Microbiome research is a rapidly evolving field but much is still unknown including the fundamental question of whether a dysfunctional microbiome is the cause of reproductive issues or the effect of some other mechanism. Featuring new insights and data, the two-day workshop charted the impact of the microbiome on women’s health in general, in early pregnancy and in infertility; and its role in the immune system and in endometriosis.
Antibiotics are no longer viewed as a magic bullet for treating dysbiosis in the long term because of recurrence. New therapeutic options beyond antibiotics currently being investigated include microbiota transplants with work led by Henriette Svarre Nielsen’s group from the University of Copenhagen in Denmark. While still in the preliminary stages, her team has successfully transplanted vaginal secretion from women with a favourable microbiome to those with an unfavourable one. Tine Wrønding said genomic profiling demonstrates that the donor transplant is colonizing the recipient’s vagina and not the recipient’s microbiome spontaneously becoming healthy. Looking to the future in this research area, she said: “We know something is working – we just need to dive in deeper to see what it is”. What also emerged during this talk and the campus in general is that transplanting the whole microbial community is key to restoring an imbalanced vaginal microbiota.
Dysbiosis is associated with poor implantation and poor early pregnancy development and many products are commercially available which claim to screen for dysbiosis. However, ESHRE guidelines which reference microbiota testing conclude that it should not be recommended except for couples in a research setting. Could routine screening have a role in future IVF settings? Dr Thor Haar from Aarhus University Hospital, Denmark, presented data on the use of antibiotic (clindamycin) alone or in combination with a prescription live therapeutic (Lactin-V). The results suggest neither approach prior to embryo transfer improved reproductive outcomes (1).
Although Lactin-V may not be effective in improving IVF outcomes, other evidence presented at the meeting suggests that a live biotherapeutic containing lactobacillus crispatus may benefit women at risk of preterm birth. A disbalanced pregnancy vaginal microbiome contributes to preterm birth (PTB) risks and Philip Bennett from Imperial College in London described what he said were ‘promising’ follow-up data from the first observational study where a course of Lactin-V was given to women at high risk of PTB. This showed that the microbiome became healthy in most women and that the lactobacillus was most likely to colonise in patients without an existing lactobacillus colony. The next step now is a randomised control trial (2).
Another approach on the horizon is metabolic profiling of the vaginal microbiome-host interactions during pregnancy. Clinicians often experience long waits to obtain lab results from standard swab testing. Professor Bennett described a technique called DESI-MS which provides fast results which potentially means women at risk of preterm birth could be identified sooner. The screening tool developed by his team based on mass spectrometry can be used in the clinic to monitor women; and data show the technique is capable of monitoring vaginal microbiome diversity and instability throughout pregnancy (3).
While there is consensus on the clinical relevance of the vaginal microbiome, the significance of the endometrial microbiome in relation to reproductive outcomes remains more elusive. This topic was robustly debated during this campus with presenters providing evidence for and against the endometrial microbiome affecting endometrial receptivity and reproductive health. Kilian Vomstein from Copenhagen University discussed several hypotheses for the presence of lactobacillus and other bacteria in the uterus including microbial ‘tourism’ or ‘invasion’ from the vagina; or the microbes as ‘residents’. He also highlighted how research to assess the physiological composition of the uterus has been hampered by challenges in testing, sample contamination, and the fact the vaginal microbiome can change daily depending on the stage of menses.
RNA- and DNA-based sequencing techniques have yielded new insights in endometrial microbiome research because the technology can screen out contamination, as evidenced by Alberto Sola-Leyva. Dr Sola-Leyva from the Karolinska Institutet in Sweden presented data from his own as yet unpublished study – the first to compare endometrial microbial identification using meta-genomic and meta-transcriptomics in the same cohort – which suggest that what might have been previously identified as the uterine environment may reflect the vaginocervical area. However, Carlos Simon cited several studies which show that the endometrial microbiome is significantly associated with reproductive outcomes although he acknowledged that contamination cannot be ruled out. To support his viewpoint, Professor Simon from the University of Valencia presented data which found that a dysbiotic endometrial microbiota was associated with unsuccessful outcomes whereas lactobacillus was consistently enriched in patients with successful live birth (4).
At this campus, the focus was primarily on the female microbiome with researchers studying women and men separately. But Signe Altmae said it is important not to overlook the man’s contribution towards a couple’s microbiome health. In her presentation, Professor Altmae from the University of Granada discussed the concept of the seminovaginal microbiome where microbes from the male enter the female via sexual intercourse. She presented evidence suggesting that predominance of gardnerella vaginalis in women is related to inflammation in the male genital tract and that lactobacillus crispatus decreases significantly after intercourse (REF). In other research, results showed that adhesion of bacteria (especially lactobacillus) from vaginal fluid reduced sperm motility. Professor Altmae postulated that this process may benefit healthy couples attempting to conceive because it reduces competition but not for those for whom there are fewer sperm to achieve fertilisation (5).
Other notable highlights from the campus included new data that suggests that heritability from mother to daughter may determine presence of vaginal lactobacilli in women and the latest understanding on baby loss and dysbiosis which indicates that the focus should be on chromosomally normal miscarriage, not on aneuploidy which can be discounted as a cause of spontaneous abortion in women with lactobacillus depletion. Questions were also raised over the role of caesarean birth in microbiome composition on the basis that babies get their microbiota from their mothers as they pass through the birth canal.
References:
1 Haahr T et al. Effect of clindamycin and a live biotherapeutic on the reproductive outcomes of IVF patients with abnormal vaginal microbiota: protocol for a double-blind, placebo-controlled multicentre trial. BMJ Open Vol 10 (10); https://bmjopen.bmj.com/content/10/10/e035866
2 Bayar E et al. Safety, tolerability, and acceptability of Lactobacillus crispatus CTV-05 (LACTIN-V) in pregnant women at high-risk of preterm birth. Beneficial Microbes Feb 2023; https://brill.com/view/journals/bm/14/1/article-p45_4.xml
3 Pruski P et al. Direct on-swab metabolic profiling of vaginal microbiome host interactions during pregnancy and preterm birth. Nat Commun 12, 5967 (2021). https://doi.org/10.1038/s41467-021-26215-w
4 Moreno I et al. Endometrial microbiota composition is associated with reproductive outcome in infertile patients. Microbiome 10, 1 (2022). https://doi.org/10.1186/s40168-021-01184-w
5 Wang H et al (2020). Evaluation of the inhibitory effects of vaginal microorganisms on sperm motility in vitro. Experimental and Therapeutic Medicine, 19, 535-544. https://doi.org/10.3892/etm.2019.8237
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