Contribution

    Conceptualization, Writing – review and editing

    Competing interests

    No competing interests declared

18. David A MacIntyre

    1. Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom
    2. March of Dimes European Prematurity Research Centre, Imperial College London, London, United Kingdom
    3. Tommy's National Centre for Miscarriage Research, Imperial College London, London, United Kingdom

    Contribution

    Conceptualization, Formal analysis, Supervision, Funding acquisition, Investigation, Visualization, Methodology, Writing – original draft, Project administration, Writing – review and editing

    Contributed equally with

    Shahriar Mowla, Linda Farahani and Channa N Jayasena

    For correspondence

    d.macintyre@imperial.ac.uk

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-4186-5567

19. Channa N Jayasena

    1. Section of Endocrinology & Investigative Medicine, Imperial College London, London, United Kingdom
    2. Department of Andrology, Hammersmith Hospital, Imperial College NHS Trust, London, United Kingdom

    Contribution

    Conceptualization, Data curation, Supervision, Funding acquisition, Methodology, Writing – original draft, Writing – review and editing

    Contributed equally with

    Shahriar Mowla, Linda Farahani and David A MacIntyre

    For correspondence

    c.jayasena@imperial.ac.uk

    Competing interests

    Receives an investigator-led grant from LogixX Pharma Ltd

    "This ORCID iD identifies the author of this article:" 0000-0002-2578-8223

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